Hayes M A, Roberts E, Safe S H, Farber E, Cameron R G
J Natl Cancer Inst. 1986 Apr;76(4):683-91. doi: 10.1093/jnci/76.4.683.
The influences of different polychlorinated biphenyl (PCB) isomers and congeners on distinct hepatotoxic responses to the hepatocarcinogen N-2-fluorenylacetamide [(2-FAA) CAS: 53-96-3] were examined in F344 rats. Cytocidal toxicity of 2-FAA (25-400 microM), determined by lactate dehydrogenase release during 20 hours in primary monolayer cultures of isolated rat hepatocytes, was reduced by in vivo pretreatment with either phenobarbitone [(PB) CAS: 50-06-6] or 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP), a PB-type PCB inducer. However, cytocidal toxicity of 2-FAA was substantially potentiated by either 3-methylcholanthrene [(MCA) CAS: 56-49-5] or 3,3',4,4'-tetrachlorobiphenyl [(TCBP) CAS: 32598-13-3], an MCA-type PCB. In the same cell culture assays, all four pretreatments similarly reduced cytocidal toxicity of N-hydroxy-N-2-fluorenylacetamide (0.32-32 microM; CAS: 53-95-2). By comparison, pretreatments with either the PB-type or MCA-type PCB's (50-200 mumol/kg) diminished mitoinhibitory toxicity of 2-FAA in vivo, as measured by hepatic regenerative growth and hepatocyte labeling indices 7 days after partial hepatectomy (PH) in rats given 3 consecutive daily doses of 2-FAA (20/mg/kg/day) before PH. This regimen of 2-FAA and PH promoted rapid selective growth of gamma-glutamyltranspeptidase-positive (gamma-GT+) nodules at 2 and 4 weeks after PH in rats previously given an initiating hepatocarcinogen, diethylnitrosamine [(DENA) CAS: 55-18-5]. However, various PCB's, including 2,2',4,4',5,5'-HCBP, 3,3',4,4'-TCBP, 2,2',4,4'-TCBP, 2,2',5,5'-TCBP, and the commercial mixture Aroclor 1254, each given as a single dose of 50 mumol/kg by gavage 10 days after DENA and 7 days before 2-FAA, all reduced the size of 2-FAA-selected gamma-GT+ nodules during the 4-week period after PH. These results indicate that, in spite of predictable inducer-specific opposite influences of different types of PCB's on cytocidal toxicity of 2-FAA, all PCB's similarly reduce nodule selection by 2-FAA in initiated livers. Reduced growth of 2-FAA-selected nodules correlated with the consistent ability of all PCB's to enhance regeneration of liver mass after 2-FAA and PH.
在F344大鼠中研究了不同的多氯联苯（PCB）异构体和同系物对肝癌致癌物N-2-芴基乙酰胺[（2-FAA），CAS：53-96-3]的不同肝毒性反应的影响。通过在分离的大鼠肝细胞原代单层培养物中20小时内乳酸脱氢酶释放来测定的2-FAA（25-400 microM）的杀细胞毒性，在体内用苯巴比妥[（PB），CAS：50-06-6]或2,2'，4,4'，5,5'-六氯联苯（HCBP，一种PB型PCB诱导剂）预处理后降低。然而，2-FAA的杀细胞毒性被3-甲基胆蒽[（MCA），CAS：56-49-5]或3,3'，4,4'-四氯联苯[（TCBP），CAS：32598-13-3，一种MCA型PCB]显著增强。在相同的细胞培养试验中，所有四种预处理同样降低了N-羟基-N-2-芴基乙酰胺（0.32-32 microM；CAS：53-95-2）的杀细胞毒性。相比之下，用PB型或MCA型PCB（50-200 mumol/kg）预处理可降低2-FAA在体内的有丝分裂抑制毒性，这通过在大鼠部分肝切除（PH）前连续3天每天给予2-FAA（20/mg/kg/天）后7天的肝再生生长和肝细胞标记指数来测量。这种2-FAA和PH方案促进了在先前给予起始致癌物二乙基亚硝胺[（DENA），CAS：55-18-5]的大鼠中PH后2周和4周时γ-谷氨酰转肽酶阳性（γ-GT+）结节的快速选择性生长。然而，各种PCB，包括2,2'，4,4'，5,5'-HCBP、3,3'，4,4'-TCBP、2,2'，4,4'-TCBP、2,2'，5,5'-TCBP以及商业混合物Aroclor 1254，在DENA后10天和2-FAA前7天通过灌胃以50 mumol/kg的单剂量给予，在PH后的4周期间均减小了2-FAA选择的γ-GT+结节的大小。这些结果表明，尽管不同类型的PCB对2-FAA的杀细胞毒性有可预测的诱导剂特异性相反影响，但所有PCB同样减少了起始肝脏中2-FAA的结节选择。2-FAA选择的结节生长减少与所有PCB在2-FAA和PH后增强肝脏质量再生的一致能力相关。
