The relationship among microsomal enzyme induction, liver weight and histological change in beagle dog toxicology studies.
The present study represents a retrospective analysis of hepatic microsomal enzyme induction data collected over a period of years for the beagle dog. Comparisons were completed for up to six enzyme activities and P450 content versus histopathological examination of the liver for hepatic changes and serum chemistry data analysis for markers indicative of hepatic injury. In addition, qualitative comparisons were made for these compounds to data reported in the rat by the same authors. In this analysis of canine study data for nine different compounds comprising five different pharmacological classes, significant elevations in several microsomal enzyme activities were observed under study conditions that did not result in liver weight increases, histological changes or serum chemistry changes that would be indicative of hepatocellular or hepatobiliary damage. Despite some species differences in cytochrome P450 homologues, for this compound set, there was clearly a general association between the response in dog liver and that of the rat liver. Compounds that elicited significant increases in more than one canine P450 endpoints were also likely to produce an inductive response in rat liver; however, the magnitude of the response and the P450 endpoint involved were not always identical. We conclude that hepatic drug-metabolizing enzyme induction in the beagle dog liver is typically a benign adaptive response, which parallels that reported previously in the rat.
Amacher
D E
DE
Drug Safety Evaluation, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. david_e_amacher@groton.pfizer.com
Schomaker
S J
SJ
Burkhardt
J E
JE
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D023381:Endpoint Determination; D004790:Enzyme Induction; D005189:False Positive Reactions; D005260:Female; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D012016:Reference Values; D018675:Toxicity Tests
D003577:Cytochrome P-450 Enzyme System