Chen Z Y, White C C, He C Y, Liu Y F, Eaton D L
Department of Environmental Health, University of Washington, Seattle 98195, USA.
J Environ Pathol Toxicol Oncol. 1995;14(2):83-99.
Both increased cell proliferation and "altered" CYP gene expression are prominent phenomena associated with liver tumor promotion by nongenotoxic carcinogen treatment. To further characterize these two responses, groups of rats were kept on powdered rat chow diet containing 0.05% phenobarbital (PB) or 0.025% ciprofibrate (Cip) for 8 days or given 8 daily doses by gavage of pregnenolone 16 alpha-carbonitrile (PCN, 150 mg/kg/ml corn oil), 3,3',4,4'-tetrachlorobiphenyl (PCB-MC, 3 mg/kg/ml corn oil) or 2,2',4,4'-tetrachlorobiphenyl (PCB-PB, 7.5 mg/kg/ml corn oil). A minipump was implanted in the rat abdominal cavity to release bromodeoxyuridine (BRDU) 5 days after the start of nongenotoxic carcinogen treatment and the experiment was terminated 3 days later. BRDU-labeled parenchymal nuclei were observed primarily in the periportal area independent of nongenotoxic carcinogen treatment. Treatment with each of the 5 nongenotoxic carcinogens resulted in profound alterations in CYP gene expression at both the transcriptional and translational levels. Expression of CYP1A1, 1A1/2, 3A1, 2B1/2, and 4A immunoproteins demonstrated nongenotoxic carcinogen-specific patterns in both magnitude and zonal distribution. In agreement with the CYP immunoprotein data, treatment with each of the five nongenotoxic carcinogens resulted in a unique composition of mRNAs of CYP2B1, 2B2, 2C6, 2C11, 3A1, 3A2, and 4A1, which were variably increased or decreased relative to the untreated control livers, depending on the treatment. Similarly, the rate and pattern of CYP enzyme-mediated hydroxylation toward testosterone, 17 beta-estradiol, corticosterone, and lauric acid were greatly altered by nongenotoxic carcinogen treatment. According to the zonal distribution patterns of CYP immunoproteins, each hepatocyte in the cell plate from the periportal triad to the central vein has a characteristic and nongenotoxic carcinogen-specific composition of CYP enzymes. Because many endogenous substrates are modulators of DNA and RNA synthesis, intracellular kinetics of endogenous substrates of CYP enzymes in the corresponding hepatocytes could contribute, at least in part, to the differences in gene expression, differentiation, and cell proliferation among the hepatocytes in the cell plate.
细胞增殖增加和“改变的”CYP基因表达都是与非遗传毒性致癌物处理促进肝脏肿瘤相关的突出现象。为了进一步描述这两种反应，将几组大鼠分别喂饲含0.05%苯巴比妥（PB）或0.025%环丙贝特（Cip）的粉状大鼠饲料8天，或每天经口灌胃给予孕烯醇酮16α-腈（PCN，150mg/kg/ml玉米油）、3,3',4,4'-四氯联苯（PCB-MC，3mg/kg/ml玉米油）或2,2',4,4'-四氯联苯（PCB-PB，7.5mg/kg/ml玉米油），共8天。在非遗传毒性致癌物处理开始5天后，将微型泵植入大鼠腹腔以释放溴脱氧尿苷（BRDU），并在3天后终止实验。无论非遗传毒性致癌物处理如何，BRDU标记的实质细胞核主要在门静脉周围区域观察到。用5种非遗传毒性致癌物中的每一种进行处理均导致CYP基因在转录和翻译水平上发生深刻改变。CYP1A1、1A1/2、3A1、2B1/2和4A免疫蛋白的表达在强度和区域分布上均表现出非遗传毒性致癌物特异性模式。与CYP免疫蛋白数据一致，用5种非遗传毒性致癌物中的每一种进行处理均导致CYP2B1、2B2、2C6、2C11、3A1、3A2和4A1 mRNA的独特组成，相对于未处理的对照肝脏，其表达根据处理情况而有不同程度的增加或减少。同样，非遗传毒性致癌物处理极大地改变了CYP酶介导的对睾酮、17β-雌二醇、皮质酮和月桂酸的羟基化速率和模式。根据CYP免疫蛋白的区域分布模式，从门静脉三联体到中央静脉的细胞板中的每个肝细胞都具有CYP酶的特征性且非遗传毒性致癌物特异性组成。由于许多内源性底物是DNA和RNA合成的调节剂，相应肝细胞中CYP酶内源性底物的细胞内动力学至少可以部分解释细胞板中肝细胞之间基因表达、分化和细胞增殖的差异。
