HEPATIC-MICROSOMAL ENZYME-INDUCTION, BETA-OXIDATION, AND CELL-PROLIFERATION FOLLOWING ADMINISTRATION OF CLOFIBRATE, GEMFIBROZIL, OR BEZAFIBRATE IN THE CD RAT
De. Amacher et al., HEPATIC-MICROSOMAL ENZYME-INDUCTION, BETA-OXIDATION, AND CELL-PROLIFERATION FOLLOWING ADMINISTRATION OF CLOFIBRATE, GEMFIBROZIL, OR BEZAFIBRATE IN THE CD RAT, Toxicology and applied pharmacology, 142(1), 1997, pp. 143-150
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