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Bioactive Constituents, Metabolites, and Functions
Conjugate Position of Glucuronide and Sulfate in Piceatannol Derivatives Affects the Stability and Hydrolytic Resistance of the Conjugate in Biological MatricesClick to copy article linkArticle link copied!
- Miyu NishikawaMiyu NishikawaDepartment of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, JapanMore by Miyu Nishikawa
- Mai NakayamaMai NakayamaDepartment of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, JapanMore by Mai Nakayama
- Keisuke FukayaKeisuke FukayaDepartment of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, JapanMore by Keisuke Fukaya
- Daisuke UrabeDaisuke UrabeDepartment of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, JapanMore by Daisuke Urabe
- Shinichi Ikushiro*Shinichi Ikushiro*Email: [email protected]Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, JapanMore by Shinichi Ikushiro
Abstract
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Piceatannol, a stilbene compound, undergoes a comprehensive phase II metabolism mediated by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) in humans. Despite their well-documented beneficial effects on health, their detailed pharmacokinetic fate, including the metabolite structure and properties, is poorly understood. Thus, we determined the structure of seven glucuronides and six sulfates transformed from piceatannol and its methylated derivatives in recombinant yeast cells expressing UGTs or SULTs. We evaluated their properties in human and rat plasma samples. The conjugate that was substituted at the 3′- or 4′-catecholic hydroxy moiety exhibited increased stability. The sulfatase-mediated hydrolysis assay results in incomplete digestion or compound degradation of certain sulfates, suggesting a potential risk of underestimation by using indirect quantification methods. These findings emphasize the importance of an authentic standard for accurate pharmacokinetic studies of phase II metabolites that will be useful for understanding the mechanisms underlying the functional contribution of piceatannol in the body.
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Copyright © 2024 American Chemical Society
Introduction
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Piceatannol (trans-3,3′,4,5′-tetrahydroxystilbene) is a polyphenolic stilbene present abundantly in the seeds of passion fruit (Passiflora edulis). (1,2) Additionally, it can be produced from resveratrol by cytochrome P450 enzyme CYP1B1 in humans. (3) To date, several health benefits of piceatannol have been reported, including antioxidant, anticancer, anti-inflammatory, and sirtuin 1-activation effects. (1,4−9) In addition to these health-beneficial effects, cosmetic skin-protecting potencies, such as collagen synthesis, melanogenesis inhibition, and UV-protective effects have been demonstrated. (2,10−12) In certain cases, piceatannol exhibits higher biological activity than that of resveratrol, a major dietary stilbene. (6,13−15) Despite the well-documented health benefits of piceatannol, its pharmacokinetics in humans remain poorly understood.
Similar to pharmaceutical drugs, polyphenols, including stilbene compounds, are preferably converted into conjugated metabolites by phase II xenobiotic metabolizing enzymes (XMEs) including uridine-5′-diphospho-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and catechol-O-methyltransferases (COMTs). In human liver microsomes containing UGT enzymes, piceatannol is transformed into three glucuronides in the presence of uridine-5′-diphospho-glucuronic acid (UDP-GA). (16) A glucuronidation assay using recombinant UGT suggested that UGT1A1, 1A8, and 1A10 are highly involved in piceatannol glucuronidation. (16) A pharmacokinetic study of piceatannol in rats revealed that a variety of conjugated metabolites were present in the plasma after piceatannol administration, including methylated and mixed conjugates, such as glucuronide of methylated piceatannol, in addition to monoglucuronides and sulfates. (17) In the same study, the dominant form in the plasma was the conjugated metabolite at up to 2–4 h after piceatannol administration, whereas piceatannol aglycone reached Cmax within 15 min and rapidly decreased thereafter. (17) More recently, the two COMT-mediated conjugates of piceatannol that were generated in human liver cytosol have been identified as 4′- or 3′-O-methylated conjugates (rhapontigenin and isorhapontigenin, respectively) (18) (Figure 1). Such gradually elucidated profiles of piceatannol metabolism may also increase the potential risk of food-drug interactions by inhibiting XME activity. The UGT inhibition assay, in which the glucuronidation of probe substrates such as 4-methyl-umbelliferone and imipramine by recombinant UGTs was evaluated in the presence of piceatannol, demonstrated that the substrate drugs of several UGT1A isoforms pose a potential risk of food-drug interactions in the presence of piceatannol. (19) Thus, it is necessary to comprehensively understand the pharmacokinetic fate of piceatannol in the body to safely utilize its biological potential for human health. However, detailed information regarding piceatannol conjugates, including their structures and properties, is lacking.
Figure 1
Figure 1. Piceatannol and its 3′- or 4′-methoxy derivatives used in this study. In addition to piceatannol, rhapontigenin (4′-methoxy derivative of piceatannol) and isorhapontigenin (3′-methoxy derivative of piceatannol) were used in the present study.
Multiple phenolic hydroxyl groups in the polyphenol structure are the target sites for XMEs, resulting in the formation of positional isomers of the conjugate. In addition to such comprehensive XME-mediated metabolism, the limited commercial availability of the authentic standard of the conjugate has caused a research bottleneck in detailed pharmacokinetic studies of polyphenols. Several studies have attempted to determine the pharmacokinetics of polyphenols without standard target metabolites, where the conjugate is indirectly quantified after enzymatic hydrolysis to generate an aglycone. However, incomplete enzymatic digestion and compound degradation pose potential risks for underestimation. Moreover, a standard for the dominant metabolite in the body is required to evaluate biological activities, and this may result in a better understanding of the functional contribution of the conjugated metabolite in vivo. To overcome these limitations, we developed a technical platform for the biosynthesis of conjugated metabolites based on a heterologous expression system for human and mammalian phase II XMEs in yeast cells. (20−22) Furthermore, these recombinant yeast cells can generate cofactors of XMEs, such as UDP-GA in UGT-expressing cells and 3′-phosphoadenosine-5′-phosphosulfate (PAPS) in SULT-expressing cells, thus enabling us to prepare milligrams of XME-mediated metabolites without additional supply of these expensive cofactors. (20−22)
In this study, we prepared positional isomers of UGT and SULT-mediated metabolites of piceatannol and its methylated derivatives using recombinant yeast cells harboring UGT and SULT isoforms. The chemical structure of the conjugate was determined by using NMR spectroscopy. Finally, the properties of the conjugates, including stability in biological matrices and susceptibility to β-glucuronidase and sulfatase, were compared, based on their ability to affect the accuracy of the indirect quantitative analysis of piceatannol metabolites.
Materials and Methods
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Reagents
Piceatannol, rhapontigenin, and isorhapontigenin were purchased from the Tokyo Chemical Industry (Tokyo, Japan). β-Glucuronidase type IX-A from Escherichia coli, sulfatase type H-1 from Helix pomatia, sulfatase type V from Patella vulgate, sulfatase type VI from Aerobacter aerogenes, sulfatase type VIII from Abalone entrails, and d-saccharic acid 1,4-lactone were purchased from Sigma-Aldrich (St. Louis, MO). Human liver microsomes (150 donor-pooled), liver cytosol, intestinal microsomes, and intestinal cytosol were purchased from Corning (NY). Microsomal and cytosolic fractions of the rat liver and intestines were prepared using 10- to 12-week-old Sprague–Dawley male rats, in accordance with the Guidelines for Animal Experiments at Toyama Prefectural University and were approved by the Animal Research and Ethics Committee of Toyama Prefectural University (approval number: R2–10). Pooled normal human plasma (50 donors: 25 males and 25 females) was purchased from George King Bio-Medical, Inc. (Overland Park, KS). All other chemicals were purchased from standard commercial sources of the appropriate quality.
In Vitro Glucuronidation and Sulfation of Piceatannol Derivatives in Liver and Intestine
Glucuronidation was conducted under conditions that included 2 mg of protein/mL microsomal fraction, 10 mmol/L MgCl2, 100 mmol/L potassium phosphate buffer (pH 7.4), 2 mmol/L UDP-GA, 2 mmol/L d-saccharic acid, 1,4-lactone, 10 mmol/L l-ascorbic acid, and 0.1 mmol/L of substrates. The sulfation reaction was conducted under conditions that included 2 mg of protein/mL S9 fraction, 2.5 mmol/L MgCl2, 100 mmol/L potassium phosphate buffer (pH 7.4), 0.2 mmol/L PAPS, 10 mmol/L l-ascorbic acid, and 0.1 mmol/L of substrates. After incubation at 37 °C for 30 min, the reaction was stopped by the addition of an equal volume of acetonitrile followed by centrifugation at 15,000g for 10 min. The supernatant after filtration was subjected to HPLC or LC-MS.
