Effects of chronic treatment with the leukotriene D4-antagonist compound LY171883 on B6C3F1 mice.
A 2-year toxicity/oncogenicity study was done to evaluate the potential effects of the leukotriene antagonist LY171883 in B6C3F1 mice. Dietary concentrations of LY171883 during the initial 7 months of the study were 0.0, 0.005, 0.015, or 0.05% but were increased to 0.0, 0.0075, 0.0225, or 0.075% during Months 7 through 24. The estimated average daily compound intake was 0.0, 7.3, 22.5, or 80.5 mg/kg for males and 0.0, 9.2, 27.5, or 95.9 mg/kg for females. Survival was not adversely affected by treatment, however, body weight of males and females in the high dose group was significantly lower than that of controls. The chronic toxicity was localized primarily to the liver. Liver weights were increased in males in the high dose group and in females in the mid and high dose groups. Microsomal p-nitroanisole-O-demethylase activity was increased in mid and high dose females. Hepatic peroxisomal beta-oxidation was increased approximately twofold in both sexes in the high dose group only. Centrilobular eosinophilic granular change of hepatocytes was a common histopathologic finding in male and female mice in the high dose group, with the incidence and severity being greater in females. An increased incidence of hepatocellular carcinomas was observed in female mice in the mid and high dose groups. The number of male mice in the high dose group with hepatocellular carcinomas was higher than that of controls but the change was not statistically significant. Hepatocellular adenomas were increased in females in the high dose group but not in males. All groups of treated females had increased nodular hepatocellular hyperplasia.(ABSTRACT TRUNCATED AT 250 WORDS)
Bendele
A M
AM
Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, Indiana 46140.
Hoover
D M
DM
van Lier
R B
RB
Foxworthy
P S
PS
Eacho
P I
PI
D000098:Acetophenones / Q000633:toxicity*; D000818:Animals; D012898:Autacoids / Q000037:antagonists & inhibitors*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D004032:Diet; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D013189:SRS-A / Q000037:antagonists & inhibitors*; D012737:Sex Factors; D013777:Tetrazoles / Q000633:toxicity*
D000098:Acetophenones; D012898:Autacoids; D002273:Carcinogens; D013189:SRS-A; D013777:Tetrazoles; C044660:LY 171883; D009575:Nitroanisole O-Demethylase