HEPATIC-MICROSOMAL ENZYME-INDUCTION, BETA-OXIDATION, AND CELL-PROLIFERATION FOLLOWING ADMINISTRATION OF CLOFIBRATE, GEMFIBROZIL, OR BEZAFIBRATE IN THE CD RAT

Male and female CD rats were administered one of two dose levels of cl ofibrate, gemfibrozil, or bezafibrate daily by oral gavage for a perio d of 14 days in order to establish an empirical data base using the Ch arles River CD rat with a single class of drugs against which the pote ncy of novel proprietary compounds could be compared. Subsequent gross examination of the liver indicated significant and dose-related incre ases in relative and absolute liver weights in males following clofibr ate and gemfibrozil. In females, absolute and relative liver weights w ere significantly elevated to a similar degree with either dose of gem fibrozil, and absolute liver weights were higher in clofibrate-dosed a nimals. Bezafibrate had no effect on female liver weights. Clofibrate and gemfibrozil increased hepatic palmitoyl CoA beta-oxidation in both sexes; however, clofibrate had the greater effect in males and gemfib rozil had the least effect in females. Bezafibrate treatment resulted in a very pronounced elevation of palmitoyl CoA beta-oxidation in the males but had no similar effect in the females. Concurrent ELISA analy sis for cytochrome CYP4A revealed very good correspondence between bet a-oxidation and cytochrome induction for each of the three compounds i n males, but other cytochromes were not greatly affected, except CYP1A 1 which was elevated in bezafibrate-dosed females. For males, further analysis for markers of cellular proliferation, namely cyclin-dependen t kinases (CDK) and proliferating cell nuclear antigen (PCNA), indicat ed dose-related increases for both with clofibrate, increases at the h igh dose for gemfibrozil, and, for PCNA, a dose-related increase for b ezafibrate. In females, both markers for cell proliferation showed eit her slight or no increases following any of the three drug treatments. These results demonstrate clear sex-dependent differences in terms of relative potency in the hepatic response of the Sprague-Dawley-derive d rat to these peroxisome proliferators. Bezafibrate is most potent an d gemfibrozil is least potent in stimulating peroxisome-associated bet a-oxidation and cytochrome P450 4A induction in the males. Even though gemfibrozil significantly increased liver weights, beta-oxidation and cytochrome P450 4A in the females increased only after clofibrate tre atment, although to a lesser degree than in the males administered the same dose. Similar sex-related differences were observed for cell pro liferation. In conclusion, sex-related differences were noted in the p otency to stimulate acyl Go-A oxidation, its association with hepatome galy, and the stimulation of cell proliferation, but CYP4A induction a lways accompanied any substantial drug-dependent increases in beta-oxi dation. (C) 1997 Academic Press