Kornbrust D, Dietz D
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Cell Biol Toxicol. 1987 Jun;3(2):143-64. doi: 10.1007/BF00058453.
Studies were conducted to assess the effects of inducers of hepatic mixed function oxidases on DNA repair responses to 13 different genotoxic agents in hepatocytes from adult male mice. Phenobarbital pretreatment increased DNA repair elicited by diethylnitrosamine but had no effect on responses to the other compounds. Pretreatment with p,p'-dichlorodiphenyltrichlorethane, 3-methyl-cholanthrene or beta-naphthoflavone induced the DNA repair responses to a variety of activation-dependent carcinogens. DNA repair responses to the direct-acting alkylating agents methyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine were not increased by any of the pretreatments, which indicated that the pretreatment-related enhancement of responses to the other compounds was due to induction of their metabolic activation. Taken together, the findings suggest that Aroclor, or other pretreatments, may increase the sensitivity of the hepatocyte DNA repair assay for detecting the genotoxicity of certain compounds; however, the potential benefit may be limited due to specific features of the assay. In contrast, Aroclor pretreatment did not produce any enhancement of in vivo DNA repair elicited by dimethylnitrosamine, diethylnitrosamine, o-aminoazotoluene, 2-acetylaminofluorene, 3-methylcholanthrene or aflatoxin B1, and thus does not appear to be useful for improving the sensitivity of the in vivo/in vitro assay. Whereas the amount of DNA repair produced by dimethylnitrosamine was not increased by classical inducers of liver microsomal enzymes, pretreatment with pyrazole greatly augmented in vitro and in vivo DNA repair responses to dimethylnitrosamine; responses to diethylnitrosamine were increased to a lesser degree by pyrazole pretreatment. The effects of lactational exposure to enzyme inducing agents on DNA repair in neonatal hepatocytes was also investigated.
开展了多项研究，以评估肝混合功能氧化酶诱导剂对成年雄性小鼠肝细胞中13种不同基因毒性剂的DNA修复反应的影响。苯巴比妥预处理可增加二乙基亚硝胺引发的DNA修复，但对其他化合物的反应没有影响。用对，对'-二氯二苯三氯乙烷、3-甲基胆蒽或β-萘黄酮预处理可诱导对多种依赖活化的致癌物的DNA修复反应。任何预处理均未增加对直接作用的烷化剂甲磺酸甲酯和N-甲基-N'-硝基-N-亚硝基胍的DNA修复反应，这表明与预处理相关的对其他化合物反应的增强是由于其代谢活化的诱导。综上所述，这些发现表明，多氯联苯混合物或其他预处理可能会提高肝细胞DNA修复试验检测某些化合物基因毒性的敏感性；然而，由于该试验的特定特征，潜在益处可能有限。相比之下，多氯联苯混合物预处理并未增强二甲基亚硝胺、二乙基亚硝胺、邻氨基偶氮甲苯、2-乙酰氨基芴、3-甲基胆蒽或黄曲霉毒素B1在体内引发的DNA修复作用，因此似乎无助于提高体内/体外试验的敏感性。虽然肝微粒体酶的经典诱导剂并未增加二甲基亚硝胺产生的DNA修复量，但吡唑预处理可大大增强体外和体内对二甲基亚硝胺的DNA修复反应；吡唑预处理对二乙基亚硝胺反应的增强程度较小。还研究了哺乳期接触酶诱导剂对新生肝细胞DNA修复的影响。
