Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemfibrozil is a widely used hypolipidemic drug in humans that causes peroxisome proliferation and hepatocarcinogenesis in rodents. The induction of hepatomegaly and hepatic peroxisome proliferation (measured as peroxisomal acyl CoA oxidase activity), was determined and compared to another peroxisome proliferator, WY-14,643 (0.1% in the diet) in male F344 rats. In a 21-day study, dietary no-observable-effect and lowest-observable-effect levels of gemfibrozil for both hepatomegaly and peroxisome proliferation were 0.002% and 0.005%, respectively. In a 42-day study, dietary concentrations of 0.9-2.0% gemfibrozil induced a similar magnitude of hepatomegaly to WY-14,643 (2.3-fold) but a higher level of peroxisome proliferation (16-18-fold) than the maximum induction for WY-14,643 (13-fold). The plateau in magnitude of gemfibrozil-induced peroxisome proliferation across the 0.9-2.0% dietary concentrations was associated with a plateau in serum concentration of gemfibrozil (approximately 20 micrograms/ml), similar to concentrations reported in human subjects receiving oral gemfibrozil. These results indicate that maximal induction of peroxisome proliferation by gemfibrozil can exceed that of a more potent compound such as WY-14,643, and further suggest that maximal induction of peroxisome proliferation can be limited by steady-state serum concentrations. Moreover, the reported lack of hepatic responses to gemfibrozil in humans is unlikely to be the result of inefficacy or unavailability of this drug, compared to other peroxisome proliferators, in rodents.
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PMID:Gemfibrozil-induced peroxisome proliferation and hepatomegaly in male F344 rats. 749 72

Gemfibrozil, a human pharmaceutical agent, causes hepatomegaly and hepatic peroxisome proliferation in rats, which have been associated with hepatocarcinogenesis. Hamsters are less susceptible than rats to peroxisome proliferation, and no hepatotoxicity has been reported in humans using gemfibrozil. The relationship between hepatic peroxisome proliferation in rodents and human cancer risk is unclear. We investigated the metabolism and excretion of [14C]gemfibrozil in male and female Sprague-Dawley rats and Syrian golden hamsters to better understand species differences in gemfibrozil-induced toxicity. Bile-duct cannulated rats and hamsters excreted 99% and 7 to 20% of a single i.v. gemfibrozil dose in bile, respectively. Cumulative urinary and fecal excretion of gemfibrozil-derived radioactivity after a single oral dose (30 or 2000 mg/kg) were dependent on species and, in rats, on dose. Hamsters excreted 90% of the dose in urine. Rats excreted 55 to 60% of the dose in feces after the low dose and 55 to 70% in urine after the high dose, suggesting possible saturation of biliary excretion. Repeated administration of the low dose to male rats did not alter the routes of excretion compared to a single dose. Major metabolites present in urine and bile were the glucuronide conjugates of gemfibrozil, the 4'-ring hydroxylated metabolite, and the meta-benzoic acid metabolite. The extensive urinary excretion of radioactivity by hamsters and enterohepatic recycling in rats suggests that rats were exposed to a much higher effective dose of gemfibrozil, which may in part explain the previously reported species differences in gemfibrozil-induced toxicity.
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PMID:Comparative metabolism and disposition of gemfibrozil in male and female Sprague-Dawley rats and Syrian golden hamsters. 988 23