GEMFIBROZIL-INDUCED PEROXISOME PROLIFERATION AND HEPATOMEGALY IN MALEF344 RATS

Gemfibrozil is a widely used hypolipidemic drug in humans that causes peroxisome proliferation and hepatocarcinogenesis in rodents. The indu ction of hepatomegaly and hepatic peroxisome proliferation (measured a s peroxisomal acyl CoA oxidase activity), was determined and compared to another peroxisome proliferator, WY-14,643 (0.1% in the diet) in ma le F344 rats. In a 21-day study, dietary no-observable-effect and lowe st-observable-effect levels of gemfibrozil for both hepatomegaly and p eroxisome proliferation were 0.002% and 0.005%, respectively. In a 42- day study, dietary concentrations of 0.9-2.0% gemfibrozil induced a si milar magnitude of hepatomegaly to WY-14,643 (2.3-fold) but a higher l evel of peroxisome proliferation (16-18-fold) than the maximum inducti on for WY-14,643 (13-fold). The plateau in magnitude of gemfibrozil-in duced peroxisome proliferation across the 0.9-2.0% dietary concentrati ons was associated with a plateau in serum concentration of gemfibrozi l (similar to 20 mu g/ml), similar to concentrations reported in human subjects receiving oral gemfibrozil. These results indicate that maxi mal induction of peroxisome proliferation by gemfibrozil can exceed th at of a more potent compound such as WY-14,643, and further suggest th at maximal induction of peroxisome proliferation can be limited by ste ady-state serum concentrations. Moreover, the reported lack of hepatic responses to gemfibrozil in humans is unlikely to be the result of in efficacy or unavailability of this drug, compared to other peroxisome proliferators, in rodents.