title: Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites.
abstract: 1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1'-hydroxylation, diltiazem N-demethylation and testosterone 6beta-hydroxylation with K(i) ranging from 3 to 37 micro M in human liver microsomes. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6beta-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding k(inact) and K(i) of 0.04 min(-1) and 0.2 micro M for tamoxifen and 0.08 min(-1) and 2.6 micro M for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation. There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors. Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhao
authors.forename: D R
authors.initials: DR
authors.lastname: Jones
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Wang
authors.forename: S W
authors.initials: SW
authors.lastname: Grimm
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D018076:DNA, Complementary / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013629:Tamoxifen / Q000378:metabolism* / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002121:Calcium Channel Blockers; D018076:DNA, Complementary; D018757:GABA Modulators; D010078:Oxazines; D013629:Tamoxifen; D013739:Testosterone; C007649:ethoxyresorufin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D004110:Diltiazem; D008874:Midazolam