De. Amacher et al., THE RELATIONSHIP AMONG MICROSOMAL-ENZYME INDUCTION, LIVER WEIGHT AND HISTOLOGICAL CHANGE IN RAT TOXICOLOGY STUDIES, Food and chemical toxicology, 36(9-10), 1998, pp. 831-839
The purpose of this study was to determine what histological changes,
if any, accompany liver enlargement and microsomal enzyme induction in
rats administered high doses of therapeutic agents in preclinical tox
icology studies. This was accomplished by evaluating a database derive
d from a series of 11 induction studies in rats with 10 novel compound
s comprising five therapeutic classes. Results from serum enzyme chemi
stry analyses, gross organ weight changes, and histological analyses o
f the liver sections were evaluated and compared with the magnitude an
d extent of hepatic cytochrome P450 induction. All compounds were admi
nistrated via oral intubation once a day for the duration of the study
using multiple doses, each proportionally based on body weight. Durin
g the course of these studies, serum clinical chemistry data and clini
cal observations were recorded. After necropsy, histopathology observa
tions were made, and hepatic microsomes were assayed for cytochrome P4
50 content and associated drug-metabolizing enzymes. In some cases, cy
anide-insensitive beta-oxidation of palmitoyl CoA was also assayed. Li
ver weight increases of 20% or greater were associated with histologic
al evidence of hypertrophy, but neither the severity of hypertrophy no
r the magnitude of liver weight increase correlated with the magnitude
of drug-metabolizing enzyme elevations. Hypertrophy alone was not ass
ociated with serum enzyme increases. While there was a correlation bet
ween the incidence of increased liver weights and microsomal enzyme in
duction, the magnitudes of these increases were not related. Decreased
serum triglycerides were often associated with elevated beta-oxidatio
n attributed to hepatic peroxisome proliferation. It was concluded tha
t, while slight ALT elevations occasionally were observed, hepatic mic
rosomal enzyme induction was generally not accompanied by substantial
morphological changes or elevated serum enzyme levels considered indic
ative of liver injury. (C) 1998 Elsevier Science Ltd. All rights reser
ved.