Comparative metabolism of chloroacetamide herbicides and selected metabolites in human and rat liver microsomes.
Comparative metabolism of chloroacetamide herbicides and selected metabolites in human and rat liver microsomes.
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人和大鼠肝微粒体中氯乙酰氨酰胺除草剂和选定的代谢产物的比较代谢。
DOI：
10.1289/ehp.001081151
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发表时间：
2000-12
影响因子：
10.4
通讯作者：
Rose RL
中科院分区：
文献类型：
--
作者：
Coleman S;Linderman R;Hodgson E;Rose RL
乙草胺[2-氯-N-（乙氧基甲基）-N-（2-乙基-6-甲基-苯基）-乙酰胺]、甲草胺[N-（甲氧基甲基）-2-氯-N-（2，6-二乙基-苯基）乙酰胺]、丁草胺（丁氧基甲基）-2-氯-N-（2，6-二乙基-苯基）乙酰胺]，和异丙甲草胺[2-chloro-N-（2-乙基-6-甲基苯基）-N-（2-甲氧基-1-甲基乙基）乙酰胺]是用于农作物生产的芽前除草剂。这些除草剂对大鼠具有致癌性：乙草胺和甲草胺导致鼻甲肿瘤，丁草胺导致胃肿瘤，异丙甲草胺导致肝肿瘤。已经表明，这些化合物的致癌性涉及复杂的代谢活化途径，导致DNA反应性二烷基苯醌亚胺。这一途径中的重要中间体是由甲草胺和丁草胺产生的2-氯-N-（2，6-二乙基苯基）乙酰胺（CDEPA）和由乙草胺和异丙甲草胺产生的2-氯-N-（2-甲基-6-乙基苯基）乙酰胺（CMEPA）。CDEPA和CMEPA的后续代谢产生2，6-二乙基苯胺（DEA）和2-甲基-6-乙基苯胺（MEA），它们通过对羟基化和随后的氧化被生物活化为拟定的致癌产物二烷基苯醌亚胺。目前的研究扩展了我们早期对甲草胺的研究，并表明大鼠肝微粒体将乙草胺和异丙甲草胺代谢为CMEPA（分别为0.065 nmol/min/mg和0.0133 nmol/min/mg），而人肝微粒体只能将乙草胺代谢为CMEPA（0.023 nmol/min/mg）。丁草胺在大鼠肝微粒体中代谢为CDEPA的程度（0.045 nmol/min/mg）比在人肝微粒体中代谢为CDEPA的程度（< 0.001 nmol/min/mg）大得多。我们已经确定，大鼠和人的肝脏都将CMEPA代谢为MEA（分别为0.308 nmol/min/mg和0.541 nmol/min/mg），将CDEPA代谢为DEA（分别为0.350 nmol/min/mg和0.841 nmol/min/mg）。我们已经表明，大鼠和人肝微粒体代谢MEA（分别为0.035 nmol/min/mg和0.069 nmol/min/mg）和DEA（分别为0.041 nmol/min/mg和0.040 nmol/min/mg）。我们还发现，负责人体代谢乙草胺、丁草胺和异丙甲草胺的细胞色素P450亚型是CYP 3A 4和CYP 2B 6。
Acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methyl-phenyl)-acetamide], alachlor [N-(methoxymethyl)-2-chloro-N-(2, 6-diethyl-phenyl)acetamide], butachlor [N-(butoxymethyl)-2-chloro-N-(2,6-diethyl-phenyl)acetamide], and metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide] are pre-emergent herbicides used in the production of agricultural crops. These herbicides are carcinogenic in rats: acetochlor and alachlor cause tumors in the nasal turbinates, butachlor causes stomach tumors, and metolachlor causes liver tumors. It has been suggested that the carcinogenicity of these compounds involves a complex metabolic activation pathway leading to a DNA-reactive dialkylbenzoquinone imine. Important intermediates in this pathway are 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) produced from alachlor and butachlor and 2-chloro-N-(2-methyl-6-ethylphenyl)acetamide (CMEPA) produced from acetochlor and metolachlor. Subsequent metabolism of CDEPA and CMEPA produces 2,6-diethylaniline (DEA) and 2-methyl-6-ethylaniline (MEA), which are bioactivated through para-hydroxylation and subsequent oxidation to the proposed carcinogenic product dialkylbenzoquinone imine. The current study extends our earlier studies with alachlor and demonstrates that rat liver microsomes metabolize acetochlor and metolachlor to CMEPA (0.065 nmol/min/mg and 0.0133 nmol/min/mg, respectively), whereas human liver microsomes can metabolize only acetochlor to CMEPA (0.023 nmol/min/mg). Butachlor is metabolized to CDEPA to a much greater extent by rat liver microsomes (0.045 nmol/min/mg) than by human liver microsomes (< 0.001 nmol/min/mg). We have determined that both rat and human livers metabolize both CMEPA to MEA (0.308 nmol/min/mg and 0.541 nmol/min/mg, respectively) and CDEPA to DEA (0.350 nmol/min/mg and 0.841 nmol/min/mg, respectively). We have shown that both rat and human liver microsomes metabolize MEA (0.035 nmol/min/mg and 0.069 nmol/min/mg, respectively) and DEA (0.041 nmol/min/mg and 0.040 nmol/min/mg, respectively). We have also shown that the cytochrome P450 isoforms responsible for human metabolism of acetochlor, butachlor, and metolachlor are CYP3A4 and CYP2B6.