Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse
Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse
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DOI：
10.1124/dmd.110.032201
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发表时间：
2010-05-01
影响因子：
3.9
通讯作者：
Grollman, Arthur P.
中科院分区：
文献类型：
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作者：
Rosenquist, Thomas A.;Einolf, Heidi J.;Grollman, Arthur P.
马兜铃酸 (AA) 是植物源性肾毒素和致癌物质，可导致慢性肾功能衰竭和相关尿路上皮细胞癌，以及几种统称为马兜铃酸肾病 (AAN) 的临床综合征。小鼠为 AAN 研究提供了一个有用的模型，因为 AA 治疗小鼠的肾脏组织病理学与人类惊人相似。对于组织谱与人类略有不同的小鼠来说，AA 也是一种强效致癌物。 AA对小鼠的中毒剂量高于人体；据推测，这种易感性差异反映了物种之间不同的解毒率。最近对小鼠的研究表明，肝细胞色素 P450 系统可以解毒 AA，而芳基烃反应的诱导剂可以保护小鼠免受 AA 的肾毒性作用。本研究的目的是确定特定细胞色素 P450 (P450) 酶在体内 AA 代谢中的作用。在 18 种人类 P450 酶中，我们仅调查了两种，CYP1A1 和 CYP1A2，它们能有效将 8-甲氧基-6-硝基-菲-(3,4-d)-1,3-二氧杂并-5-羧酸 (AAI) 去甲基化为无毒衍生物 8-hydroxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAIa).动力学分析显示人和大鼠 CYP1A2 形成 AAIa 的效率相似。我们还在此报告，CYP1A2 缺陷小鼠对 AAI 的肾毒性作用表现出更高的敏感性。此外，Cyp1a2 敲除小鼠在肾脏中积累 AAI 衍生的 DNA 加合物的速度比对照小鼠更高。 AAI 的生物利用度或肝脏代谢、CYP1A2 的表达或体内竞争性硝基还原途径的效率的差异可以解释人类和啮齿动物对 AAI 敏感性之间的明显差异。
Aristolochic acids (AAs) are plant-derived nephrotoxins and carcinogens responsible for chronic renal failure and associated urothelial cell cancers in several clinical syndromes known collectively as aristolochic acid nephropathy (AAN). Mice provide a useful model for study of AAN because the renal histopathology of AA-treated mice is strikingly similar to that of humans. AA is also a potent carcinogen in mice with a tissue spectrum somewhat different from that in humans. The toxic dose of AA in mice is higher than that in humans; this difference in susceptibility has been postulated to reflect differing rates of detoxication between the species. Recent studies in mice have shown that the hepatic cytochrome P450 system detoxicates AA, and inducers of the arylhydrocarbon response protect mice from the nephrotoxic effects of AA. The purpose of this study was to determine the role of specific cytochrome P450 (P450) enzymes in AA metabolism in vivo. Of 18 human P450 enzymes we surveyed only two, CYP1A1 and CYP1A2, which were effective in demethylating 8-methoxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) to the nontoxic derivative 8-hydroxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAIa). Kinetic analysis revealed similar efficiencies of formation of AAIa by human and rat CYP1A2. We also report here that CYP1A2-deficient mice display increased sensitivity to the nephrotoxic effects of AAI. Furthermore, Cyp1a2 knockout mice accumulate AAI-derived DNA adducts in the kidney at a higher rate than control mice. Differences in bioavailability or hepatic metabolism of AAI, expression of CYP1A2, or efficiency of a competing nitroreduction pathway in vivo may explain the apparent differences between human and rodent sensitivity to AAI.