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 clofibrate, gemfibrozil, or bezafibrate daily by oral gavage for a period of 14 days in order to establish an empirical data base using the Charles River CD rat with a single class of drugs against which the potency of novel proprietary compounds could be compared. Subsequent gross examination of the liver indicated significant and dose-related increases in relative and absolute liver weights in males following clofibrate and gemfibrozil. In females, absolute and relative liver weights were significantly elevated to a similar degree with either dose of gemfibrozil, and absolute liver weights were higher in clofibrate-dosed animals. 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 gemfibrozil 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 analysis for cytochrome CYP4A revealed very good correspondence between beta-oxidation and cytochrome induction for each of the three compounds in males, but other cytochromes were not greatly affected, except CYP1A1 which was elevated in bezafibrate-dosed females. For males, further analysis for markers of cellular proliferation, namely cyclin-dependent kinases (CDK) and proliferating cell nuclear antigen (PCNA), indicated dose-related increases for both with clofibrate, increases at the high dose for gemfibrozil, and, for PCNA, a dose-related increase for bezafibrate. In females, both markers for cell proliferation showed either 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-derived rat to these peroxisome proliferators. Bezafibrate is most potent and gemfibrozil is least potent in stimulating peroxisome-associated beta-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 treatment, although to a lesser degree than in the males administered the same dose. Similar sex-related differences were observed for cell proliferation. In conclusion, sex-related differences were noted in the potency to stimulate acyl Co-A oxidation, its association with hepatomegaly, and the stimulation of cell proliferation, but CYP4A induction always accompanied any substantial drug-dependent increases in beta-oxidation.
Amacher
D E
DE
Drug Safety Evaluation, Cellular Toxicology Laboratory, Pfizer Central Research, Groton, Connecticut 06340, USA.
Beck
R
R
Schomaker
S J
SJ
Kenny
C V
CV
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001629:Bezafibrate / Q000494:pharmacology*; D002994:Clofibrate / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics
D000924:Anticholesteremic Agents; D007527:Isoenzymes; D018809:Proliferating Cell Nuclear Antigen; D010171:Palmitoyl Coenzyme A; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019363:Cytochrome P-450 CYP1A1; D042926:Cytochrome P-450 CYP4A; D018844:Cyclin-Dependent Kinases; D002994:Clofibrate; D015248:Gemfibrozil; D001629:Bezafibrate