In vitro metabolism of alachlor by human liver microsomes and human cytochrome P450 isoforms
In vitro metabolism of alachlor by human liver microsomes and human cytochrome P450 isoforms
复制标题
DOI：
10.1016/s0009-2797(99)00107-6
复制
发表时间：
1999-08-30
影响因子：
5.1
通讯作者：
Rose, RL
中科院分区：
文献类型：
--
作者：
Coleman, S;Liu, SM;Rose, RL
甲草胺（2-氯-N-甲氧基甲基-N-（2，6-二乙基苯基）乙酰胺）是一种广泛使用的芽前氯乙酰苯胺除草剂，已被美国环保局列为可能的人类致癌物。假定的致癌代谢物2，6-二乙基苯醌亚胺（DEBQI）是通过一系列复杂的氧化和非氧化步骤形成的，这些步骤已在大鼠、小鼠和猴中得到表征，但在人类中没有。导致DEBQI形成的关键代谢物是2-氯-N-（2，6-二乙基苯基）乙酰胺（CDEPA）。这项研究表明，男性肝微粒体能够将甲草胺代谢为CDEPA。人肝微粒体的CDEPA形成速率（0.0031 +/- 0.0007 nmol/min/mg）显著低于大鼠肝微粒体（0.0353 +/- 0.0036 nmol/min/mg）或小鼠肝微粒体（0.0106 +/- 0.0007）的CDEPA形成速率。此外，我们还筛选了人细胞色素P450亚型1A 1、1A 2、2B 6、2C 8、2C 9、2C 18、2C 19、2D 6、2 E1和3A 4，并确定人CYP 3A 4负责将甲草胺代谢为CDEPA。需要进一步的工作来确定人类能够通过随后的代谢步骤代谢CDEPA导致DEBQI形成的程度。(C)1999爱思唯尔科学爱尔兰有限公司保留所有权利。
Alachlor (2-chloro-N-methoxymethyl-N-(2,6-diethylphenyl)acetamide) is a widely used pre-emergent chloroacetanilide herbicide which has been classified by the USEPA as a probable human carcinogen. The putative carcinogenic metabolite, 2, 6-diethylbenzoquinone imine (DEBQI), is formed through a complex series of oxidative and non-oxidative steps which have been characterized in rats, mice, and monkeys but not in humans. A key metabolite leading to the formation of DEBQI is 2-chloro-N-(2, 6-diethylphenyl) acetamide (CDEPA). This study demonstrates that male human liver microsomes are able to metabolize alachlor to CDEPA. The rate of CDEPA formation for human liver microsomes (0.0031 +/- 0.0007 nmol/min per mg) is significantly less than the rates of CDEPA formation for rat liver microsomes (0.0353 +/- 0.0036 nmol/min per mg) or mouse liver microsomes (0.0106 +/- 0.0007). Further, we have screened human cytochrome P450 isoforms 1A1, 1A2, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4 and determined that human CYP 3A4 is responsible for metabolism of alachlor to CDEPA. Further work is necessary to determine the extent to which humans are able to metabolize CDEPA through subsequent metabolic steps leading to the formation of DEBQI. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.