Hepatotumorigenicity and peroxisome proliferation induced by the hypolipidemic CI-924 in a two-year study in male and female B6C3F1 mice.
The hepatic tumorigenicity of CI-924 (5,5'-(1,1'-biphenyl)-2,5-diylbis(oxy)(2,2-dimethylpentanoic acid)), a hypolipidemic agent, was evaluated in 50 B6C3F1 mice/sex/dose given drug in the diet at 0, 5, 25, and 75 mg/kg/day for 2 yr. Peroxisomal and drugmetabolizing enzyme determinations, as well as ultrastructural evaluations, were conducted in subsets of these same groups, because drugs of this class cause peroxisome proliferation and hepatic tumors in rodents. CI-924 elicited dose-dependent increases in the incidence of hepatocellular adenomas and carcinomas in both sexes that were statistically significant at 75 mg/kg. Stereologic evaluation revealed significant increases in hepatocellular peroxisome volume ratio, due to increased numbers of peroxisomes, in females at all doses and males at 75 mg/kg. Peroxisomal enzyme activity measurements revealed no change in catalase, but dose-dependent increases in carnitine acetyltransferase and cyanide-insensitive beta-oxidation in both sexes. Peroxisome proliferation, determined biochemically or ultrastructurally, was twice as great in females compared to males. Total cytochrome P-450 was increased in both sexes given 75 mg/kg. There were dose-dependent decreases in glutathione S-transferase in males and increased glutathione peroxidase in both sexes at 25 and 75 mg/kg. In conclusion, this study demonstrated that while CI-924 induced hepatic tumors in male and female B6C3F1 mice the associated peroxisome proliferation, while moderate in females, was only weak in the males after 2 yr of exposure.
Walker
R M
RM
Parke-Davis Research Institute, Mississauga, Ontario, Canada. walke01@aa.wl.com
Wojcinski
Z W
ZW
Hofstra
A H
AH
King
L M
LM
Rogers
J E
JE
Baker
K W
KW
Chang
P K
PK
Smith
G S
GS
D000236:Adenoma / Q000139:chemically induced / Q000473:pathology / Q000648:ultrastructure; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004798:Enzymes / Q000097:blood; D005260:Female; D015248:Gemfibrozil / Q000031:analogs & derivatives* / Q000633:toxicity; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D018901:Peroxisomal Disorders / Q000139:chemically induced* / Q000473:pathology
D004798:Enzymes; D000960:Hypolipidemic Agents; C038574:CI 924; D003577:Cytochrome P-450 Enzyme System; D015248:Gemfibrozil