Cytochrome p450-dependent metabolism of trichloroethylene in rat kidney.
Cytochrome p450-dependent metabolism of trichloroethylene in rat kidney.
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DOI：
10.1093/toxsci/60.1.11
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发表时间：
2001-03
期刊：
影响因子：
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通讯作者：
Brian S. Cummings;J. C. Parker;L. Lash
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文献类型：
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作者：
Brian S. Cummings;J. C. Parker;L. Lash
本文研究了细胞色素P450(P450)对三氯乙烯(Tri)在肝、肾组织匀浆和雄性Fischer 344大鼠肾近端小管(PT)和远端肾小管(DT)细胞中的代谢。水合氯醛(CH)是唯一稳定检测到的代谢物，并被用来测量Tri的P450依赖的代谢。大鼠经吡啶处理后，肝、肾微粒体中的CH生成均增加，而氯贝特处理的大鼠只增加肾微粒体中的CH生成。吡啶可增加肝脏和肾脏微粒体中细胞色素P4502的表达，而氯贝特对肝脏无影响，但可增加肾脏中的细胞色素P4502和C11的蛋白水平。这些结果提示，在Tri的肝和肾代谢中，细胞色素P450 2 E1I可能起作用，而在Tri的肾脏代谢中，细胞色素P450 2 11可能起作用。对一般P450抑制剂SKF-525A和竞争底物CYP2E1氯唑沙宗的研究为这两种组织中的作用提供了额外的支持。在PT细胞中，CH的生成高于在DT细胞中的生成，并且具有时间依赖性和减少烟酰胺腺嘌呤二核苷酸磷酸(NADPH)的作用。然而，无论是吡啶还是氯贝特预先处理大鼠，都不影响细胞内细胞色素P450_2E_1和细胞色素P_2_2_(11)的蛋白水平，也不影响细胞内CH的形成。这些数据首次表明Tri可以在肾脏中代谢到至少一种其P450代谢物，并定量研究了P450诱导对Tri在大鼠肾脏中代谢的影响。
The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was studied in microsomes from liver and kidney homogenates and from isolated renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite consistently detected and was used as a measurement of P450-dependent metabolism of Tri. Pretreatment of rats with pyridine increased CH formation in both liver and kidney microsomes, whereas pretreatment of rats with clofibrate increased CH formation only in kidney microsomes. Pyridine increased CYP2E1 expression in both liver and kidney microsomes, whereas clofibrate had no effect on hepatic but increased renal CYP2E1 and CYP2C11 protein levels. These results suggest a role for CYP2E1 in both the hepatic and renal metabolism of Tri and a role for CYP2C11 in the renal metabolism of Tri. Studies with the general P450 inhibitor SKF-525A and the CYP2E1 competitive substrate chlorzoxazone provided additional support for the role of CYP2E1 in both tissues. CH formation was higher in PT cells than in DT cells and was time and reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent. However, pretreatment of rats with either pyridine or clofibrate had no effect on CYP2E1 or CYP2C11 protein levels or on CH formation in isolated cells. These data show for the first time that Tri can be metabolized to at least one of its P450 metabolites in the kidneys and quantitate the effect of P450 induction on Tri metabolism in the rat kidney.