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.