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Cytochrome P450 3A4-Mediated Bioactivation of Raloxifene:  Irreversible Enzyme Inhibition and Thiol Adduct Formation

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    Cytochrome P450 3A4-Mediated Bioactivation of Raloxifene:  Irreversible Enzyme Inhibition and Thiol Adduct Formation
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    Departments of Drug Metabolism and Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065
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    Chemical Research in Toxicology

    Cite this: Chem. Res. Toxicol. 2002, 15, 7, 907–914
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    https://doi.org/10.1021/tx0200109
    Published June 7, 2002
    Copyright © 2002 American Chemical Society
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    Abstract

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    Raloxifene is a selective estrogen receptor modulator which is effective in the treatment of osteoporosis in postmenopausal women. We report herein that cytochrome P450 (P450)3A4 is inhibited by raloxifene in human liver microsomal incubations. The nature of the inhibition was irreversible and was NADPH- and preincubation time-dependent, with KI and kinact values estimated at 9.9 μM and 0.16 min-1, respectively. The observed loss of P450 3A4 activity was attenuated partially by glutathione (GSH), implying the involvement of a reactive metabolite(s) in the inactivation process. Subsequently, GSH adducts of raloxifene were identified in incubations with human liver microsomes; substitution with GSH occurred at the 5- or 7-position of the benzothiophene moiety or at the 3‘-position of the phenol ring, with the 7-glutathionyl derivative being most abundant based on LC/MS and NMR analyses. These adducts are postulated to derive from addition of GSH to raloxifene arene oxides followed by dehydration and aromatization. Alternatively, raloxifene may be oxidized to an extended quinone intermediate, which then is trapped by GSH conjugation. The bioactivation of raloxifene most likely is catalyzed by P450 3A4, since the formation of GSH adducts was almost abolished when liver microsomes were pretreated with ketoconazole or with an inhibitory anti-P450 3A4 IgG. The GSH adducts also were detected in incubations of raloxifene with rat or human hepatocytes, while the corresponding N-acetylcysteine adducts were identified in the bile and urine from rats treated orally with the drug at 5 mg/kg. Taken together, these data indicate that P450 3A4-mediated bioactivation of raloxifene in vitro is accompanied by loss of enzyme activity. The significance of these findings with respect to the clinical use of raloxifene remains to be determined.

    Copyright © 2002 American Chemical Society

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    †

     Department of Drug Metabolism.

    ‡

     Department of Medicinal Chemistry.

    *

     Correspondence should be addressed to this author at the Department of Drug Metabolism, Merck & Co., P.O. Box 2000, RY800-B211, Rahway, NJ 07065. Tel:  (732) 594-4501; Fax:  (732) 594-4820.

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    This article is cited by 123 publications.

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    Cite this: Chem. Res. Toxicol. 2002, 15, 7, 907–914
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    https://doi.org/10.1021/tx0200109
    Published June 7, 2002
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