Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Science, Smętna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2012;64(6):1411-8. doi: 10.1016/s1734-1140(12)70938-6.
Cytochrome P450 3A (CYP3A) subfamily is involved in the metabolism of xenobiotics (e.g., drugs) and endogenous substances (e.g., steroids). The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the level and activity of CYP3A in rat liver, measured as a rate of testosterone 2β- and 6β-hydroxylation.
The reactions were studied in control liver microsomes in the presence of neuroleptics, as well as in the microsomes of rats treated intraperitoneally (ip) with pharmacological doses of the drugs (promazine and thioridazine 10 mg/kg; chlorpromazine 3 mg/kg; haloperidol 0.3 mg/kg; risperidone 0.1 mg/kg; sertindole 0.05 mg/kg) for one day or two weeks (twice a day), in the absence of the neuroleptics in vitro.
The investigated neuroleptics added in vitro to control liver microsomes produced a moderate or week inhibitory effects on CYP3A activity. After one-day exposure of rats to neuroleptics, only chlorpromazine significantly increased the activity of CYP3A. Chronic treatment of rats with thioridazine diminished the protein level and activity of CYP3A, while risperidone induced this enzyme.
The observed changes in the CYP3A expression after prolonged exposition to neuroleptics suggest their influence on the enzyme regulation.
细胞色素 P4503A（CYP3A）亚家族参与外源性物质（如药物）和内源性物质（如类固醇）的代谢。本研究旨在探讨经典和非典型抗精神病药对大鼠肝 CYP3A 水平和活性的影响，以睾酮 2β-和 6β-羟化率来衡量。
在神经递质存在的情况下，在对照肝微粒体中研究反应，以及在大鼠肝微粒体中研究反应，这些大鼠经腹腔（ip）给予药物（奋乃静和硫利达嗪 10mg/kg；氯丙嗪 3mg/kg；氟哌啶醇 0.3mg/kg；利培酮 0.1mg/kg；曲马多 0.05mg/kg）的药理剂量处理一天或两周（每天两次），在体外无神经递质的情况下。
在体外加入对照肝微粒体的研究神经递质对 CYP3A 活性产生中度或轻度抑制作用。大鼠经一天暴露于神经递质后，只有氯丙嗪显著增加 CYP3A 活性。噻吨类药物（如氯丙嗪）的慢性治疗降低了 CYP3A 的蛋白水平和活性，而利培酮则诱导了这种酶。
在长期暴露于神经递质后观察到 CYP3A 表达的变化表明它们对酶调节的影响。
