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Inactivation of Cytochrome P450 3A4 by Bergamottin, a Component of Grapefruit Juice

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Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, and Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, Michigan 48105
Cite this: Chem. Res. Toxicol. 1998, 11, 4, 252–259
Publication Date (Web):March 4, 1998
Copyright © 1998 American Chemical Society

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    Grapefruit juice has been found to significantly increase oral bioavailability of several drugs metabolized by cytochrome P450 3A4 (P450 3A4) through inhibiting the enzymatic activity and decreasing the content of intestinal P450 3A4. HPLC/MS/MS and HPLC/UV analyses of ethyl acetate extracts from grapefruit juice revealed the presence of several furanocoumarins of which bergamottin (BG) is the major one. BG was shown to inactivate P450 3A4 in a reconstituted system consisting of purified P450 3A4, NADPH-cytochrome P450 reductase, cytochrome b5, and phospholipids. Inactivation was time- and concentration-dependent and required metabolism of BG. The loss of catalytic activity exhibited pseudo-first-order kinetics. The values of kinactivation and KI calculated from the inactivation studies were 0.3 min-1 and 7.7 μM, respectively. While approximately 70% of the erythromycin N-demethylation activity was lost during incubation with BG in the reconstituted system, P450 3A4 retained more than 90% of the heme as determined either by UV−visible spectroscopy or by HPLC. However, approximately 50% of the apoP450 in the BG-inactivated P450 3A4 incubation mixture could not be recovered from a reverse-phase HPLC column when compared with the −NADPH control. The mechanism of the inactivation appears to involve modification of the apoP450 in the active site of the enzyme instead of heme adduct formation or heme fragmentation. These results indicate that BG, the primary furanocoumarin extracted from grapefruit juice, is a mechanism-based inactivator of P450 3A4. BG was also found to inhibit the activities of P450s 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes.

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     University of Michigan.

     Parke-Davis Pharmaceutical Research.


     Corresponding author address:  Department of Pharmacology, University of Michigan, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0632. Tel:  313-764-8166. Fax:  313-763-4450. E-mail: [email protected].

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