Enzymatic Synthesis of the Conjugate Standard
Glucuronides were enzymatically synthesized from piceatannol, rhapontigenin, and isorhapontigenin using recombinant yeast cells harboring the mammalian UGT isoform and UDP-glucose dehydrogenase. (20) Sulfates were enzymatically synthesized from piceatannol, rhapontigenin, and isorhapontigenin using recombinant yeast cells harboring the SULT isoform. (21) The synthetic procedure was performed as previously described with slight modifications. (20−22) Briefly, the substrate was incubated with the most effective UGT- or SULT-expressing yeast cells (Table S1). After incubation, the reaction mixture was centrifuged at 5000g for 10 min to remove the yeast cells, and the supernatant was applied to an open column (2.5 cm × 15 cm) filled with C18 resins (Cosmosil 140C18-OPN; Nacalai Tesque, Inc., Kyoto, Japan). The column was washed with 100 mL of water, and the conjugate-containing fraction was eluted with 10–50% methanol in water. The conjugate was further purified using preparative HPLC equipped with a Cosmosil 5C18-MS-II column (20 mm × 250 mm; Nacalai Tesque, Inc., Kyoto, Japan). The gradient slope elution with water and methanol at a flow rate of 4 mL/min was monitored at 303 nm. The pH of the isolated sulfate fraction was neutralized by adding 1/100 vol of ammonia solution to avoid deconjugation of the sulfates to the parent compound. The purified glucuronide and sulfate fractions were freeze-dried after evaporation to remove the organic solvent. For NMR analysis, the dried conjugate was dissolved in methanol-d4 (>99.8% purity, chemical shift: δ = 3.31; 1H NMR, δ = 49.0; 13C NMR) or DMSO-d6 (>99.9% purity, chemical shift: δ = 2.49; 1H NMR, δ = 39.52; 13C NMR). 1H NMR (500 MHz), 13C NMR (125 MHz), and HMBC (500 MHz) spectra were recorded on an AVANCE NEO 500 spectrometer (Bruker; Billerica, MA) at room temperature.
Stability Assay in Biological Matrix
Aliquots of 100 μmol/L glucuronide, sulfate, and parent compound were respectively incubated in human and rat plasma at 37 °C for 2 h. The reaction was terminated by adding an equal volume of acetonitrile containing 20 μmol/L pterostilbene as an internal standard. After centrifugation at 15,000g for 10 min, the supernatant was injected into the HPLC system. The residual ratio of the compound was determined as the ratio of the peak areas of the incubated and unincubated samples.
Enzymatic Hydrolysis of Glucuronides and Sulfates
For the glucuronide hydrolysis assay, rat plasma spiked with 20 μmol/L glucuronide was diluted with an equal volume of distilled water. Next, the diluted sample was incubated with 0.1 units/μL β-glucuronidase in the presence of 100 mmol/L potassium phosphate buffer (pH 6.8) at 37 °C for 1 h. Similarly, for the sulfate hydrolysis assay, 20 μmol/L of sulfate in rat plasma was diluted with an equal volume of distilled water. Afterward, the diluted sample was incubated with four commercially available sulfatases (details are provided in the Reagents section) in the presence of 100 mmol/L ammonium acetate (pH 4.5) at 37 °C for 2 h. The reaction was terminated by the addition of an equal volume of acetonitrile. After centrifugation at 15,000g for 10 min, the supernatant was injected into the HPLC system.
HPLC Analysis
HPLC was performed using a HITACHI Lachrom ELITE system (HITACHI, Tokyo, Japan) equipped with a COSMOSIL 2.5C18-MS-II, 2.0 mm I.D. × 100 mm (Nacalai Tesque, Inc., Kyoto, Japan). Next, 0.1% trifluoroacetate (solvent A) and acetonitrile containing 0.1% trifluoroacetate (solvent B) were used as the mobile phases. The details of elution using a gradient program are as follows: Program no.1 for piceatannol glucuronide: 0.0–8.0 min, 5–45% B; 8.0–8.5 min, 45–70% B; 8.5–9.5 min, 70% B; 9.5–10.0 min, 70–5% B; 10.0–12.0 min, 5% B at 0.5 mL/min with detection at 303 nm. Program no. 2 for other compounds: 0.0–6.5 min, 10% B; 6.5–13.5 min, 10–45% B; 13.5–14.5 min, 45% B; 14.5–15.0 min, 45–10% B; 15.0–17.0 min, 10% B at 0.5 mL/min with detection at 303 nm.
LC-MS Analysis
The mass spectrum of the synthesized conjugate was confirmed via LC-ESI-MS/MS using an Agilent 1260 Infinity LC system (Agilent Technologies, Santa Clara, CA) and a 3200 QTRAP LC-MS/MS system (SCIEX, Framingham). Separation was performed using a Cosmosil 5C18-MS II, 5 μm, (4.6 mm I.D. × 100 mm) (Nacalai Tesque, Inc., Kyoto, Japan) with a solvent system consisting of 0.1% formic acid (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The gradient elution profile is described in the section on HPLC analysis. All MS data were collected in negative ion mode. The parameters for LC-MS/MS analysis are listed in Table S2.
Results and Discussion
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UGT- and SULT-Mediated Metabolic Profile of Piceatannol Derivatives in the Subcellular Fraction of Liver and Intestine
After in vitro glucuronidation in the liver and intestinal microsomes, piceatannol was converted to three metabolite peaks labeled as P-G1, -G2, and -G3 in Figure 2A, which corresponded to the glucuronidation profiles in a previous study. (16) The MS spectra indicated that these three peaks were the monoglucuronide peaks of piceatannol, as they exhibited fragmentation of glucuronide (m/z 419 [M – H]−) to aglycone (m/z 243 [M – H]−) (Figure 2A). Similarly, rhapontigenin and isorhapontigenin were converted to two monoglucuronides, labeled as R-G1 and R-G2, and I-G1 and I-G2 in Figure 2B,C, with the MS fragmentation from glucuronide (m/z 433 [M – H]−) to aglycone m/z 257 ([M – H]−), respectively (Figure 2B,C). After in vitro sulfation in the liver and intestinal cytosol, piceatannol was converted to two mono sulfates labeled as P–S1 and P–S2 that displayed MS fragmentation of sulfate (m/z 323 [M – H]−) to aglycone (m/z 243 [M – H]−) (Figure 3A). Rhapontigenin and isorhapontigenin were also converted into two monosulfates, labeled as R-S1 and R-S2, and I–S1 and I–S2, with MS fragmentation from m/z 337 ([M – H]−) to m/z 257 ([M – H]−), respectively (Figure 3B,C). The MS fragmentation profiles of the parent compounds and their conjugates were consistent with those of previous reports, (17,18) and this also supports that the peaks detected by HPLC are metabolites derived from piceatannol, rhapontigenin, and isorhapontigenin, respectively.
Figure 2
Figure 2. In vitro glucuronidation of piceatannol derivatives in liver and intestinal microsomes of humans and rats. Representative HPLC-UV chromatograms and MS spectra of the metabolites in the ESI-negative ion mode transformed from (A) piceatannol (PIC), (B) rhapontigenin (RHA), and (C) isorhapontigenin (ISO) in liver and intestinal microsomes. HL, human liver; RL, rat liver; HI, human intestine; RI, rat intestine. P-G, piceatannol glucuronide; R-G, rhapontigenin glucuronide; I-G, isorhapontigenin glucuronide.
Figure 3
Figure 3. In vitro sulfation of piceatannol derivatives in liver and intestinal cytosols of humans and rats. Representative HPLC-UV chromatogram and MS spectrum of metabolites in the ESI-negative ion mode transformed from (A) piceatannol (PIC), (B) rhapontigenin (RHA), and (C) isorhapontigenin (ISO) in the liver and intestinal cytosol. HL, human liver; RL, rat liver; HI, human intestine; RI, rat intestine. P–S, piceatannol sulfate; R-S, rhapontigenin sulfate; I–S, isorhapontigenin sulfate.
