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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh071
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received November 5, 2003; accepted January 2, 2004
© 2004 Society of Toxicology

In Vitro Toxicology and Alternative Testing

Characterization of the Species-Specificity of Peroxisome Proliferators in Rat and Human Hepatocytes

Manuel Ammerschlaeger 1, Jürgen Beigel 1, Kai-Uwe Klein 1, and Stefan O. Mueller 1*

1 Molecular Toxicology, Institute of Toxicology, Merck KGaA, 64271 Darmstadt, Germany

* To whom correspondence should be addressed. E-mail: stefan.o.mueller{at}merck.de.


  Abstract

Peroxisome proliferation is a well-defined pleiotropic effect that is mediated by the ligand inducible transcription factor peroxisome proliferator-activated receptor (PPAR) {alpha}. 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{alpha}-mediated reporter gene activity in rat FAO and primary hepatocytes on rat but not on human PPAR{alpha} response elements (PPREs). In contrast, in human HepG2 and primary human hepatocytes, peroxisome proliferators did not induce either human or rat PPAR{alpha} 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{alpha}. Remarkably, no distinct peroxisome proliferation related responses were observed in human hepatocytes when rat PPAR{alpha} was transfected, although human hepatocytes were responsive to PPAR{alpha}-mediated induction of carnitine palmitoyl transferase-1A and 3-hydroxy-3-methylglutaryl-CoA synthase. These results confirmed that PPAR{alpha} 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{alpha} expression.

Key Words: PPAR{alpha}, HepG2, FAO, primary hepatocytes, fibrates, Wy 14643 .


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