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Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor-β1 gene expression in the rat, Syrian hamster and guinea pig

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Author: Lake, B.G. · Rumsby, P.C. · Price, R.J. · Cunninghame, M.E.
Type:article
Date:2000
Institution: TNO BIBRA TNO Kwaliteit van Leven
Source:Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 2, 448, 213-225
Identifier: 280420
doi: doi:10.1016/S0027-5107(99)00238-9
Keywords: Hepatic peroxisome proliferation · Replicative DNA synthesis · Species differences · Syrian hamster · Transforming growth factor-β1 · ciprofibrate · messenger RNA · methylclofenapate · peroxisome proliferator · peroxisome proliferator activated receptor · pirinixic acid · somatomedin B receptor · transforming growth factor beta1 · animal model · animal tissue · cell division · controlled study · DNA synthesis · enzyme activity · fatty acid oxidation · liver weight · nonhuman · species difference · Syrian hamster · Animals · Cell Division · Clofenapate · Clofibric Acid · Cricetinae · DNA · Gene Expression · Guinea Pigs · Liver · Male · Mesocricetus · Molecular Structure · Organ Size · Peroxisome Proliferators · Pyrimidines · Rats · Rats, Sprague-Dawley · Receptor, IGF Type 2 · Species Specificity · Transforming Growth Factor beta · Cavia · Cavia porcellus · Cricetinae · Mesocricetus auratus · Rodentia · Sus scrofa · Zea mays

Abstract

The objective of this study was to evaluate species differences in the hepatic effects of three potent rodent peroxisome proliferators, namely methylclofenapate (MCP), ciprofibrate (CIP) and Wy-14,643 (WY), particularly with respect to effects on replicative DNA synthesis and transforming growth factor-β1 (TGF-β1) gene expression. Male Sprague-Dawley rats, Syrian hamsters and Dunkin-Hartley guinea pigs were given daily oral doses of 0 (corn oil) and 75 mg/kg MCP for periods of 6 and 21 days. Syrian hamsters and guinea pigs were also treated with 25 mg/kg CIP and 25 mg/kg WY. Relative liver weights were significantly increased in peroxisome proliferator-treated rats and Syrian hamsters, but not in guinea pigs. Hepatic peroxisomal (palmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty acid oxidising enzyme activities and CYP4A isoform mRNA levels were significantly increased in rats and Syrian hamsters, whereas only minor effects were observed in the guinea pig. Replicative DNA synthesis was studied by implanting 7-day osmotic pumps containing 5-bromo-2'-deoxyuridine during study days -1 to 6 and 14 to 21. Hepatocyte labelling index values were increased by MCP in the rat, but neither MCP, CIP nor WY produced any significant effect on replicative DNA synthesis in the Syrian hamster and guinea pig. MCP treatment increased TGF-β1 and insulin-like growth factor II/mannose-6-phosphate (IGFII/Man6P) receptor gene expression in the rat. In the Syrian hamster, effects on TGF-β1 and IGFII/Man6P receptor gene expression were also observed in some instances, whereas TGF-β1 mRNA levels were essentially unchanged in the guinea pig. These results provide further evidence for marked species differences in response to rodent peroxisome proliferators. While peroxisome proliferators produce a wide spectrum of effects in rat liver, other species such as the Syrian hamster and guinea pig are less responsive and in the case of some endpoints (e.g., cell replication) may be refractory. Copyright (C) 2000 Elsevier Science B.V. Chemicals/CAS: ciprofibrate, 52214-84-3; Clofenapate, 21340-68-1; Clofibric Acid, 882-09-7; DNA, 9007-49-2; Peroxisome Proliferators; pirinixic acid, 50892-23-4; Pyrimidines; Receptor, IGF Type 2; Transforming Growth Factor betaChemicals/CAS: ciprofibrate, 52214-84-3; Clofenapate, 21340-68-1; Clofibric Acid, 882-09-7; DNA, 9007-49-2; Peroxisome Proliferators; pirinixic acid, 50892-23-4; Pyrimidines; Receptor, IGF Type 2; Transforming Growth Factor beta