Based on the structure of piceatannol, the three hydroxyl groups at the 3-, 3′-, and 4′-positions were identified as candidate targets for XMEs (Figure 1). Similarly, two hydroxyl groups on 3- and 3′- or 3- and 4′- positions were determined to be candidate targets of XMEs of rhapontigenin and isorhapontigenin, respectively (Figure 1). However, the in vitro sulfation of piceatannol resulted in only two monosulfates (Figure 3A). A previous report demonstrated that piceatannol is converted into two monosulfates and one disulfate in human liver cytosol in the presence of PAPS. (23) Thus, SULT isoforms in the liver and intestine exhibit positional selectivity for piceatannol sulfation.
UGT and SULT Isoforms Involved in the Conjugation of Piceatannol Derivatives
The glucuronidation and sulfation activities toward piceatannol and its methylated derivatives were screened using recombinant UGT and SULT libraries expressed in Saccharomyces cerevisiae yeast cells. (20,21) The methylated piceatannol derivatives at the 4′- and 3′-positions, specifically rhapontigenin and isorhapontigenin, are also formed in the human liver. (18) Among the UGT1A isoforms, UGT1A7, 1A8, 1A9, and 1A10 preferentially converted piceatannol derivatives with partial regioselectivity. UGT2A1 exhibited higher activity for P-G1, R-G1, and I-G1 formation with significantly higher regioselectivity, whereas the UGT2B isoforms displayed lower glucuronidation activity (Figure 4). SULT1A isoforms exerted enzymatic activity toward all piceatannol derivatives, whereas SULT2A1 exhibited only slight activity. SULT1E1 displayed relatively high regioselectivity toward piceatannol derivatives, resulting in the formation of P–S1, R-S2, and I–S1, with a lower positional isomer formation (Figure 4).
Figure 4
Figure 4. Bioconversion activity of human UGT and SULT isoforms expressed in the yeast. The activity of UGT-or SULT-expressing yeast mass for glucuronidation or sulfation of (A) piceatannol, (B) rhapontigenin, and (C) isorhapontigenin. The values are depicted as metabolite productivity per gram wet weight yeast mass for 24 h (mean of n = 2). P-G, piceatannol glucuronide; R-G, rhapontigenin glucuronide; I-G, isorhanpontigenin glucuronide. P–S, piceatannol sulfate; R-S, rhapontigenin sulfate; I–S, isorhapontigenin sulfate.
Enzymatic Synthesis of Glucuronide and Sulfate from Piceatannol Derivatives
Glucuronide and sulfate were enzymatically synthesized from piceatannol derivatives in recombinant yeast cells expressing UGT or SULT isoforms. (20,21) The positions of the glucuronide and sulfate moieties in the purified conjugate were determined by comparing the chemical shift values of the conjugate and aglycone by using 1H NMR analysis (Tables S3–S6). Furthermore, the position of the glucuronide moiety was fully confirmed by HMBC experiments (Figures 5, S1, and S2, Tables S7–S10). The anomeric proton (O-1-β) resonance in glucuronic acid is observed as characteristic chemical shift (approximately 4.9–6.0 ppm), coupling pattern (doublet), and coupling constant (6–9 Hz). (24) As an example of piceatannol glucuronide, the HMBC correlations between the anomeric proton of glucuronic acid 4.89–4.98 ppm (d, J = 7.4–7.7 Hz, 1H) and phenolic carbon 3-C, 4′-C, and 3′-C (158.4, 144.7, and 146.8 ppm) in the P-G1, -G2, and -G3 indicated that these glucuronides were 3-, 4′-, and 3′-O-glucuronide of piceatannol, respectively (Figure 5).
Figure 5
Figure 5. HMBC spectra of biosynthesized piceatannol glucuronide. HMBC spectra of P-G1, G2, and G3. A downfield shift of anomeric proton resonance was observed in P-G1, G2, and G3 as δ 4.98 (d, J = 7.7 Hz, 1H), 4.89 (d, J = 7.4 Hz, 1H) and 4.89 (d, J = 7.5 Hz, 1H), respectively. Based on the spectra, P-G1, G2, and G3 were identified as piceatannol-3-O-glucuronide, piceatannol-4′-O-glucuronide and piceatannol-3′-O-glucuronide, respectively.
Together, the conjugate metabolites prepared in the present study included piceatannol-3-O-glucuronide (P-G1), piceatannol-4′-O-glucuronide (P-G2), piceatannol-3′-O-glucuronide (P-G3), piceatannol-3-O-sulfate (P–S1), piceatannol-3′-O-sulfate (P–S2), rhapontigenin-3′-O-glucuronide (R-G1), rhapongtigenin-3-O-glucuronide (R-G2), rhapontigenin-3′-O-sulfate (R-S1), rhapongtigenin-3-O-sulfate (R-S2), isorhapontigenin-4′-O-glucuronide (I-G1), isorhapongtigenin-3-O-glucuronide (I-G2), isorhapontigenin-4′-O-sulfate (I–S1), and isorhapongtigenin-3-O-sulfate (I–S2).
The structural information regarding the glucuronide and sulfate groups of the piceatannol derivatives is summarized in Figure 6. We successfully prepared a series of monoglucuronides and sulfates of piceatannol and its methoxylated derivatives that were formed in the human liver and intestine. We further determined the structure of the conjugate by 1H NMR and HMBC analyses.
Figure 6
Figure 6. Structural information on the biosynthesized conjugate. Types of substituent and position of conjugation are summarized.
Impact of Phase II Conjugation on the Stability of Piceatannol in Biological Matrices
The low water solubility and bioavailability of stilbenes often limit their use in pharmaceutical and health science fields. (25) Additionally, stilbenes with reactive catechol hydroxyl moieties exhibit a lower stability in the body. From this aspect, it is expected that phase II conjugation would increase not only the water solubility but also the stability when the catecholic hydroxy moiety is substituted. To examine the effect of conjugation on the stability of the piceatannol derivatives in biological matrices, the conjugate and parent compounds were incubated with human and rat plasma, respectively. As expected, the stability of piceatannol aglycone was considerably low, significantly decreasing the residual ratio at 2 h in human and rat plasma, and was undetectable at 6 h in rat plasma (Figure 7A,B). Of note, the substitution at the 3′- or 4′-hydroxy groups of piceatannol with glucuronide or sulfate contributed to significantly increased stability in the biological matrices, whereas substitution at the 3-position did not fully contribute to the increased stability (Figure 7A,B). In addition to glucuronidation or sulfation at 3′- or 4′-hydroxy groups, the methyl conjugation at the same position increased the stability of piceatannol, resulting in the higher stability of isorhapontigenin and rhapontigenin aglycone compared to that of piceatannol. In particular, 4′-O-methyl conjugation of piceatannol, as indicated by the results of rhapontigenin aglycone, was more effective for increasing the stability compared to 3′-methyl-O-conjugation (isorhapontigenin) (Figure 7A,B). Additional glucuronidation or sulfation contributed further to the increased stability of 3′- or 4′-O-methyl-piceatannol, with a tendency of more highly increased stability by sulfation (Figure 7A,B).
Figure 7
Figure 7. Increased stability of 3′- or 4′-conjugate of piceatannol derivatives in biological matrix. Residual ratios of piceatannol derivatives and their conjugates in (A) human and (B) rat plasma. The residual ratios after 2 or 6 h of incubation were compared with at 0 h, respectively. The values are shown as the mean ± SD (n = 3). ND: Not detected by HPLC-UV.
Thus, phase II conjugation, including glucuronidation and sulfation, increased the stability of piceatannol derivatives in biological matrices, depending on the position of the substitution. These results suggested that the substitution of catechol in the B ring with glucuronide, sulfate, and/or methoxy groups contributed to the increased stability of piceatannol. Dai et al. detected rhapontigenin and isorhapontigenin in rat plasma after intravenous injection of piceatannol in addition to the glucuronide and sulfate of piceatannol. However, these methylated piceatannols displayed extremely rapid clearance with decreased plasma levels in the first 90 min, and they were undetectable within several hours of injection. Notably, the glucuronide of piceatannol, rhapontigenin, and isorhapontigenin and the glucuronide-sulfate of piceatannol in rat plasma after the intravenous injection of piceatannol demonstrated considerably lower clearance and remained at a higher plasma level, even at 12 h after injection. (18) Taken together, these results suggest that the phase II metabolism may contribute to the increased bioaccessibility of piceatannol through extensive systemic circulation. Additionally, the results of the present study suggest that increased stability of the conjugates in plasma could be one of the factors for longer compound life in vivo, and it would depend on the type (i.e., glucuronide or sulfate) and position of the phase II conjugates.
