STRUCTURE-ACTIVITY-RELATIONSHIPS FOR INDUCTION OF PEROXISOMAL ENZYME-ACTIVITIES IN PRIMARY RAT HEPATOCYTE CULTURES

Rat hepatocytes were cultured for 70 hr with a series of 15 chemicals (including herbicides and derivatives, hypolipidaemic agents and other compounds) and the effects on some enzyme activities were determined. All of the compounds produced concentration-related increases in the activities of peroxisomal fatty acid beta-oxidation (palmitoyl-CoA oxidation), catalase, carnitine acetyltransferase and lauric acid 12-hydroxylase. Marked differences between the potencies of the compounds were observed but some correlations were obtained between the induction of palmitoyl-CoA oxidation and the other three enzyme activities measured. Quantitative structure-activity relationships (QSARs) were observed between the induction of palmitoyl-CoA oxidation and catalase activities and compound electronic structural parameters obtained by molecular orbital calculations (MINDO/3 method). In these studies both compound bulk molecular parameters and parameters of the free carboxyl group (present in all of the chemicals examined) were important in determining compound potencies. The existence of QSARs between biological activity and chemical structure for a series of peroxisome proliferators suggests that these compounds share a common mechanism of initiation of peroxisome proliferation in rodent liver. The data also demonstrate the usefulness of rat hepatocyte cultures for screening compounds for peroxisome proliferation and for investigating structure-activity relationships.