Effect of castration on dehydroepiandrosterone-induced hepatocarcinogenesis in male rats.

Dehydroepiandrosterone (DHEA), a peroxisome proliferator, is a hepatocarcinogen in male and female rats. The incidence of DHEA-induced hepatic tumors was much higher in males compared to females, although the peroxisome proliferative effect is similar in both sexes. In this study, we have evaluated the effect of castration in male rats on DHEA-induced hepatocarcinogenesis. Orchiectomy resulted in a significant reduction in hepatocellular carcinomas (15% in castrated rats versus 81% in control rats). However, the incidence of neoplastic nodules was comparable in both orchiectomized and control groups (84% versus 94% in orchiectomized and control groups, respectively). Sixty-two percent of livers in the control group contained tumors larger than 10 mm compared to 8% in the orchiectomized group. These findings indicate that testosterone promotes the growth of neoplastic lesions induced by DHEA.

Human peroxisome proliferator-activated receptor alpha (PPARalpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver.

Peroxisome proliferators, which function as peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, induce peroxisomal, microsomal, and mitochondrial fatty acid oxidation enzymes, in conjunction with peroxisome proliferation, in liver cells. Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. The assertion that synthetic PPARalpha ligands pose negligible carcinogenic risk to humans is attributable, in part, to the failure to observe peroxisome proliferation in human hepatocytes. To explore the mechanism(s) of species-specific differences in response to PPARalpha ligands, we determined the functional competency of human PPARalpha in vivo and compared its potency with that of mouse PPARalpha. Recombinant adenovirus that expresses human or mouse PPARalpha was produced and administered intravenously to PPARalpha-deficient mice. Human as well as mouse PPARalpha fully restored the development of peroxisome proliferator-induced immediate pleiotropic responses, including peroxisome proliferation and enhanced expression of genes involved in lipid metabolism as well as nonperoxisomal genes, such as CD36, Ly-6D, Rbp7, monoglyceride lipase, pyruvate dehydrogenase kinase-4, and C3f, that have been identified recently to be up-regulated in livers with peroxisome proliferation. These studies establish that human PPARalpha is functionally competent and is equally as dose-sensitive as mouse PPARalpha in inducing peroxisome proliferation within the context of mouse liver environment and that it can heterodimerize with mouse retinoid X receptor, and this human PPARalpha-mouse retinoid X receptor chimeric heterodimer transcriptionally activates mouse PPARalpha target genes in a manner qualitatively similar to that of mouse PPARalpha.