Induction of peroxisomal fatty acyl-CoA oxidase and microsomal laurate hydroxylase activities by beclobric acid and two metabolites in primary cultures of rat hepatocytes.

Beclobrate [2-(4-[(4-chlorophenyl)methyl]phenoxy)-2-methylbutyric acid ethyl ester], a structural analog of clofibrate, is used clinically as a lipid-lowering agent. Although, like clofibrate, beclobrate produces a profound hepatomegalic response in rodents, no studies of this drug on hepatic peroxisome proliferation have appeared. We have examined, relative to clofibric acid (CPIB), the concentration-dependent effects of beclobric acid (Beclo), the activity moiety of beclobrate, and two oxidized metabolites [a carbinol (M2) and a benzophenone (M3)] on peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) activities in primary cultures of rat hepatocytes. All compounds induced FACO and LH activities in a concentration-dependent manner after a 72 hr incubation with the cultured cells. Beclo was 4.8- and 6.5-fold more potent than CPIB as an inducer of FACO and LH respectively. M2 and M3 were more potent than Beclo as inducers of FACO and LH. Additionally, all compounds produced significant elevations relative to untreated control cultures in cellular lactate dehydrogenase activity (1.6- to 2.2-fold). We conclude that (1) Beclo is more potent than CPIB as an inducer of peroxisome proliferation-associated enzyme activities; (2) two metabolites of Beclo are more potent than the parent molecule as inducers of these activities and (3) these metabolites may contribute to the lipid-lowering and/or hepatomegalic effects of beclobrate in rats.