Hepatocellular proliferation in ibuprofen-treated mice.
Female B6C3F1 mice were treated with ibuprofen for 2 wk or 90 days to monitor effects on hepatocellular proliferation during acute and subchronic exposure. Proliferation was assessed by bromodeoxyuridine labeling. Mice treated with 100, 200, or 400 mg/kg ibuprofen for 2 wk had significantly increased liver weights. A dose-related increase in the number of labeled hepatocytes per 1,000 hepatocytes suggested that the weight increases were in part a result of hepatocellular proliferation. Hepatocellular hypertrophy also contributed to the increased liver size as indicated by decreases in the number of hepatocytes per high power field. Ultrastructural evaluation indicated that hepatocyte peroxisome size increased significantly in treated mice. Mice treated with 100 or 200 mg/kg ibuprofen for 90 days and given bromodeoxyuridine during the last 2 wk of ibuprofen exposure had statistically significant increases in relative liver weights. However, the number of labeled hepatocytes per 1,000 hepatocytes was not increased, and there was no evidence of hepatocellular hypertrophy. Mice given 200 mg/kg ibuprofen for 90 days had significantly decreased serum triglycerides. These findings indicate that ibuprofen treatment of mice results in hepatomegaly characterized by hepatocellular hypertrophy and hyperplasia. Peroxisomal changes may be contributory to the pathogenesis of this lesion.
Toxicology Division, Eli Lilly and Co., Greenfield, Indiana 46140.
A M
AM
Bendele
J F
JF
Hulman
S
S
White
C
C
Brodhecker
R A
RA
Bendele
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007052:Ibuprofen / Q000633:toxicity*; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000187:drug effects; D008854:Microscopy, Electron; D009929:Organ Size / Q000187:drug effects; D013997:Time Factors
D007052:Ibuprofen