Role of testosterone in the induction of hepatic peroxisome proliferation by clofibrate.
Hepatic peroxisome proliferation is induced by a number of agents, including clofibrate. Sustained proliferation of peroxisomes is associated with the development of hepatocellular carcinoma. In the present study, we have investigated the role of testosterone in peroxisome proliferation induced by clofibrate. Three groups of male rats (intact, castrated, and castrated replaced with testosterone) were studied. Proliferation of peroxisomes was induced by feeding clofibrate (0.25%, 0.50%, and 1.0% of diet) for 2 weeks. Peroxisome proliferation was monitored by measuring total peroxisomal beta-oxidation activity. In intact rats, the peroxisomal beta-oxidation activity (nmol/min/mg protein) increased in a dose-dependent manner and was 7.2 +/- 0.4, 52.6 +/- 7.5, 63.2 +/- 3.7, and 92.4 +/- 4.0 at clofibrate doses of 0%, 0.25%, 0.50%, and 1.0%, respectively. In contrast, in castrated rats, the total peroxisomal beta-oxidation activity was significantly (P < .01) lower at clofibrate levels of 0.25% and 0.50% (25.8 +/- 2.7 and 42.5 +/- 2.2, respectively), but not at the clofibrate level of 1.0% (85.0 +/- 6.3). Testosterone replacement of castrated rats restored the peroxisomal beta-oxidation activity. To determine whether the above results were related to the metabolism of clofibrate in the absence or presence of testosterone, we measured serum clofibrate levels. These levels were 50% lower in castrated rats than in intact rats or in testosterone-treated castrated rats. The activity of hepatic uridine diphosphate (UDP)-glucuronyltransferase, the enzyme catalyzing the glucuronidation of clofibrate, was measured using either bilirubin or 4-methylumbelliferone as substrates and was found to be unaffected by castration or testosterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Paul
H S
HS
Department of Medicine, University of Pittsburgh School of Medicine, PA.
Sekas
G
G
Winters
S J
SJ
D000818:Animals; D002994:Clofibrate / Q000097:blood / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure*; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000648:ultrastructure*; D009929:Organ Size; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood / Q000502:physiology*
D013739:Testosterone; D014453:Glucuronosyltransferase; D002994:Clofibrate