Importance of Authentic Standards of Piceatannol Metabolites in an Appropriate Quantitative Analysis
Enzymatic hydrolysis of the conjugate into an aglycone is a common approach to indirectly determine the total amount of the target compound or conjugate in biological samples. However, this method exhibits significant limitations for quantitative analysis due to the incomplete enzymatic digestion or low stability of the target compounds. A previous study demonstrated that enzymatic hydrolysis failed to convert sulfated rhapontigenin and isorhapontigenin to free aglycones, although these conjugates were identified as sulfates by LC-MS/MS without information detailing the conjugation position. (17) Thus, we examined the digestion efficacy of commercially available hydrolytic enzymes against glucuronide and sulfate prepared in this study. Detailed pharmacokinetic studies have estimated that the total plasma concentration of polyphenols, including their conjugated metabolites, can reach dozens of micromolars at Cmax. (17,33) Therefore, we examined the hydrolytic efficacy of the enzymes against a 20 μmol/L conjugate spiked into the rat plasma. When glucuronide was incubated with 0.1 unit/μL β-glucuronidase type IX-A from Escherichia coli, the β-glucuronidase completely digested all of the glucuronides after 1 h of incubation (Figure 8A,B). The calculated glucuronide concentration determined from the deconjugated aglycone after glucuronide hydrolysis mostly corresponded to the actual glucuronide concentration (20 μmol/L; Figure 8B), indicating the validity of indirect glucuronide measurements using this enzyme. However, enzymatic hydrolysis of sulfates exposed multiple limitations to indirect quantitative analysis by enzymatic hydrolysis. First, the total amount of sulfate after hydrolysis was significantly degraded into several types of sulfates, such as piceatannol-3-O-sulfate and isorhapontigenin-3-O-sulfate (P-3S and I-3S in Figure 9). Second, most sulfatases failed to digest sulfate completely within 2 h. For example, sulfatase type H-1 from Helix pomatia that is a commonly used hydrolytic enzyme exhibiting both sulfatase and β-glucuronidase activity has not exerted good hydrolysis activity against any sulfate (Figure 9). Enhanced enzymatic activity that included an extended reaction time and increased enzyme concentration resulted only in substrate degradation (data not shown). Additionally, the hydrolytic efficacy of sulfatase differed considerably among the sulfates. Although sulfatase type VI from Aerobacter aerogenes was the only enzyme to exhibit higher hydrolytic activity, rhapontigenin-3′-O-sulfate and isorhapontigenin-4′-O-sulfate exhibited higher resistance against this enzyme (R-3′S and I-4′S in Figures 9 and 10). Furthermore, the yield of piceatannol-3-O-sulfate and piceatannol-3′-O-sulfate after hydrolysis by this enzyme was considerably low, whereas they were completely converted to the aglycones (P-3S, P-3′S, and I-3S in Figure 9). This result may be due to the lower stability of aglycone in rat plasma (Figure 7B). Therefore, rhapontigenin-3-O-sulfate may be the only sulfate that can be indirectly measured via enzymatic hydrolysis.
Figure 8
Figure 8. Yield of the aglycone after hydrolysis of the glucuronide by β-glucuronidase. (A) Representative HPLC chromatogram glucuronide-spiked rat plasma after incubation with β-glucuronidase type IX-A from Escherichia coli. for 0 and 1 h. Arrows present the same absorbance unit. (B) Yield of the deconjugated aglycone after β-glucuronidase digestion of 20 μmol/L glucuronide of piceatannol (PIC), rhapontigenin (RHA), and isorhapontigenin (ISO). The value is shown as the mean ± SD (n = 3).
Figure 9
Figure 9. Yield of the aglycone after hydrolysis of the sulfate by different types of sulfatases. After incubation with 20 μmol/L piceatannol sulfate, rhapontigenin sulfate, or isorhapontigenin sulfate and four types of sulfatases (H–I, V, VIII, and VI) for 2 h, the concentrations of aglycone and sulfate were determined using standard solutions. The values are shown as the mean ± standard deviation (SD) (n = 3).
Figure 10
Figure 10. Representative HPLC chromatogram of sulfate-spiked rat plasma after incubation with sulfatase type VI for 0 and 2 h. (A) Complete digestion of rhapontigenin-3-O-sulfate (R-3S) and high hydrolysis resistance of rhapontigenin-3′-O-sulfate (R-3′S). (B) Complete digestion of isorhapontigenin-3-O-sulfate (I-3S) and high hydrolysis resistance of isorhapontigenin-4′-O-sulfate (I-4′S) with the degradation of aglycone (ISO), respectively. Arrows present the same absorbance unit.
These results strongly suggest that the indirect quantitative analysis of sulfate conjugates by enzymatic hydrolysis processes has serious limitations in elucidating the comprehensive metabolism of piceatannol in vivo. More importantly, the properties of the conjugates, including their stability and susceptibility to hydrolytic enzymes in the biological matrix, differ considerably among the types of conjugates and their positions. This emphasizes that a series of authentic standards for conjugates are essential for pharmacokinetic-based studies of the health-contributing mechanisms of piceatannol. To date, phase II metabolism has been recognized as an elimination pathway, as the conjugate generally becomes water-soluble. However, in recent years, other physiological aspects of the conjugate have been gradually revealed through detailed metabolic analyses. For example, resveratrol-3- and 4-O-sulfate exerted antiproliferation effects on human colorectal cancer cells via conversion back to resveratrol aglycone and the subsequent induction of autophagy and senescence. (26,27) The cellular uptake of resveratrol was cancer cell-specific, likely due to the higher relative expression of specific membrane transporters such as the organic anion transporting peptide isoform OATP1B3 that contributes to sulfate uptake in cancer cells. This antiproliferative effect was abolished by the addition of a sulfatase inhibitor, and this reduced the intracellular levels of resveratrol. (26,27) Others have also suggested the physiological roles of the conjugate as a delivery form in the body, including the antiosteoclastic effect of curcumin-glucuronide via local generation of free curcumin by hematopoietic β-glucuronidase in the bone marrow. (28) More recently, it has been demonstrated that resveratrol-3-O-glucuronide and resveratrol-3-O-sulfate, other than free resveratrol, bind to the 67 kDa laminin receptor (67LR) with a high affinity. (29) Notably, resveratrol-3-O-glucuronide protects neuronal cells from death induced by serum starvation at picomolar and nanomolar concentrations via the 67LR- and cAMP-mediated signaling pathways. (29) These effective concentrations are the possible physiological concentrations of glucuronide in the brain after resveratrol consumption. (30,31) Additionally, other studies have reported that quercetin glucuronide and sulfate possess a potential affinity for 67LR. (32) Thus, these findings demonstrate that the phase II conjugation of polyphenols is a process that generates a safe and stable delivery form and even a biologically active form in the body. Furthermore, these findings support the importance of an authentic standard of such polyphenol conjugates to elucidate the mechanisms underlying the health-promoting potency of polyphenols that often exhibit conjugate-dominant metabolic profiles in blood circulation.
Implications, Limitations, and Prospects of This Study
In this study, we demonstrated for the first time that phase II conjugate metabolites of piceatannol derivatives display different properties depending on the type and position of the conjugate. Although most conjugations mediated by UGT, SULT, and COMT contributed to increasing the stability of the parent compound, the 3-O-glucuronidation of piceatannol did not exhibit potential efficacy. In contrast, glucuronidation or sulfation of the catecholic hydroxy moiety (3′- and 4′-O-position of the B ring) was more effective for stabilization of the compound. The preparation of a series of conjugates contributes to the novel findings of this study. However, one limitation of the present study is that the preparation of comprehensive conjugates such as diglucuronides and mixed conjugates is required to comprehensively understand the metabolic fate of piceatannol. In our previous study, to elucidate the pharmacokinetic fate of quercetin in rats, we conducted a direct quantitative LC-MS analysis using a series of conjugate standards, and this resulted in mixed conjugates with sulfate such as quercetin-7-O-glucuronide-4′-O-sulfate and 3′-O-methyl-quercetin-7-O-glucuronide-4′-O-sulfate being identified as the most abundant metabolites, occupying greater than 60 and 20% of the total quercetin derivatives, respectively. (33) More recently, we have reported that selective accumulation of mixed conjugates with 4′-O-sulfate in plasma resulted from limited urinary excretion of the conjugate. (34) Such simultaneous quantification approaches for polyphenol conjugates are useful for revealing the fate of dietary polyphenols in the body and may provide an opportunity to elucidate the novel physiological functions of the conjugate.
