HUMAN LIVER-MICROSOMES ARE EFFICIENT CATALYSTS OF 1,3-BUTADIENE OXIDATION - EVIDENCE FOR MAJOR ROLES BY CYTOCHROMES P450 2A6 AND 2E1
HUMAN LIVER-MICROSOMES ARE EFFICIENT CATALYSTS OF 1,3-BUTADIENE OXIDATION - EVIDENCE FOR MAJOR ROLES BY CYTOCHROMES P450 2A6 AND 2E1
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DOI：
10.1006/abbi.1994.1246
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发表时间：
1994-06-01
影响因子：
3.9
通讯作者：
ELFARRA, AA
中科院分区：
文献类型：
--
作者：
DUESCHER, RJ;ELFARRA, AA
以前，我们提供的证据参与多种细胞色素P450酶的代谢1，3-丁二烯，啮齿动物和可能的人类致癌物，丁二烯一氧化物在小鼠和大鼠肝微粒体。在这项研究中，1，3-丁二烯氧化7 cDNA表达的人P450酶和人，小鼠和大鼠肝微粒体的特点。与cDNA表达的人P450 1A 2、2A 6、2B 6、2D 6和2 E1孵育导致形成一氧化丁二烯，而与P450 1A 1和3A 4孵育未导致检测到任何代谢物。活性同工酶检查，P450 2A 6和2 E1是最活跃的丁二烯一氧化物的形成率时，归一化的微粒体的P450含量。在6份人肝微粒体样本中，1，3-丁二烯氧化在检测到的一氧化丁二烯量方面表现出近3倍的个体差异，一氧化丁二烯的形成具有NADPH和时间依赖性，并可通过添加1-苄基咪唑或4-甲基吡唑（已知的细胞色素P450抑制剂）抑制。相关性研究为P450 2A 6和2 E1在人肝微粒体中1，3-丁二烯氧化中的主要作用提供了证据。人肝微粒体中的一氧化二烯形成率与小鼠肝微粒体中获得的速率相似或更高，而人和小鼠肝微粒体中的1，3-丁二烯氧化率高于大鼠肝微粒体中获得的速率。这些结果提供了1，3-丁二烯是多种P450酶的底物的直接证据，并表明与小鼠或大鼠相比，人类可能具有更高的表达1，3-丁二烯毒性的风险。此外，这些结果表明，小鼠可能是评估人类风险的更合适的动物模型。(C)1994年出版社出版。
Previously, we provided evidence for the involvement of multiple cytochrome P450 enzymes in the metabolism of 1,3-butadiene, a rodent and possibly a human carcinogen, to butadiene monoxide in mouse and rat liver microsomes. In this study, 1,3-butadiene oxidation by seven cDNA-expressed human P450 enzymes and by human, mouse, and rat liver microsomes was characterized. Incubations with cDNA-expressed human P450 1A2, 2A6, 2B6, 2D6, and 2E1 resulted in the formation of butadiene monoxide, whereas incubations with P450 1A1 and 3A4 did not lead to the detection of any metabolite. Of the active isozymes examined, P450 2A6 and 2E1 were the most active when butadiene monoxide formation rates were normalized for the P450 content of the microsomes. With six human liver microsomal samples, 1,3-butadiene oxidation exhibited nearly threefold individual variation in the amounts of butadiene monoxide detected, and butadiene monoxide formation was NADPH- and time-dependent and was inhibited by the addition of 1-benzylimidazole or 4-methylpyrazole, known cytochrome P450 inhibitors. Correlation studies provided evidence for major roles by P450 2A6 and 2E1 in 1,3-butadiene oxidation in human liver microsomes. Butadiene monoxide formation rates in human liver microsomes were similar, or higher, than the rate obtained in mouse liver microsomes, whereas 1,3-butadiene oxidation rates in human and mouse liver microsomes were higher than the rate obtained in rat liver microsomes. These results provide direct evidence that 1,3-butadiene is a substrate for multiple P450 enzymes and suggest that humans may be at higher risk of expressing 1,3-butadiene toxicity compared to mice or rats. In addition, these results suggest that the mouse may be the more appropriate animal model to assess human risk. (C) 1994 Academic Press, Inc.