ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 78, 229-240 (2004)
Toxicological Sciences vol. 78 no. 2 © Society of Toxicology; all rights reserved.
Characterization of the Species-Specificity of Peroxisome Proliferators in Rat and Human Hepatocytes
Molecular Toxicology, Institute of Toxicology, Merck KGaA, 64271 Darmstadt, Germany
Received November 5, 2003; accepted January 2, 2004
Peroxisome proliferation is a well-defined pleiotropic effect that is mediated by the ligand inducible transcription factor peroxisome proliferator-activated receptor (PPAR) 
. Because marked peroxisome proliferation occurs in rodents but not in humans, we aimed to elucidate the molecular and cellular determinants of this species-specificity in hepatocytes. Analysis of peroxisomal marker enzyme activities confirmed that peroxisome proliferators induced acyl-CoA oxidase (ACOX) and to a lesser extent catalase in rat hepatocytes, but not in human hepatoma HepG2 cells. Transient transfection assays revealed that ciprofibrate and Wy 14,643 induced rat but not human PPAR-mediated reporter gene activity in rat FAO and primary hepatocytes on rat but not on human PPAR response elements (PPREs). In contrast, in human HepG2 and primary human hepatocytes, peroxisome proliferators did not induce either human or rat PPAR activity regardless of rat or human PPRE sequences. In addition, no induction of ACOX gene expression was observed in human hepatocytes independent of the expression level of human PPAR. Remarkably, no distinct peroxisome proliferation related responses were observed in human hepatocytes when rat PPAR was transfected, although human hepatocytes were responsive to PPAR-mediated induction of carnitine palmitoyl transferase-1A and 3-hydroxy-3-methylglutaryl-CoA synthase. These results confirmed that PPAR and PPREs are important determinants for the species-specificity of peroxisome proliferation. Nevertheless, our results showed that human hepatocytes limit the extent of peroxisome proliferation regardless of PPAR expression.
Key Words: PPAR; HepG2; FAO; primary hepatocytes; fibrates; Wy 14643.
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