In conclusion, we suggest that the different properties of conjugates should be considered in the pharmacokinetic studies of polyphenols including piceatannol. An authentic standard for the conjugate may be useful to elucidate the detailed pharmacokinetics and molecular mechanisms underlying the biological activity of piceatannol.
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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jafc.4c08072.
Detailed information on the structural determination of the biosynthesized conjugates; HMBC spectra of glucuronide of rhapontigenin and isorhapontigenin; enzymatic sources for conjugate preparation; analytical conditions for LC-MS; and NMR summary data on the chemical shift of 1H and 13C (PDF)
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Author Information
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- Miyu Nishikawa - Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, Japan;
https://orcid.org/0000-0001-7958-1247 - Keisuke Fukaya - Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, Japan;https://orcid.org/0000-0002-7148-4714
- Daisuke Urabe - Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu-shi, Toyama 939-0398, Japan;https://orcid.org/0000-0002-1999-9374
MI.N., MA.N., and S.I. participated in research design. MA.N., MI.N., K.F., D.U., and S.I. conducted experiments. MI.N., MA.N., K.F., D.U., and S.I. performed data analysis. MI.N., MA.N., K.F., D.U., and S.I. wrote or contributed to the writing of the manuscript.
This work was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (Grant Number 21H02143).
| COMT | catechol-O-methyltransferase |
| ISO | isorhapontigenin |
| 67LR | 67 kDa laminin receptor |
| OATP | organic anion transporting polypeptide |
| PAPS | 3′-phosphoadenosine-5′-phosphosulfate |
| PIC | piceatannol |
| RHA | rhapontigenin |
| SULT | sulfotransferase |
| UDP-GA | uridine-5′-diphospho-glucuronic acid |
| UGT | uridine-5′-diphospho-glucuronosyltransferase |
| XME | xenobiotic metabolizing enzyme |
References
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This article references 34 other publications.
- 1Piotrowska, H.; Kucinska, M.; Murias, M. Biological Activity of Piceatannol: Leaving the Shadow of Resveratrol. Mutat. Res./Rev. Mutat. Res. 2012, 750 (1), 60– 82, DOI: 10.1016/j.mrrev.2011.11.001Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhs1Oru7fM&md5=16f9cfe02fb53afcc6ed8f8f58d2357cBiological activity of piceatannol: Leaving the shadow of resveratrolPiotrowska, Hanna; Kucinska, Malgorzata; Murias, MarekMutation Research, Reviews in Mutation Research (2012), 750 (1), 60-82CODEN: MRRRFK; ISSN:1383-5742. (Elsevier B.V.)A review. Resveratrol (3,4',5-trans-trihydroxystilbene), a naturally occurring stilbene, is considered to have a no. of beneficial effects, including anticancer, anti-aethrogenic, anti-oxidative, anti-inflammatory, anti-microbial and estrogenic activity. Piceatannol (3,3',4,5'-trans-trihydroxystilbene), a naturally occurring hydroxylated analog of resveratrol, is less studied than resveratrol but displays a wide spectrum of biol. activity. Piceatannol has been found in various plants, including grapes, passion fruit, white tea, and Japanese knotweed. Besides antioxidative effects, piceatannol exhibits potential anticancer properties as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including leukemia, lymphoma; cancers of the breast, prostate, colon and melanoma. The growth-inhibitory and proapoptotic effects of piceatannol are mediated through cell-cycle arrest; upregulation of Bid, Bax, Bik, Bok, Fas; P21WAF1 down-regulation of Bcl-xL; BCL-2, cIAP, activation of caspases (-3, -7, -8, -9), loss of mitochondrial potential, and release of cytochrome c. Piceatannol has been shown to suppress the activation of some transcription factors, including NF-κB, which plays a central role as a transcriptional regulator in response to cellular stress caused by free radicals, UV irradn., cytokines, or microbial antigens. Piceatannol also inhibits JAK-1, which is a key member of the STAT pathway that is crucial in controlling cellular activities in response to extracellular cytokines and is a COX-2-inducible enzyme involved in inflammation and carcinogenesis. Although piceatannol has been shown to induce apoptosis in cancer cells, there are examples of its anti-apoptotic pro-proliferative activity. Piceatannol inhibits Syk kinase, which plays a crucial role in the coordination of immune recognition receptors and orchestrates multiple downstream signaling pathways in various hematopoietic cells. Piceatannol also binds estrogen receptors and stimulates growth of estrogen-dependent cancer cells. Piceatannol is rapidly metabolized in the liver and is converted mainly to a glucuronide conjugate; however, sulfation is also possible, based on in vitro studies. The pharmacol. properties of piceatannol, esp. its antitumor, antioxidant, and anti-inflammatory activities, suggests that piceatannol might be a potentially useful nutritional and pharmacol. biomol.; however, more data are needed on its bioavailability and toxicity in humans.
- 2Matsui, Y.; Sugiyama, K.; Kamei, M.; Takahashi, T.; Suzuki, T.; Katagata, Y.; Ito, T. Extract of Passion Fruit (Passiflora edulis) Seed Containing High Amounts of Piceatannol Inhibits Melanogenesis and Promotes Collagen Synthesis. J. Agric. Food Chem. 2010, 58 (20), 11112– 11118, DOI: 10.1021/jf102650dGoogle Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFWrur%252FE&md5=be4789e8e3cb96087a61dd07e51e18dcExtract of Passion Fruit (Passiflora edulis) Seed Containing High Amounts of Piceatannol Inhibits Melanogenesis and Promotes Collagen SynthesisMatsui, Yuko; Sugiyama, Kenkichi; Kamei, Masanori; Takahashi, Toshio; Suzuki, Tamio; Katagata, Yohtaro; Ito, TatsuhikoJournal of Agricultural and Food Chemistry (2010), 58 (20), 11112-11118CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)The effect of passion fruit, the fruit of Passiflora edulis, on melanin inhibition and collagen synthesis was studied using cultured human melanoma and fibroblast cells. Passion fruit was divided into three parts, rind (PF-R), pulp (PF-P), and seed (PF-S), and each part was extd. using 80% ethanol. The concn. of polyphenols was higher in PF-S than in PF-R or PF-P. Treatment of melanoma cells with PF-S led to inhibition of melanogenesis. In addn., the prodn. of total sol. collagen was elevated in dermal fibroblast cells cultured in the presence of PF-S. PF-R and PF-P did not yield these effects. Furthermore, the removal of polyphenols from PF-S led to the abolishment of the effects described above. We discovered that piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene) is present in passion fruit seeds in large amts. and that this compd. is the major component responsible for the PF-S effects obsd. on melanogenesis and collagen synthesis.
- 3Potter, G. A.; Patterson, L. H.; Wanogho, E.; Perry, P. J.; Butler, P. C.; Ijaz, T.; Ruparelia, K. C.; Lamb, J. H.; Farmer, P. B.; Stanley, L. A.; Burke, M. D. The Cancer Preventative Agent Resveratrol is Converted to the Anticancer Agent Piceatannol by the Cytochrome P450 Enzyme CYP1B1. Br. J. Cancer 2002, 86 (5), 774– 778, DOI: 10.1038/sj.bjc.6600197Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtVKjsbc%253D&md5=e43b1868ca30069c7531c75bb42bd5b9The cancer preventative agent Resveratrol is converted to the anticancer agent Piceatannol by the cytochrome P450 enzyme CYP1B1Potter, G. A.; Patterson, L. H.; Wanogho, E.; Perry, P. J.; Butler, P. C.; Ijaz, T.; Ruparelia, K. C.; Lamb, J. H.; Farmer, P. B.; Stanley, L. A.; Burke, M. D.British Journal of Cancer (2002), 86 (5), 774-778CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from Resveratrol by having an addnl. arom. hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumors and catalyzes arom. hydroxylation reactions. The authors report here that the cancer preventative agent Resveratrol undergoes metab. by the cytochrome P 450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukemic agent Piceatannol. The metabolite was identified by high-performance liq. chromatog. anal. using fluorescence detection and the identity of the metabolite was further confirmed by derivatization followed by gas chromatog.-mass spectrometry studies using authentic Piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of Resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compd. with known anticancer activity by an enzyme that is found in human tumors. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumors may be functioning as a growth suppressor enzyme.
- 4Wang, D.; Zhang, Y.; Zhang, C.; Gao, L.; Li, J. Piceatannol Pretreatment Alleviates Acute Cardiac Injury via Regulating PI3K-Akt-eNOS Signaling in H9c2 Cells. Biomed. Pharmacother. 2019, 109, 886– 891, DOI: 10.1016/j.biopha.2018.10.120Google ScholarThere is no corresponding record for this reference.
