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首页> 外文期刊>Journal of biochemical and molecular toxicology >Comparative cytotoxicity of alachlor, acetochlor, and metolachlor herbicides in isolated rat and cryopreserved human hepatocytes.
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Comparative cytotoxicity of alachlor, acetochlor, and metolachlor herbicides in isolated rat and cryopreserved human hepatocytes.

机译：甲草胺，乙草胺和甲草胺除草剂在离体大鼠和冷冻保存的人肝细胞中的比较细胞毒性。

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Noncancerous adverse effects observed at the lowest dose for chloroacetanilide herbicides alachlor [2-chloro-2',6'-diethyl-N-(methoxymethyl)-acetanilide] and acetochlor [2-chloro-2'-methyl-6'-ethyl-N-(ethoxymethyl)acetanilide], but not metolachlor [2-chloro-2'-ethyl-6'-methyl-N-(1-methyl-2-methoxymethyl)acetanilide], are hepatotoxicity in rats and dogs. Liver microsomal N-dealkylation, a step in the putative activating pathway, of acetochlor exceeds that of alachlor and is negligible for metolachlor. In the present investigation, cytotoxicity of the three chloroacetanilides was ranked using isolated rat and cryopreserved human hepatocytes to correlate this endpoint with CYP3A-dependent metabolism. Chloroacetanilide cytotoxicity in rat hepatocyte suspensions was time dependent (e.g., LC(50 - alachlor/2 h) vs. LC(50 - alachlor/4 h) = 765 vs. 325 muM). Alachlor and acetochlor were more potent than metolachlor after 2 and 4 h, times when N-dealkylated alachlor product 2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) formation was readily detectable. Alachlor and acetochlor potencies with cryopreserved human hepatocytes at 2 h were comparable to freshly isolated rat hepatocytes, and alachlor metabolism to CDEPA was likewise detectable. Unlike rat hepatocytes, metolachlor potency was equivalent to acetochlor and alachlor in human hepatocytes. Furthermore, chloroacetanilide cytotoxicity from two sources of human hepatocytes varied inversely with CYP3A4 activity. Collectively, while cytotoxicity in rat hepatocytes was consistent with chloroacetanilide activation by CYP3A, an activating role for CYP3A4 was not supported with human hepatocytes.
机译：在最低剂量下观察到的氯乙酰苯胺除草剂丙草胺[2-氯-2'，6'-二乙基-N-（甲氧基甲基）-乙酰苯胺]和乙草胺[2-氯-2'-甲基-6'-乙基- N-（乙氧基甲基）乙酰苯胺]而不是异丙甲草胺[2-氯-2'-乙基-6'-甲基-N-（1-甲基-2-甲氧基甲基）乙酰苯胺]对大鼠和狗具有肝毒性。乙草胺的肝微粒体N-脱烷基化（假定的活化途径中的一个步骤）超过了甲草胺，对于甲草胺可忽略不计。在本研究中，使用分离的大鼠和冷冻保存的人肝细胞对这三种氯乙酰苯胺的细胞毒性进行了分级，以将该终点与CYP3A依赖性代谢相关联。大鼠肝细胞悬液中的氯乙酰苯胺的细胞毒性是时间依赖性的（例如LC（50-甲草胺/ 2 h）vs.LC（50-甲草胺/ 4 h）= 765 vs.325μM）。在2和4小时后，可以容易地检测到N-脱烷基甲草胺产品2-氯-N-（2,6-二乙基苯基）乙酰胺（CDEPA）形成的时间，丙草胺和乙草胺比甲草胺更有效。冷冻保存的人肝细胞在2 h时的甲草胺和乙草胺效价与新鲜分离的大鼠肝细胞相当，同样可以检测到甲草胺代谢成CDEPA。与大鼠肝细胞不同，异丙甲草胺的效力与人肝细胞中的乙草胺和甲草胺相当。此外，来自人肝细胞的两种来源的氯乙酰苯胺的细胞毒性与CYP3A4活性成反比。总体而言，虽然大鼠肝细胞的细胞毒性与CYP3A对氯乙酰苯胺的激活相一致，但人类肝细胞不支持CYP3A4的激活作用。

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