Dialkylquinoneimine metabolites of chloroacetanilide herbicides induce sister chromatid exchanges in cultured human lymphocytes
Dialkylquinoneimine metabolites of chloroacetanilide herbicides induce sister chromatid exchanges in cultured human lymphocytes
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DOI：
10.1016/s1383-5718(97)00163-0
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发表时间：
1997-12-12
影响因子：
1.9
通讯作者：
Casida, JE
中科院分区：
文献类型：
--
作者：
Hill, AB;Jefferies, PR;Casida, JE
一些最广泛使用的除草剂是氯乙酰苯胺，例如甲草胺和丁草胺（由2,6-二乙基苯胺衍生）和甲草胺和乙草胺（由2-乙基-6-甲基苯胺合成）。这项调查验证了先前观察到的这些除草剂的致癌性是由于遗传毒性中间体，如二乙基苯并醌亚胺，一种据称的甲草胺代谢物的假设。本文报道了相应的2,6-二烷基苯并醌亚胺、选定的氯乙酰二烷基苯并醌亚胺和其他几种候选或已知代谢物的合成。二乙基苯并醌亚胺对鼠伤寒沙门菌TA98和TA100的致突变性进行了试验，结果表明TA100对二乙基苯并醌亚胺诱导了碱基对取代突变，呈弱阳性反应。10 μ M的甲草胺和2 μ M的乙基苯胺能提高中国仓鼠卵巢细胞姐妹染色单体交换（SCE）的频率，而30 μ M和3 μ M的乙基甲基苯胺不能提高姐妹染色单体交换的频率。本文利用两名人类供体分离培养的外周血淋巴细胞（主要是T细胞），研究氯乙酰苯胺及其代谢物对人原代细胞的影响。在10 μ M的试验中，甲草胺和可能的乙草胺增加了SCE频率，但丁草胺、甲草胺、二甲草胺（2,6-二甲基类似物）和二甲胺（2,4-二甲基-3 -噻吩胺类似物）没有增加SCE频率。在培养的人淋巴细胞中，在0.3 μ M时，甲草胺、相应的氯乙酰苯胺（N-dealkyl-alachlor）和苯胺代谢物（及其4-羟基衍生物）和二乙基苯并醌仅在两个供体中的一个供体中失活或有活性，而在0.1-0.3 μ M时，二乙基苯并醌亚胺处理细胞的SCE比率始终高于乙基甲基和二甲基苯并醌亚胺。所有被测试的化合物对淋巴细胞都有毒性，但有丝分裂指数的降低和细胞周期的延长与SCE诱导没有直接联系。先前的研究表明，氯乙酰苯胺类除草剂，如2,6-二烷基苯胺衍生的甲草胺，可代谢为2,6-二烷基苯醌亚胺，本研究首次提供了直接证据，证明这些代谢物在人类淋巴细胞中具有遗传毒性。(C) 1997爱思唯尔科学有限公司
Some of the most widely-used herbicides are the chloroacetanilides exemplified by alachlor and butachlor (derived from 2,6-diethylaniline) and metolachlor and acetochlor (synthesized from 2-ethyl-6-methyIaniline). This investigation tests the hypothesis that the previously-observed oncogenicity of these herbicides is due to genotoxic intermediates such as diethylbenzoquinoneimine, a purported alachlor metabolite. Syntheses are reported here for the corresponding 2,6-dialkylbenzoquinoneimines, selected chloroacetyldialkylbenzoquinoneimines and several other candidate or known metabolites. The possible mutagenicity of diethylbenzoquinoneimine was tested in Salmonella typhimurium strains TA98 and TA100 with a weakly-positive response in the TA100 strain indicating induction of base-pair substitution mutations. The frequency of sister chromatid exchange (SCE) in Chinese hamster ovary cells was increased by alachlor at 10 mu M and diethylaniline but not ethylmethylaniline at 30 and 3 mu M Isolated and cultured peripheral lymphocytes (mostly T cells) were used from two human donors to study the effects of the chloroacetanilides and their metabolites on primary human cells. In tests at 10 mu M, the SCE frequency was increased by alachlor and possibly acetochlor but not by butachlor, metolachlor, dimethachlor (a 2,6-dimethyl analog) and dimethenamid (an analog based on 2,4-dimethyl-3 -thienylamine). At 0.3 mu M in cultured human lymphocytes, alachlor, the corresponding chloroacetanilide( N-dealkyl-alachlor) and aniline metabolites (and their 4-hydroxy derivatives), and diethylbenzoquinone were inactive or active in only one of the two donors whereas at 0.1-0.3 mu M the SCE ratio for treated cells divided by the controls was always higher for diethylbenzoquinoneimine than for ethylmethyl- and dimethylbenzoquinoneimines. All the tested compounds were toxic to lymphocytes, but the depression of the mitotic index and increased duration of the cell cycle were not directly linked with SCE induction. Previous investigations have suggested that chloroacetanilide herbicides such as alachlor derived from 2,6-dialkylanilines are metabolized to 2,6-dialkylbenzoquinoneimines and the present study provides the first direct evidence that these metabolites are genotoxic in human lymphocytes. (C) 1997 Elsevier Science B.V.