- 5Banik, K.; Ranaware, A. M.; Harsha, C.; Nitesh, T.; Girisa, S.; Deshpande, V.; Fan, L.; Nalawade, S. P.; Sethi, G.; Kunnumakkara, A. B. Piceatannol: A Natural Stilbene for the Prevention and Treatment of Cancer. Pharmacol. Res. 2020, 153, 104635 DOI: 10.1016/j.phrs.2020.104635Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFeis7s%253D&md5=dae18af2fa0e14146115c2d10b525aa0Piceatannol: A natural stilbene for the prevention and treatment of cancerBanik, Kishore; Ranaware, Abhishek Manoj; Harsha, Choudhary; Nitesh, Thakur; Girisa, Sosmitha; Deshpande, Vishwas; Fan, Lu; Nalawade, Savita Pravin; Sethi, Gautam; Kunnumakkara, Ajaikumar B.Pharmacological Research (2020), 153 (), 104635CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)A review. The World Health Organization (WHO) has documented that cancer is the second foremost reason for death worldwide. Various factors are responsible for cancer, for instance, exposure to different phys., chem. and biol. carcinogens, infections, hereditary, poor dietary habits and lifestyle etc. Cancer is a preventable disease if detected at an early stage; however, most of the cases of cancer are diagnosed at an incurable advanced or metastatic stage. According to WHO about 70% of deaths due to cancer occur in countries with low- or middle-income. The major problems assocd. with the conventional therapies are cancer recurrence, development of chemoresistance, affordability, late-stage diagnosis, adverse side effects and inaccessible treatment. Thus, there is an urgent need to find alternative treatment modalities, which have easy accessibility and are affordable with min. side effects. In this article, we reviewed the natural stilbene known as "Piceatannol" for its anticancer properties. Numerous preclin. studies have reported the potential of Piceatannol to prevent or impede the growth of various cancers originating from different organs such as brain, breast, cervical, colon, liver, lung, prostate, skin, etc. The current review primarily emphasizes on the insights of Piceatannol source, chem., and the mol. mechanisms involved in the regression of the tumor. This review supports Piceatannol as a potential anticancer and chemopreventive agent and suggests that it can be effectively employed as a capable anti-cancer drug.
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- 24Walker, G. S.; Atherton, J.; Bauman, J.; Kohl, C.; Lam, W.; Reily, M.; Lou, Z.; Mutlib, A. Determination of Degradation Pathways and Kinetics of Acyl Glucuronides by NMR Spectroscopy. Chem. Res. Toxicol. 2007, 20 (6), 876– 886, DOI: 10.1021/tx600297uGoogle Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVymtrw%253D&md5=b0ffe295d85c8a7a6816f3e22eac5becDetermination of Degradation Pathways and Kinetics of Acyl Glucuronides by NMR SpectroscopyWalker, Gregory S.; Atherton, James; Bauman, Jonathan; Kohl, Christopher; Lam, Wing; Reily, Michael; Lou, Zhen; Mutlib, AbdulChemical Research in Toxicology (2007), 20 (6), 876-886CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Acyl glucuronides have been implicated in the toxicity of many xenobiotics and marketed drugs. These toxicities are hypothesized to be a consequence of covalent binding of the reactive forms of the acyl glucuronide to proteins. Reactive intermediates of the acyl glucuronide arise from the migration of the aglycon leading to other positional and stereoisomers under physiol. conditions. In order to screen for the potential liabilities of these metabolites during the early phase of pharmaceutical development, an NMR method based on the disappearance of the anomeric resonance of the O-1-acyl glucuronide was used to monitor the degrdn. kinetics of 11 structurally diverse acyl glucuronides, including those produced from the known nonsteroidal anti-inflammatory drugs (NSAIDs). The acyl glucuronides were either chem. synthesized or were isolated from biol. matrixes (bile, urine, and liver microsomal exts.). The half-lives attained utilizing this method were found to be comparable to those reported in the literature. NMR anal. also enabled the delineation of the two possible pathways of degrdn.: acyl migration and hydrolytic cleavage. The previously characterized 1H resonances of acyl migrated products are quite distinguishable from those that arise from hydrolysis. The NMR method described here could be used to rank order acyl glucuronide forming discovery compds. based on the potential reactivity of the conjugates and their routes of decompn. under physiol. conditions. Furthermore, we have shown that in vitro systems such as liver microsomal prepns. can be used to generate sufficient quantities of acyl glucuronides from early discovery compds. for NMR characterization. This is particularly important, as we often have limited supply of early discovery compds. to conduct in vivo studies to generate sufficient quantities of acyl glucuronides for further characterization.
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Abstract
Figure 1
Figure 1. Piceatannol and its 3′- or 4′-methoxy derivatives used in this study. In addition to piceatannol, rhapontigenin (4′-methoxy derivative of piceatannol) and isorhapontigenin (3′-methoxy derivative of piceatannol) were used in the present study.
Figure 2
Figure 2. In vitro glucuronidation of piceatannol derivatives in liver and intestinal microsomes of humans and rats. Representative HPLC-UV chromatograms and MS spectra of the metabolites in the ESI-negative ion mode transformed from (A) piceatannol (PIC), (B) rhapontigenin (RHA), and (C) isorhapontigenin (ISO) in liver and intestinal microsomes. HL, human liver; RL, rat liver; HI, human intestine; RI, rat intestine. P-G, piceatannol glucuronide; R-G, rhapontigenin glucuronide; I-G, isorhapontigenin glucuronide.
Figure 3
Figure 3. In vitro sulfation of piceatannol derivatives in liver and intestinal cytosols of humans and rats. Representative HPLC-UV chromatogram and MS spectrum of metabolites in the ESI-negative ion mode transformed from (A) piceatannol (PIC), (B) rhapontigenin (RHA), and (C) isorhapontigenin (ISO) in the liver and intestinal cytosol. HL, human liver; RL, rat liver; HI, human intestine; RI, rat intestine. P–S, piceatannol sulfate; R-S, rhapontigenin sulfate; I–S, isorhapontigenin sulfate.
Figure 4
Figure 4. Bioconversion activity of human UGT and SULT isoforms expressed in the yeast. The activity of UGT-or SULT-expressing yeast mass for glucuronidation or sulfation of (A) piceatannol, (B) rhapontigenin, and (C) isorhapontigenin. The values are depicted as metabolite productivity per gram wet weight yeast mass for 24 h (mean of n = 2). P-G, piceatannol glucuronide; R-G, rhapontigenin glucuronide; I-G, isorhanpontigenin glucuronide. P–S, piceatannol sulfate; R-S, rhapontigenin sulfate; I–S, isorhapontigenin sulfate.
Figure 5
Figure 5. HMBC spectra of biosynthesized piceatannol glucuronide. HMBC spectra of P-G1, G2, and G3. A downfield shift of anomeric proton resonance was observed in P-G1, G2, and G3 as δ 4.98 (d, J = 7.7 Hz, 1H), 4.89 (d, J = 7.4 Hz, 1H) and 4.89 (d, J = 7.5 Hz, 1H), respectively. Based on the spectra, P-G1, G2, and G3 were identified as piceatannol-3-O-glucuronide, piceatannol-4′-O-glucuronide and piceatannol-3′-O-glucuronide, respectively.
Figure 6
Figure 6. Structural information on the biosynthesized conjugate. Types of substituent and position of conjugation are summarized.
Figure 7
Figure 7. Increased stability of 3′- or 4′-conjugate of piceatannol derivatives in biological matrix. Residual ratios of piceatannol derivatives and their conjugates in (A) human and (B) rat plasma. The residual ratios after 2 or 6 h of incubation were compared with at 0 h, respectively. The values are shown as the mean ± SD (n = 3). ND: Not detected by HPLC-UV.
Figure 8
Figure 8. Yield of the aglycone after hydrolysis of the glucuronide by β-glucuronidase. (A) Representative HPLC chromatogram glucuronide-spiked rat plasma after incubation with β-glucuronidase type IX-A from Escherichia coli. for 0 and 1 h. Arrows present the same absorbance unit. (B) Yield of the deconjugated aglycone after β-glucuronidase digestion of 20 μmol/L glucuronide of piceatannol (PIC), rhapontigenin (RHA), and isorhapontigenin (ISO). The value is shown as the mean ± SD (n = 3).
