Wilson M W, Lay L T, Chow C K, Tai H H, Robertson L W, Glauert H P
Department of Nutrition and Food Science, University of Kentucky, Lexington 40506-0054, USA.
Arch Toxicol. 1995;69(7):491-7. doi: 10.1007/s002040050203.
Several hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rodents. These agents induce and promote hepatocarcinogenesis by unknown mechanisms, since most studies have not found them to be genotoxic. Peroxisome proliferators increase the expression of several genes, including those for the enzymes of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. The peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA) were therefore examined for their ability to alter hepatic eicosanoid concentrations. Rats received injections of 3 or 10 mg PFDA/kg body weight every 14 days or were fed 0.01% ciprofibrate for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. The activity of the peroxisomal enzyme fatty acyl CoA oxidase was significantly increased by both ciprofibrate and PFDA at all times. Hepatic concentrations of prostaglandins E2 and F2a (PGE2, PGF2a), thromboxane B2 (TXB2), and leukotriene C4 (LTC4) were measured by immunoassay. Concentrations of PGE2, PGF2a, and TXB2 were decreased in livers of rats receiving ciprofibrate or PFDA compared to livers of control rats, with ciprofibrate exerting a greater effect than PFDA at the doses used. Hepatic LTC4 concentrations were significantly increased by ciprofibrate at 10 days and PFDA at 54 weeks, and significantly decreased by PFDA at 26 weeks. These alterations in eicosanoid concentrations may be important in the natural history of peroxisome proliferator-induced hepatocarcinogenesis.
几种降血脂药物、增塑剂及其他化学物质可在啮齿动物中诱发肝脏过氧化物酶体增殖及肝细胞癌。这些物质通过未知机制诱导并促进肝癌发生，因为大多数研究并未发现它们具有基因毒性。过氧化物酶体增殖剂可增加多种基因的表达，包括过氧化物酶体β-氧化途径的酶及细胞色素P-450 4A家族的基因，这些基因参与脂质代谢，包括类花生酸及其前体脂肪酸。因此，研究了过氧化物酶体增殖剂环丙贝特和全氟癸酸（PFDA）改变肝脏类花生酸浓度的能力。大鼠每14天接受3或10 mg PFDA/kg体重的注射，或喂食0.01%环丙贝特10天、24天、6周、26周或54周。环丙贝特和PFDA在所有时间均显著增加了过氧化物酶体酶脂肪酰辅酶A氧化酶的活性。通过免疫测定法测量了肝脏中前列腺素E2和F2a（PGE2、PGF2a）、血栓素B2（TXB2）和白三烯C4（LTC4）的浓度。与对照大鼠的肝脏相比，接受环丙贝特或PFDA的大鼠肝脏中PGE2、PGF2a和TXB2的浓度降低，在所使用的剂量下，环丙贝特的作用比PFDA更大。环丙贝特在10天时显著增加了肝脏LTC4浓度，PFDA在54周时显著增加，而PFDA在26周时显著降低。类花生酸浓度的这些改变可能在过氧化物酶体增殖剂诱导的肝癌发生自然史中具有重要意义。
