Kornbrust D, Dietz D
Environ Mutagen. 1985;7(6):857-70. doi: 10.1002/em.2860070607.
Inducers of liver mixed function oxidase (MFO) activities have profound effects on the genotoxicity of substances that undergo metabolic activation by the MFO system. The polychlorinated biphenyl mixture Aroclor 1254 is a broad-spectrum inducer of liver MFO activities that has been employed as a pretreatment to augment the metabolic activation capabilities of rat liver fractions used in a number of short-term tests for genotoxicity, including the Ames Salmonella/bacterial mutagenicity assay. The present study was designed to characterize the effects of Aroclor pretreatment of rats on the DNA repair responses elicited by various chemicals in the in vitro hepatocyte primary culture/DNA repair (HPC/DR) assay as well as the in vivo/in vitro HPC/DR assay. The amount of DNA repair produced in vitro by diethylnitrosamine (DEN), benzo(a)pyrene (B(a)P), 3-methylcholanthrene (3-MC), 2-acetylaminofluorene (2-AAF), o-aminoazotoluene (o-AT), and aflatoxin B1 (AFB1) was significantly greater in hepatocytes derived from Aroclor-pretreated rats than in control rat hepatocytes; in vitro responses to dimethylnitrosamine (DMN), 7,12-dimethylbenzanthracene (DMBA), benzidine (BZ), and 2-naphthylamine (2-NA) were not significantly affected by Aroclor pretreatment. DNA repair elicited by the direct-acting alkylating agents methyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine was also not increased by Aroclor pretreatment, which indicated that Aroclor does not exert a general stimulatory effect on the hepatocellular DNA repair capacity. Therefore, the pretreatment-related potentiation of DNA repair observed for 6 out of 12 compounds tested in vitro was considered to be due to enhanced metabolic activation. These results suggested that pretreatment with Aroclor may increase the sensitivity of the in vitro HPC/DR assay to certain compounds. In contrast, Aroclor pretreatment had little effect on the amount of hepatocellular DNA repair elicited by in vivo administration of DMN, DEN, o-AT, 2-AAF, 3-MC, or AFB1, which indicated that this pretreatment regimen may have little utility for improving the sensitivity of the in vivo/in vitro HPC/DR assay.
肝脏混合功能氧化酶（MFO）活性诱导剂对经MFO系统进行代谢活化的物质的遗传毒性有深远影响。多氯联苯混合物Aroclor 1254是一种肝脏MFO活性的广谱诱导剂，已被用作预处理，以增强大鼠肝脏组分在许多遗传毒性短期试验（包括艾姆斯沙门氏菌/细菌致突变性试验）中的代谢活化能力。本研究旨在表征Aroclor预处理大鼠对体外肝细胞原代培养/DNA修复（HPC/DR）试验以及体内/体外HPC/DR试验中各种化学物质引发的DNA修复反应的影响。在体外，二乙基亚硝胺（DEN）、苯并(a)芘（B(a)P）、3-甲基胆蒽（3-MC）、2-乙酰氨基芴（2-AAF）、邻氨基偶氮甲苯（o-AT）和黄曲霉毒素B1（AFB1）在来自Aroclor预处理大鼠的肝细胞中产生的DNA修复量显著高于对照大鼠肝细胞；体外对二甲基亚硝胺（DMN）、7,12-二甲基苯并蒽（DMBA）、联苯胺（BZ）和2-萘胺（2-NA）的反应不受Aroclor预处理的显著影响。直接作用的烷基化剂甲磺酸甲酯和N-甲基-N'-硝基-N-亚硝基胍引发的DNA修复也未因Aroclor预处理而增加，这表明Aroclor对肝细胞DNA修复能力没有普遍的刺激作用。因此，在体外测试的12种化合物中有6种观察到的与预处理相关的DNA修复增强被认为是由于代谢活化增强。这些结果表明，Aroclor预处理可能会增加体外HPC/DR试验对某些化合物的敏感性。相比之下，Aroclor预处理对体内给予DMN、DEN、o-AT、2-AAF、3-MC或AFB1引发的肝细胞DNA修复量影响很小，这表明这种预处理方案可能对提高体内/体外HPC/DR试验的敏感性作用不大。
