Peroxisomal Enzymes and 8-Hydroxydeoxyguanosine in Rat Liver Treated with Perfluorooctanoic Acid

Although peroxisome proliferators are considered non-genotoxic agents, most of them, nevertheless, were found to promote and/or induce, hepatocellular carcinoma (HCC) in rodents. The aim of the present study is, first, to investigate whether the peroxisome proliferator perfluorooctanoic acid (PFOA) possesses inherent liver cancer promoting activity, and second, to study the possible mechanisms involved. To acheive these aims two protocols have been applied, a biphasic protocol (initiation by diethyl-nitrozamine (DEN) 200 mg/kg i.p. followed by treatment with 0.005% or 0.02% perflourooctanoic acid (PFOA) for 14 and 25 weeks) and a triphasic initiation, selection-promotion (IS) protocol (initiation by giving 200 mg/kg DEN i.p. followed by a selection procedure for 2 weeks consisting of giving 0.03% 2-acetylaminofluorene (2-AAF) in diet). In the middle of this treatment a single oral dose of carbon tetrachloride (2.0 ml/kg) was given, followed by giving diet containg 0.015% of PFOA for 25 weeks. After applying both protocols, our results showed slight increase in the catalase activity while acyl CoA oxidase activity was markedly increased. Both experiments indicated that PFOA has a liver cancer promoting activity. Other groups of rats were given either basal diet or diet containing 0.02% PFOA. Five or nine weeks later they were sacrificed and the levels of 8-hydroxydeoxyguanosine in the isolated DNA were estimated. The data showed a slight nonetheless insignificant increase in 8-hydroxydeoxyguanosine. From the present data, it is concluded that PFOA is a true liver cancer promoter that may not require extensive initial DNA damage for its promoting activity.

[1]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[2]  C. Hignite,et al.  HYPOLIPIDEMIC HEPATIC PEROXISOME PROLIFERATORS FORM A NOVEL CLASS OF CHEMICAL CARCINOGENS , 1980 .

[3]  Y. Yun,et al.  Formation of 8-oxodeoxyguanosine in liver DNA and hepatic injury by peroxisome proliferator clofibrate and perfluorodecanoic acid in rats. , 1998, The Journal of toxicological sciences.

[4]  E. Staffeldt,et al.  Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. , 1971, Cancer research.

[5]  R. Cattley,et al.  Possible mechanisms in hepatocarcinogenesis by the peroxisome proliferator di(2-ethylhexyl)phthalate. , 1989, Drug metabolism reviews.

[6]  M. Rao,et al.  Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis. , 1989, Mutation research.

[7]  R. Schulte‐Hermann,et al.  Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in rodents and its implications on human risk. , 1996, Critical reviews in toxicology.

[8]  K P Lee,et al.  Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. , 1987, Experimental and molecular pathology.

[9]  J. Vamecq,et al.  Implication of a peroxisomal enzyme in the catabolism of glutaryl-CoA. , 1984, The Biochemical journal.

[10]  P. Baudhuin,et al.  Tissue fractionation studies. 17. Intracellular distribution of monoamine oxidase, aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase and catalase in rat-liver tissue. , 1964, The Biochemical journal.

[11]  N. Lalwani,et al.  Excessive accumulation of autofluorescent lipofuscin in the liver during hepatocarcinogenesis by methyl clofenapate and other hypolipidemic peroxisome proliferators. , 1982, Cancer research.

[12]  J. Corton,et al.  Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. , 2000, Annual review of pharmacology and toxicology.

[13]  M. Roberfroid,et al.  Peroxisome proliferation and modulation of rat liver carcinogenesis by 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, perfluorooctanoic acid and nafenopin. , 1990, Carcinogenesis.

[14]  M Tanaka,et al.  The induction of peroxisome proliferation in rat liver by perfluorinated fatty acids, metabolically inert derivatives of fatty acids. , 1985, Journal of biochemistry.

[15]  R. Cattley,et al.  Possible Mechanisms in Hepatocarcinogensis by the Peroxisome Proliferator Di(2-Ethylhexyl)Phthalate , 1989 .

[16]  K. Wallace,et al.  Perfluorooctanoate, perflourooctanesulfonate, and N-ethyl perfluorooctanesulfonamido ethanol; peroxisome proliferation and mitochondrial biogenesis. , 2002, Toxicology letters.

[17]  T. Suga,et al.  Different regulation of hepatic peroxisomal beta-oxidation activity in rats treated with clofibrate and partially hydrogenated marine oil. , 1990, Biochemical and biophysical research communications.

[18]  M. Wilson,et al.  Increased 8-hydroxydeoxyguanosine in hepatic DNA of rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid. , 1994, Cancer letters.

[19]  J. Reddy,et al.  Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. , 1983, Critical reviews in toxicology.

[20]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[21]  D. Noonan,et al.  Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids. , 1998, General pharmacology.

[22]  G. Ramadori,et al.  Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury. , 1995, Gastroenterology.

[23]  J. Reddy,et al.  Peroxisome proliferation and lipid peroxidation in rat liver. , 1986, Cancer research.

[24]  J. Ward,et al.  Dissimilar patterns of promotion by di(2-ethylhexyl)phthalate and phenobarbital of hepatocellular neoplasia initiated by diethylnitrosamine in B6C3F1 mice. , 1983, Carcinogenesis.

[25]  C. Elcombe,et al.  Lack of DNA damage or lipid peroxidation measured in vivo in the rat liver following treatment with peroxisomal proliferators. , 1987, Carcinogenesis.

[26]  R. Schulte‐Hermann.  Tumor promotion in the liver , 1985, Archives of Toxicology.

[27]  Y Kurokawa,et al.  Short-term exposure to the peroxisome proliferators, perfluorooctanoic acid and perfluorodecanoic acid, causes significant increase of 8-hydroxydeoxyguanosine in liver DNA of rats. , 1991, Cancer letters.

[28]  J. Reddy,et al.  Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator. , 1989, Cancer research.

[29]  J. Carrino,et al.  Transcription regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Reddy,et al.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens , 1980, Nature.

[31]  M. Roberfroid,et al.  Phenobarbital as a promoter in the initiation/selection process of experimental rat hepatocarcinogenesis. , 1983, Carcinogenesis.

[32]  D. Grandér,et al.  Reactive oxygen species and mitochondria mediate the induction of apoptosis in human hepatoma HepG2 cells by the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid. , 2001, Toxicology and applied pharmacology.