Gemfibrozil-induced peroxisome proliferation and hepatomegaly in male F344 rats.
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.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015248:Gemfibrozil / Q000633:toxicity*; D006529:Hepatomegaly / Q000139:chemically induced*; D006801:Humans; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D011743:Pyrimidines / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D000960:Hypolipidemic Agents; D011743:Pyrimidines; C006253:pirinixic acid; D015248:Gemfibrozil