Figure 9
Figure 9. Yield of the aglycone after hydrolysis of the sulfate by different types of sulfatases. After incubation with 20 μmol/L piceatannol sulfate, rhapontigenin sulfate, or isorhapontigenin sulfate and four types of sulfatases (H–I, V, VIII, and VI) for 2 h, the concentrations of aglycone and sulfate were determined using standard solutions. The values are shown as the mean ± standard deviation (SD) (n = 3).
Figure 10
Figure 10. Representative HPLC chromatogram of sulfate-spiked rat plasma after incubation with sulfatase type VI for 0 and 2 h. (A) Complete digestion of rhapontigenin-3-O-sulfate (R-3S) and high hydrolysis resistance of rhapontigenin-3′-O-sulfate (R-3′S). (B) Complete digestion of isorhapontigenin-3-O-sulfate (I-3S) and high hydrolysis resistance of isorhapontigenin-4′-O-sulfate (I-4′S) with the degradation of aglycone (ISO), respectively. Arrows present the same absorbance unit.
References
This article references 34 other publications.
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- 3Potter, G. A.; Patterson, L. H.; Wanogho, E.; Perry, P. J.; Butler, P. C.; Ijaz, T.; Ruparelia, K. C.; Lamb, J. H.; Farmer, P. B.; Stanley, L. A.; Burke, M. D. The Cancer Preventative Agent Resveratrol is Converted to the Anticancer Agent Piceatannol by the Cytochrome P450 Enzyme CYP1B1. Br. J. Cancer 2002, 86 (5), 774– 778, DOI: 10.1038/sj.bjc.66001973https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtVKjsbc%253D&md5=e43b1868ca30069c7531c75bb42bd5b9The cancer preventative agent Resveratrol is converted to the anticancer agent Piceatannol by the cytochrome P450 enzyme CYP1B1Potter, G. A.; Patterson, L. H.; Wanogho, E.; Perry, P. J.; Butler, P. C.; Ijaz, T.; Ruparelia, K. C.; Lamb, J. H.; Farmer, P. B.; Stanley, L. A.; Burke, M. D.British Journal of Cancer (2002), 86 (5), 774-778CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from Resveratrol by having an addnl. arom. hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumors and catalyzes arom. hydroxylation reactions. The authors report here that the cancer preventative agent Resveratrol undergoes metab. by the cytochrome P 450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukemic agent Piceatannol. The metabolite was identified by high-performance liq. chromatog. anal. using fluorescence detection and the identity of the metabolite was further confirmed by derivatization followed by gas chromatog.-mass spectrometry studies using authentic Piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of Resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compd. with known anticancer activity by an enzyme that is found in human tumors. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumors may be functioning as a growth suppressor enzyme.
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- 15Arai, D.; Kataoka, R.; Otsuka, S.; Kawamura, M.; Maruki-Uchida, H.; Sai, M.; Ito, T.; Nakao, Y. Piceatannol is Superior to Resveratrol in Promoting Neural Stem Cell Differentiation into Astrocytes. Food Funct. 2016, 7 (10), 4432– 4441, DOI: 10.1039/C6FO00685JThere is no corresponding record for this reference.
- 16Miksits, M.; Maier-Salamon, A.; Vo, T. P.; Sulyok, M.; Schuhmacher, R.; Szekeres, T.; Jäger, W. Glucuronidation of Piceatannol by Human Liver Microsomes: Major Role of UGT1A1, UGT1A8 and UGT1A10. J. Pharm. Pharmacol. 2010, 62 (1), 47– 54, DOI: 10.1211/jpp.62.01.0004There is no corresponding record for this reference.
- 17Setoguchi, Y.; Oritani, Y.; Ito, R.; Inagaki, H.; Maruki-Uchida, H.; Ichiyanagi, T.; Ito, T. Absorption and Metabolism of Piceatannol in Rats. J. Agric. Food Chem. 2014, 62 (12), 2541– 2548, DOI: 10.1021/jf404694y17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXktF2nurg%253D&md5=9cf44c9717ffdaf7cf7a8df102a9b06bAbsorption and Metabolism of Piceatannol in RatsSetoguchi, Yuko; Oritani, Yukihiro; Ito, Ryouichi; Inagaki, Hiroyuki; Maruki-Uchida, Hiroko; Ichiyanagi, Takashi; Ito, TatsuhikoJournal of Agricultural and Food Chemistry (2014), 62 (12), 2541-2548CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)Piceatannol (trans-3,3',4,5'-tetrahydroxystilbene), a natural analog of resveratrol, has multiple biol. functions. Nevertheless, piceatannol's biol. fate is yet to be detd. In this study, we evaluated the absorption and metab. of piceatannol in rats. Furthermore, the area under the plasma concn. curves (AUC) and metabolic pathway of piceatannol were compared with those of resveratrol. We detd. the plasma concns. of piceatannol, resveratrol, and their resp. metabolites following their intragastric administration. Resveratrol metabolites were only conjugates, whereas piceatannol metabolites were piceatannol conjugates, O-Me piceatannol, and its conjugates. The AUC for piceatannol, resveratrol, and their metabolites increased in a dose-dependent manner (90-360 μmol/kg). The AUC for total piceatannol was less than that for total resveratrol, whereas the AUC for piceatannol (8.6 μmol·h/L) after piceatannol and resveratrol coadministration was 2.1 times greater than that for resveratrol (4.1 μmol·h/L). The greater AUC for piceatannol was a result of its higher metabolic stability.
- 18Dai, Y.; Lim, J. X.; Yeo, S. C. M.; Xiang, X.; Tan, K. S.; Fu, J. H.; Huang, L.; Lin, H. S. Biotransformation of Piceatannol, a Dietary Resveratrol Derivative: Promises to Human Health. Mol. Nutr. Food Res. 2020, 64 (2), 1900905 DOI: 10.1002/mnfr.201900905There is no corresponding record for this reference.
- 19Jiang, L.; Wang, Z.; Wang, X.; Wang, S.; Wang, Z.; Liu, Y. Piceatannol Exhibits Potential Food-Drug Interactions Through the Inhibition of Human UDP-glucuronosyltransferase (UGT) in Vitro. Toxicol. in Vitro 2020, 67, 104890 DOI: 10.1016/j.tiv.2020.104890There is no corresponding record for this reference.
- 20Ikushiro, S.; Nishikawa, M.; Masuyama, Y.; Shouji, T.; Fujii, M.; Hamada, M.; Nakajima, N.; Finel, M.; Yasuda, K.; Kamakura, M.; Sakaki, T. Biosynthesis of Drug Glucuronide Metabolites in the Budding Yeast Saccharomyces cerevisiae. Mol. Pharmaceutics 2016, 13 (7), 2274– 2282, DOI: 10.1021/acs.molpharmaceut.5b0095420https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xos12ntLs%253D&md5=28bfbb94fd772400b5a79bd213d5a07eBiosynthesis of Drug Glucuronide Metabolites in the Budding Yeast Saccharomyces cerevisiaeIkushiro, Shinichi; Nishikawa, Miyu; Masuyama, Yuuka; Shouji, Tadashi; Fujii, Miharu; Hamada, Masahiro; Nakajima, Noriyuki; Finel, Moshe; Yasuda, Kaori; Kamakura, Masaki; Sakaki, ToshiyukiMolecular Pharmaceutics (2016), 13 (7), 2274-2282CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)Glucuronidation is one of the most common pathways in mammals for detoxification and elimination of hydrophobic xenobiotic compds., including many drugs. Metabolites, however, can form active or toxic compds., such as acyl glucuronides, and their safety assessment is often needed. The absence of efficient means for in vitro synthesis of correct glucuronide metabolites frequently limits such toxicol. analyses. To overcome this hurdle we have developed a new approach, the essence of which is a coexpression system contg. a human, or another mammalian UDP-glucuronosyltransferases (UGTs), as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding yeast, Saccharomyces cerevisiae. The system was first tested using resting yeast cells coexpressing UGDH and human UGT1A6, 7-hydroxycoumarin as the substrate, in a reaction medium contg. 8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides were readily formed and recovered from the medium. Subsequently, by selecting suitable mammalian UGT enzyme for the coexpression system we could obtain the desired glucuronides of various compds., including mols. with multiple conjugation sites and acyl glucuronides of several carboxylic acid contg. drugs, namely, mefenamic acid, flufenamic acid, and zomepirac. In conclusion, a new and flexible yeast system with mammalian UGTs has been developed that exhibits a capacity for efficient prodn. of various glucuronides, including acyl glucuronides.
