Laine Kari, Yasar Umit, Widén Jolanta, Tybring Gunnel
Department of Medical Laboratory Sciences & Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Pharmacol Toxicol. 2003 Aug;93(2):77-81.
The aim of this study was to screen the inhibitory potential of different clinically used oestrogen and progestin hormones on CYP2C9, 2C19 and 3A4 activities in human liver microsomes. The degree of inhibition by desogestrel, 3-ketodesogestrel, 17-beta-oestradiol, gestodene, aethinyloestradiol, medroxyprogesterone acetate, norethisterone or L-norgestrel were studied at 100 microM on losartan oxidation (CYP2C9), R-omeprazole 5'-hydroxylation (CYP2C19) and R-omeprazole sulphoxidation (CYP3A4) with a 10-min preincubation with NADPH in human liver microsomes prepared from 6 individual genotyped donor livers. Aethinyloestradiol was found to be a potent inhibitor (55% mean inhibition; 95% CI 32% to 79%) of losartan oxidation (CYP2C9) and R-omeprazole 5-hydroxylation (70%; 63% to 77%) (CYP2C19), while it had little effect on R-omeprazole sulphoxidation (CYP3A4) activity. 17-beta-Oestradiol did not produce significant inhibition on any of the studied enzyme activities. Of the progestin hormones studied, gestodene and 3-ketodesogestrel were potent inhibitors of CYP2C19 (57%; 47% to 67% and 51%; 29% to 45%) and CYP3A4 (45%; 30% to 59% and 40%; 19% to 62%), but had little effect on the CYP2C9 activity. In addition, medroxyprogesterone acetate was found to inhibit CYP2C9 (55%; 45% to 65%), while not having significant effect on 2C19 or 3A4. In conclusion, the liability of clinically used female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes is very distinctive and these differences among both the oestrogen and progestin hormones may, at least in part, explain the variable results from clinical trials examining inhibitory effects of hormone replacement therapy and oral contraceptives on drug metabolism.
本研究的目的是筛选不同临床使用的雌激素和孕激素对人肝微粒体中CYP2C9、2C19和3A4活性的抑制潜力。研究了去氧孕烯、3-酮去氧孕烯、17-β-雌二醇、孕二烯酮、乙炔雌二醇、醋酸甲羟孕酮、炔诺酮或左炔诺孕酮在100微摩尔浓度下对氯沙坦氧化（CYP2C9）、R-奥美拉唑5'-羟基化（CYP2C19）和R-奥美拉唑亚砜化（CYP3A4）的抑制程度，在由6个个体基因分型供体肝脏制备的人肝微粒体中与NADPH预孵育10分钟。发现乙炔雌二醇是氯沙坦氧化（CYP2C9）和R-奥美拉唑5-羟基化（70%；63%至77%）（CYP2C19）的强效抑制剂（平均抑制率55%；95%置信区间32%至79%），而对R-奥美拉唑亚砜化（CYP3A4）活性影响很小。17-β-雌二醇对任何所研究的酶活性均未产生显著抑制。在所研究的孕激素中，孕二烯酮和3-酮去氧孕烯是CYP2C19（57%；47%至67%和51%；29%至45%）和CYP3A4（45%；30%至59%和40%；19%至62%）的强效抑制剂，但对CYP2C9活性影响很小。此外，发现醋酸甲羟孕酮可抑制CYP2C9（55%；45%至65%），而对2C19或3A4无显著影响。总之，临床使用的女性甾体激素抑制人肝微粒体中CYP2C9、2C19和3A4活性的倾向非常独特，雌激素和孕激素之间的这些差异可能至少部分解释了临床试验中激素替代疗法和口服避孕药对药物代谢抑制作用的不同结果。
