Excessive accumulation of autofluorescent lipofuscin in the liver during hepatocarcinogenesis by methyl clofenapate and other hypolipidemic peroxisome proliferators.
Excessive accumulation of autofluorescent lipofuscin in the liver during hepatocarcinogenesis by methyl clofenapate and other hypolipidemic peroxisome proliferators.
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发表时间：
1982
期刊：
影响因子：
11.2
通讯作者：
Janardan K. Reddy;Narendra D. Lalwani;M. Reddy;S. A. Qureshi
中科院分区：
文献类型：
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作者：
Janardan K. Reddy;Narendra D. Lalwani;M. Reddy;S. A. Qureshi
几种降血脂药物和某些工业增塑剂可诱导啮齿动物肝脏中过氧化物酶体的增殖并增强过氧化物酶体相关酶的活性。现在有证据表明，强效肝过氧化物酶体增殖物作为一类是致癌的，尽管它们在沙门氏菌-微粒体测定系统中似乎不具有诱变性。我们现在报道，长期给药甲基-2[4-（对氯苯）苯氧基]-2-甲基丙酸，一种有效的肝脏过氧化物酶体增殖剂，以0.1% （w/w）的膳食浓度，诱导14只65至75周的雄性F344大鼠中的14只发生肝细胞癌。肿瘤细胞含有几个过氧化物酶体。与这一观察结果一致的是，在肿瘤中发现肉碱乙酰转移酶、热不稳定过氧化物酶体烯酰辅酶水合酶和过氧化物酶体β-氧化系统水平升高。正如预期的那样，氯芬酸甲酯在鼠伤寒沙门氏菌TA98和TA100的微粒体实验中没有致突变性。在患甲基-2-[4-（对氯苯）苯氧基]-2-甲基丙酸诱导的肝细胞癌的大鼠肝脏非肿瘤部位观察到大量的自荧光脂褐素积累。本研究对先前由五种其他低脂过氧化物酶体增殖剂诱导的肝细胞癌大鼠的肝脏进行了检查，为肝细胞中自身荧光色素的积累增加提供了回顾性证据。研究表明，喂食过氧化物酶体增殖剂的大鼠肝脏中脂褐素的积累可以作为过氧化氢持续增殖产生的H2O2增加生物损伤自由基产生的证据。过氧化物酶体的持续增殖和过氧化物酶体β-氧化系统的增加，通过增加细胞内dna损伤H2O2和其他活性氧中间体（OH·，O2T, 1O2）的产生，成为肝细胞肿瘤转化的内源性引发剂，这一假说有待验证。
Abstract Several hypolipidemic drugs and certain industrial plasticizers induce proliferation of peroxisomes and enhance the activities of peroxisome-associated enzymes in the livers of rodents. Evidence now suggests that potent hepatic peroxisome proliferators as a class are carcinogenic, although they do not appear to be mutagenic in the Salmonella-microsome assay system. We now report that long-term administration of methyl-2[4-(p-chlorophenyl)phenoxy]-2-methylpropionate, a potent hepatic peroxisome proliferator, at a dietary concentration of 0.1% (w/w), induced hepatocellular carcinomas in 14 of 14 male F344 rats between 65 and 75 weeks. The tumor cells contained several peroxisomes. Consistent with this observation was the finding of increased levels of carnitine acetyltransferase, heat-labile peroxisomal enoyl coenzyme hydratase, and peroxisomal β-oxidation system in the tumors. As expected, methyl clofenapate was not mutagenic in the Salmonella-microsome assay using Salmonella typhimurium strains TA98 and TA100. Abundant accumulation of autofluorescent lipofuscin in the nontumorous portions of liver in rats bearing methyl-2-[4-(p-chlorophenyl)phenoxy]-2-methylpropionate-induced hepatocellular carcinomas was observed. The examination in this study of livers of rats bearing hepatocellular carcinomas induced previously by five other hypolipidemic peroxisome proliferators provided retrospective evidence for increased accumulation of autofluorescent pigment in the liver cells. It is suggested that accumulation of lipofuscin in the livers of rats fed peroxisome proliferators serves as evidence for the increased production of biologically damaging free radicals as a result of H2O2 generated by sustained proliferation of peroxisomes. The hypothesis that persistent proliferation of peroxisomes and increase in peroxisomal β-oxidation system serves as endogenous initiator of the neoplastic transformation of liver cells by increasing the intracellular production of DNA-damaging H2O2 and other reactive oxygen intermediates (OH·, O2T, 1O2) remains to be tested.