Affiliation:
1. School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan
Abstract
Objective:
The inhibitory and stimulatory effects of several compounds, including steroid hormones and azole antifungal agents, on cortisol 6β-hydroxylation activity by cyto-chrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were com-pared with those on testosterone 6β-hydroxylation to clarify the catalytic properties of the pre-dominant forms of the human CYP3A subfamily.
Methods:
6β-Hydroxylation activities of cortisol and testosterone by CYP3A4, CYP3A5, and CYP3A7 in the absence or presence of dehydroepiandrosterone (DHEA), α-naphthoflavone (ANF), ketoconazole, itraconazole, and voriconazole were measured using high-performance liquid chromatography.
Results:
Lower concentrations of DHEA and ANF increased cortisol 6β-hydroxylation activities catalyzed by CYP3A4 but not those catalyzed by CYP3A5 and CYP3A7. The inhibition strength of azole antifungal agents against cortisol 6β-hydroxylation catalyzed by all CYP3A subfamilies was similar to that of testosterone 6β-hydroxylation. Although the Michaelis constant (Km) in-creased 2-fold in the presence of 20 μM DHEA compared to that of the control, the maximal velocity (Vmax) values gradually increased with increasing DHEA. For ANF, both Km and Vmax values increased, although the Km value decreased at 2.5 μM concentrations. Ketoconazole and itraconazole competitively inhibited cortisol 6β-hydroxylation mediated by CYP3A4 with simi-lar inhibition constants.
Conclusion:
The inhibitory/stimulatory pattern among CYP3A subfamily members differed be-tween cortisol and testosterone, and CYP3A4 was found to be the most sensitive in terms of in-hibition by azole antifungals among the CYP3A subfamily members investigated.
Publisher
Bentham Science Publishers Ltd.
Reference41 articles.
1. Shimada T.; Yamazaki H.; Mimura M.; Inui Y.; Guengerich F.P.; Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994,270(1),414-423
2. Imaoka S.; Yamada T.; Hiroi T.; Hayashi K.; Sakaki T.; Yabusaki Y.; Funae Y.; Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Biochem Pharmacol 1996,51(8),1041-1050
3. Williams J.A.; Hyland R.; Jones B.C.; Smith D.A.; Hurst S.; Goosen T.C.; Peterkin V.; Koup J.R.; Ball S.E.; Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004,32(11),1201-1208
4. Kuehl P.; Zhang J.; Lin Y.; Lamba J.; Assem M.; Schuetz J.; Watkins P.B.; Daly A.; Wrighton S.A.; Hall S.D.; Maurel P.; Relling M.; Brimer C.; Yasuda K.; Venkataramanan R.; Strom S.; Thummel K.; Boguski M.S.; Schuetz E.; Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001,27(4),383-391
5. Kitada M.; Kamataki T.; Itahashi K.; Rikihisa T.; Kato R.; Kanakubo Y.; Purification and properties of cytochrome P-450 from homogenates of human fetal livers. Arch Biochem Biophys 1985,241(1),275-280
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