EFFECT OF PROPAQUIZAFOP AND ITS FREE-ACID DERIVATIVE ON LAURIC ACID HYDROXYLATION AND PEROXISOMAL BETA-OXIDATION IN PRIMARY CULTURED RAT, MOUSE, GUINEA-PIG AND MARMOSET HEPATOCYTES

The effects of the phenoxyisopropionic acid derivative propaquizafop and its free-acid derivative on microsomal lauric acid hydroxylase and peroxisomal fatty acyl-CoA beta-oxidation have been investigated in primary cultured hepatocytes obtained from various species and compared with those induced by bezafibrate. The hepatocyte cultures were incubated with these compounds for 48 hr at concentrations between 0.1-100 mum. No signs of cytotoxicity were observed as shown by the lack of lactate dehydrogenase (LDH) release into the culture medium. Lauric acid 12-hydroxylase was found to be strongly induced after treatment of mt and mouse hepatocytes with all three compounds, but remained largely unaffected in guinea pig and marmoset hepatocytes. Concomitantly, peroxisomal fatty acyl-CoA beta-oxidation was found to be induced in mt but not in mouse hepatocytes after treatment for 48 hr. However, clearly increased beta-oxidation activities could also be observed in mouse hepatocytes after a 72-hr incubation period. In contrast, only marginally increased beta-oxidation activities were recorded, if at all, in guinea pig and marmoset hepatocytes. The results demonstrate that the effects of propaquizafop and its free-acid derivative in hepatocytes from four species are very similar to those produced by the known peroxisome proliferator (PP) bezafibrate. This is in accordance with the known difference in susceptibility of various species to PP, for example, rats and mice being most responsive whereas guinea pigs and primates including humans are far less responsive or even unresponsive.