- 21Nishikawa, M.; Masuyama, Y.; Nunome, M.; Yasuda, K.; Sakaki, T.; Ikushiro, S. Whole-cell-Dependent Biosynthesis of Sulfo-Conjugate using Human Sulfotransferase Expressing Budding Yeast. Appl. Microbiol. Biotechnol. 2018, 102 (2), 723– 732, DOI: 10.1007/s00253-017-8621-xThere is no corresponding record for this reference.
- 22Nishikawa, M.; Kada, Y.; Kimata, M.; Sakaki, T.; Ikushiro, S. Comparison of Metabolism and Biological Properties Among Positional Isomers of Quercetin Glucuronide in LPS- and RANKL-Challenged RAW264.7 cells. Biosci. Biotechnol. Biochem. 2022, 86 (12), 1670– 1679, DOI: 10.1093/bbb/zbac150There is no corresponding record for this reference.
- 23Miksits, M.; Sulyok, M.; Schuhmacher, R.; Szekeres, T.; Jäger, W. In-vitro Sulfation of Piceatannol by Human Liver Cytosol and Recombinant Sulfotransferases. J. Pharm. Pharmacol. 2009, 61 (2), 185– 191, DOI: 10.1211/jpp/61.02.0007There is no corresponding record for this reference.
- 24Walker, G. S.; Atherton, J.; Bauman, J.; Kohl, C.; Lam, W.; Reily, M.; Lou, Z.; Mutlib, A. Determination of Degradation Pathways and Kinetics of Acyl Glucuronides by NMR Spectroscopy. Chem. Res. Toxicol. 2007, 20 (6), 876– 886, DOI: 10.1021/tx600297u24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlvVymtrw%253D&md5=b0ffe295d85c8a7a6816f3e22eac5becDetermination of Degradation Pathways and Kinetics of Acyl Glucuronides by NMR SpectroscopyWalker, Gregory S.; Atherton, James; Bauman, Jonathan; Kohl, Christopher; Lam, Wing; Reily, Michael; Lou, Zhen; Mutlib, AbdulChemical Research in Toxicology (2007), 20 (6), 876-886CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)Acyl glucuronides have been implicated in the toxicity of many xenobiotics and marketed drugs. These toxicities are hypothesized to be a consequence of covalent binding of the reactive forms of the acyl glucuronide to proteins. Reactive intermediates of the acyl glucuronide arise from the migration of the aglycon leading to other positional and stereoisomers under physiol. conditions. In order to screen for the potential liabilities of these metabolites during the early phase of pharmaceutical development, an NMR method based on the disappearance of the anomeric resonance of the O-1-acyl glucuronide was used to monitor the degrdn. kinetics of 11 structurally diverse acyl glucuronides, including those produced from the known nonsteroidal anti-inflammatory drugs (NSAIDs). The acyl glucuronides were either chem. synthesized or were isolated from biol. matrixes (bile, urine, and liver microsomal exts.). The half-lives attained utilizing this method were found to be comparable to those reported in the literature. NMR anal. also enabled the delineation of the two possible pathways of degrdn.: acyl migration and hydrolytic cleavage. The previously characterized 1H resonances of acyl migrated products are quite distinguishable from those that arise from hydrolysis. The NMR method described here could be used to rank order acyl glucuronide forming discovery compds. based on the potential reactivity of the conjugates and their routes of decompn. under physiol. conditions. Furthermore, we have shown that in vitro systems such as liver microsomal prepns. can be used to generate sufficient quantities of acyl glucuronides from early discovery compds. for NMR characterization. This is particularly important, as we often have limited supply of early discovery compds. to conduct in vivo studies to generate sufficient quantities of acyl glucuronides for further characterization.
- 25Peng, Y.; Huan, Y.; Chen, J. J.; Chen, T. J.; Lei, L.; Yang, J. L.; Shen, Z. F.; Gong, T.; Zhu, P. Microbial Biotransformation to Obtain Stilbene Methylglucoside with GPR119 Agonistic activity. Front. Microbiol. 2023, 14, 1148513 DOI: 10.3389/fmicb.2023.1148513There is no corresponding record for this reference.
- 26Patel, K. R.; Andreadi, C.; Britton, R. G.; Horner-Glister, E.; Karmokar, A.; Sale, S.; Brown, V. A.; Brenner, D. E.; Singh, R.; Steward, W. P.; Gescher, A. J.; Brown, K. Sulfate Metabolites Provide an Intracellular Pool for Resveratrol Generation and Induce Autophagy with Senescence. Sci. Transl. Med. 2013, 5 (205), 205ra133 DOI: 10.1126/scitranslmed.3005870There is no corresponding record for this reference.
- 27Andreadi, C.; Britton, R. G.; Patel, K. R.; Brown, K. Resveratrol-Sulfates Provide an Intracellular Reservoir for Generation of Parent Resveratrol, Which Induces Autophagy in Cancer Cells. Autophagy 2014, 10 (3), 524– 525, DOI: 10.4161/auto.27593There is no corresponding record for this reference.
- 28Kunihiro, A. G.; Luis, P. B.; Brickey, J. A.; Frye, J. B.; Chow, H. S.; Schneider, C.; Funk, J. L. Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone. J. Nat. Prod. 2019, 82 (3), 500– 509, DOI: 10.1021/acs.jnatprod.8b00873There is no corresponding record for this reference.
- 29Gopalakrishna, R.; Aguilar, J.; Oh, A.; Lee, E.; Hou, L.; Lee, T.; Xu, E.; Nguyen, J.; Mack, W. J. Resveratrol and Its Metabolites Elicit Neuroprotection via High-Affinity Binding to the Laminin Receptor at low nanomolar concentrations. FEBS Lett. 2024, 598 (9), 995– 1007, DOI: 10.1002/1873-3468.14835There is no corresponding record for this reference.
- 30Juan, M. E.; Maijo, M.; Planas, J. M. Quantification of trans-Resveratrol and Its Metabolites in Rat Plasma and Tissues by HPLC. J. Pharm. Biomed. Anal. 2010, 51 (1), 391– 398, DOI: 10.1016/j.jpba.2009.03.026There is no corresponding record for this reference.
- 31Menet, M. C.; Baron, S.; Taghi, M.; Diestra, R.; Dargere, D.; Laprevote, O.; Nivet-Antoine, V.; Beaudeux, J. L.; Bedarida, T.; Cottart, C. H. Distribution of Transresveratrol and Its Metabolites after Acute or Sustained Administration in Mouse Heart, Brain, and Liver. Mol. Nutr. Food Res. 2017, 61 (8), 1600686 DOI: 10.1002/mnfr.201600686There is no corresponding record for this reference.
- 32Gopalakrishna, R.; Oh, A.; Hou, L.; Lee, E.; Aguilar, J.; Li, A.; Mack, W. J. Flavonoid Quercetin and Its Glucuronide and Sulfate Conjugates Bind to 67-kDa Laminin Receptor and Prevent Neuronal Cell Death Induced by Serum Starvation. Biochem. Biophys. Res. Commun. 2023, 671, 116– 123, DOI: 10.1016/j.bbrc.2023.06.007There is no corresponding record for this reference.
- 33Tanaka, S.; Trakooncharoenvit, A.; Nishikawa, M.; Ikushiro, S.; Hara, H. Comprehensive Analyses of Quercetin Conjugates by LC/MS/MS Revealed That Isorhamnetin-7- O-glucuronide-4′- O-sulfate Is a Major Metabolite in Plasma of Rats Fed with Quercetin Glucosides. J. Agric. Food Chem. 2019, 67 (15), 4240– 4249, DOI: 10.1021/acs.jafc.8b06929There is no corresponding record for this reference.
- 34Tanaka, S.; Trakooncharoenvit, A.; Nishikawa, M.; Ikushiro, S.; Hara, H. Heteroconjugates of Quercetin with 4′-O-sulfate Selectively Accumulate in Rat Plasma Due to Limited Urinary Excretion. Food Funct. 2022, 13 (3), 1459– 1471, DOI: 10.1039/D1FO03478BThere is no corresponding record for this reference.
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jafc.4c08072.
Detailed information on the structural determination of the biosynthesized conjugates; HMBC spectra of glucuronide of rhapontigenin and isorhapontigenin; enzymatic sources for conjugate preparation; analytical conditions for LC-MS; and NMR summary data on the chemical shift of 1H and 13C (PDF)
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