Differential induction of rat hepatic cytochromes P450 3A1, 3A2, 2B1, 2B2, and 2E1 in response to pyridine treatment.
Differential induction of rat hepatic cytochromes P450 3A1, 3A2, 2B1, 2B2, and 2E1 in response to pyridine treatment.
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发表时间：
2001-03
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通讯作者：
Hyesook Kim;D. Putt;R. Zangar;Wolf Cr;F. Guengerich;Edwards Rj;P. Hollenberg;Raymond F. Novak-
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作者：
Hyesook Kim;D. Putt;R. Zangar;Wolf Cr;F. Guengerich;Edwards Rj;P. Hollenberg;Raymond F. Novak-
从代谢活性、蛋白质和mRNA水平研究了吡啶（PY）对大鼠肝细胞色素P450（CYP）3A 1和3A 2表达的影响，并与CYP 2B 1/2和CYP 2 E1进行了比较。PY处理后，CYP 3A代谢活性以及CYP 3A蛋白和mRNA水平均升高。在诱导水平、剂量依赖性和mRNA稳定性方面，PY处理对CYP 3A 1和CYP 3A 2的影响不同。PY处理后，CYP 3A 1 mRNA水平最大增加约42倍，而CYP 3A 2 mRNA水平增加约4倍。此外，CYP 3A 1 mRNA水平下降更迅速地比CYP 3A 2的确定后，抑制转录与放线菌素D或虫草素。大鼠PY给药导致CYP 3A 1、CYP 3A 2和CYP 2B 1/2B 2蛋白水平呈剂量依赖性升高。与PY给药对CYP 3A 1和2B的影响相反，CYP 2 E1蛋白水平升高，而CYP 2 E1 mRNA水平未伴随升高。以200 mg/kg/天剂量给予大鼠PY 3天，可增加CYP 3A 2的蛋白和mRNA水平，而以高于200 mg/kg/天剂量给予大鼠PY 3天，可增加CYP 3A 2蛋白水平，但不增加CYP 3A 2 mRNA水平。这些数据表明，PY在不同的表达水平下调节本研究中检查的各种CYP，并且PY分别在低剂量和高剂量PY处理下通过转录激活调节CYP 3A 1表达，通过转录和转录后激活调节CYP 3A 2表达。
Pyridine (PY) effects on rat hepatic cytochromes P450 (CYP) 3A1 and 3A2 expression were examined at the levels of metabolic activity, protein, and mRNA and were compared with those of CYP2B1/2 and CYP2E1. CYP3A metabolic activity as well as CYP3A protein and mRNA levels increased following treatment of rats with PY. CYP3A1 and CYP3A2 were differentially affected by PY treatment in terms of induction levels, dose dependence, and stability of mRNA. CYP3A1 mRNA levels maximally increased ~42-fold after PY treatment, whereas CYP3A2 mRNA level increased ~4-fold. Moreover, CYP3A1 mRNA levels decreased more rapidly than those of CYP3A2 as determined following inhibition of transcription with actinomycin D or cordycepin. Treatment of rats with PY resulted in a dose-dependent increase in CYP3A1, CYP3A2, and CYP2B1/2B2 protein levels. In contrast to the effects of PY treatment on CYP3A1 and 2B, CYP2E1 protein levels increased in the absence of a concomitant increase in CYP2E1 mRNA levels. Treatment of rats with PY at 200 mg/kg/day for 3 days increased both protein and mRNA levels of CYP3A2, whereas treatment with higher than 200 mg/kg/day for 3 days increased CYP3A2 protein levels without an increase in CYP3A2 mRNA levels. These data demonstrated that PY regulates the various CYPs examined in this study at different levels of expression and that PY regulates CYP3A1 expression through transcriptional activation and CYP3A2 expression through transcriptional and post-transcriptional activation at a low- and high-dose PY treatment, respectively.