Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2009 Sep-Oct;61(5):851-8. doi: 10.1016/s1734-1140(09)70141-0.
The aim of the present study was to estimate the inhibitory effect of perazine, a phenothiazine neuroleptic with piperazine structure in a side chain, on human CYP1A2 activity measured as a rate of caffeine 3-N- and 1-N-demethylation. Moreover, the influence of perazine on other caffeine metabolic pathways such as 7-N-demethylation (CYP1A2, CYP2C8/9, CYP3A4) and 8-hydroxylation (CYP3A4, CYP1A2, CYP2C8/9) was also determined. The Dixon analysis showed that in both human liver microsomes and Supersomes CYP1A2 perazine potently and to a similar degree inhibited caffeine 3-N-demethylation (K(i) = 3.5 microM) and 1-N-demethylation (K(i) = 5 microM). Perazine moderately diminished the rate of caffeine 7-N-demethylation in Supersomes CYP1A2 (K(i) = 11.5 microM) and liver microsomes (K(i) = 20 microM), and attenuated C-8-hydroxylation (K(i) = 15.5 microM) in Supersomes CYP1A2. On the other hand, perazine weakly inhibited caffeine C-8-hydroxylation in liver microsomes (K(i) = 98 microM). About 80% of basal CYP1A2 activity was reduced by the therapeutic concentrations of perazine (5-10 microM). The obtained results show that perazine at its therapeutic concentrations is a potent inhibitor of human CYP1A2. Hence, taking account of CYP1A2 contribution to the metabolism of endogenous substances (steroids), drugs (xanthine derivatives, phenacetin, propranolol, imipramine, phenothiazine neuroleptics, clozapine) and carcinogenic compounds, the inhibition of CYP1A2 by perazine may be of physiological, pharmacological and toxicological importance.
本研究旨在评估具有哌嗪侧链结构的吩噻嗪类神经安定药哌嗪对人 CYP1A2 活性（以咖啡因 3-N-和 1-N-去甲基化速率表示）的抑制作用。此外，还确定了哌嗪对其他咖啡因代谢途径（如 7-N-去甲基化（CYP1A2、CYP2C8/9、CYP3A4）和 8-羟化（CYP3A4、CYP1A2、CYP2C8/9）的影响。Dixon 分析表明，在人肝微粒体和 Supersomes CYP1A2 中，哌嗪均能强有力地且以相似程度抑制咖啡因 3-N-去甲基化（K(i) = 3.5 μM）和 1-N-去甲基化（K(i) = 5 μM）。哌嗪适度降低 Supersomes CYP1A2 中咖啡因 7-N-去甲基化的速率（K(i) = 11.5 μM）和肝微粒体中的速率（K(i) = 20 μM），并减弱 Supersomes CYP1A2 中的 C-8-羟化（K(i) = 15.5 μM）。另一方面，哌嗪在肝微粒体中弱抑制咖啡因 C-8-羟化（K(i) = 98 μM）。治疗浓度的哌嗪可使约 80%的基础 CYP1A2 活性降低。获得的结果表明，在治疗浓度下，哌嗪是人类 CYP1A2 的强效抑制剂。因此，考虑到 CYP1A2 对内源性物质（甾体）、药物（黄嘌呤衍生物、非那西汀、普萘洛尔、丙咪嗪、吩噻嗪类神经安定药、氯氮平）和致癌化合物的代谢的贡献，哌嗪对 CYP1A2 的抑制可能具有生理、药理和毒理意义。
