Iwase M, Kurata N, Ehana R, Nishimura Y, Masamoto T, Yasuhara H
Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
Hum Exp Toxicol. 2006 Dec;25(12):715-21. doi: 10.1177/0960327106071979.
This study evaluated the effects of the commonly used hydrophilic organic solvents, acetonitrile, methanol, ethanol, 1-propanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, polyethylene glycol and propylene glycol, on CYP3A in pooled human liver microsomes, using testosterone and midazolam as substrates. Furthermore, we examined the modulation effect of organic solvents on CYP3A inhibition by ketoconazole. Testosterone 6beta-hydroxylation activity was potently inhibited in the presence of DMSO and 1-propanol in a concentration-dependent manner. Midazolam 1'-hydroxylation activity, however, was weakly inhibited only by 1% of DMSO, the highest concentration used in this study. Moreover, the potency of ketoconazole to inhibit CYP3A activities was variable, depending on the organic solvent used as a dissolving solvent for ketoconazole. Our data indicate that each organic solvent had an effect on CYP3A4 activity, evaluated by both substrates with different magnitudes. Furthermore, it was shown that the effects of organic solvents on CYP3A activity are substrate-dependent. The present study also shows that methanol had little effect on either substrate.
本研究以睾酮和咪达唑仑为底物，评估了常用亲水性有机溶剂乙腈、甲醇、乙醇、1-丙醇、二甲基亚砜（DMSO）、N，N-二甲基甲酰胺、聚乙二醇和丙二醇对人肝微粒体中CYP3A的影响。此外，我们还研究了有机溶剂对酮康唑抑制CYP3A的调节作用。在DMSO和1-丙醇存在的情况下，睾酮6β-羟基化活性以浓度依赖性方式受到强烈抑制。然而，咪达唑仑1'-羟基化活性仅在本研究中使用的最高浓度1%的DMSO作用下受到微弱抑制。此外，酮康唑抑制CYP3A活性的效力因用作酮康唑溶解溶剂的有机溶剂而异。我们的数据表明，每种有机溶剂对通过两种底物评估的CYP3A4活性都有不同程度的影响。此外，研究表明有机溶剂对CYP3A活性的影响取决于底物。本研究还表明，甲醇对两种底物的影响都很小。
