Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor-beta 1 gene expression in the rat, Syrian hamster and guinea pig

The objective of this study was to evaluate species differences in the hepa tic effects of three potent rodent peroxisome proliferators, namely methylc lofenapate (MCP), ciprofibrate (CIP) and Wy-14,643 (WY), particularly with respect to effects on replicative DNA synthesis and transforming growth fac tor-beta 1 (TGF-beta 1) gene expression. Male Sprague-Dawley rats, Syrian h amsters and Dunkin-Hartley guinea pigs were given daily oral doses of 0 (co rn 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 l iver weights were significantly increased in peroxisome proliferator-treate d rats and Syrian hamsters, but not in guinea pigs. Hepatic peroxisomal (pa lmitoyl-CoA oxidation) and microsomal (lauric acid 12-hydroxylase) fatty ac id oxidising enzyme activities and CYP4A isoform mRNA levels were significa ntly increased in rats and Syrian hamsters, whereas only minor effects were observed in the guinea pig. Replicative DNA synthesis was studied by impla nting 7-day osmotic pumps containing 5-bromo-2'-deoxyuridine during study d ays -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 eff ect on replicative DNA synthesis in the Syrian hamster and guinea pig. MCP treatment increased TGF-beta 1 and insulin-like growth factor II/mannose-6- phosphate (IGFII/Man6P) receptor gene expression in the rat. In the Syrian hamster, effects on TGF-beta 1 and IGFII/Man6P receptor gene expression wer e also observed in some instances, whereas TGF-beta 1 mRNA levels were esse ntially unchanged in the guinea pig. These results provide further evidence for marked species differences in response to rodent peroxisome proliferat ors. While peroxisome proliferators produce a wide spectrum of effects in r at 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 b e refractory. (C) 2000 Elsevier Science B.V. All rights reserved.