Induction of microsomal and peroxisomal fatty acid oxidation by chlorophenoxy acid herbicides.

Induction of the cytochrome P-450 mixed-function oxidase and specifically the cytochrome P-450 IVA1 isoenzyme by seven phenoxy acid herbicides in rat liver and kidney, have been studied. results using liver microsomes demonstrated that the 12-hydroxylation of lauric acid was significantly induced by all compounds (3-8-fold), 4-chlorophenoxyacetic acid (CPA) (300 mg/kg) being the weakest and 2,4,5-trichlorophenoxypropionic acid (2,4,5-TP) (200 mg/kg) the most potent inducers respectively. This increase in lauric acid 12-hydroxylase-activity was accompanied by an increase in the hepatic content of cytochrome P-450 IVA1 as assessed by both a qualitative Western blot procedure and a quantitative ELISA method. Furthermore, there was a parallel increase in cytochrome P-450 IVA1 mRNA and a similar increase in peroxisomal B-oxidation subsequent to exposure to these compounds. In addition, benzphetamine-N-demethylase, a marker of cytochrome P-450 IIBl and IIB2 activities, was not affected by any of the herbicides, whereas cytochrome P-450 IA1 and IA2, as assayed by ethoxyresorufin-O-deethylase activity, was significantly increased (up to 2.2-fold) by some of the compounds. Kidney microsomal parameters were not affected by any of these compounds. My in vivo studies using antipyrine, pentobarbital and zoxazolamine indicated that the metabolism of these substrates was marginally affected by only some of the compounds. In order to highlight the possible involvement of a metabolite of the chlorophenoxy acids in the induction of cytochrome P-450, I investigated four related chlorophenols. There was no significant change in cytochrome P-450 isoenzyme levels in rat liver and kidney microsomes nor was there any increase in peroxisomal beta-oxidation. Taken collectively, the results presented in this thesis indicate that the chlorinated phenoxy acid herbicides studied preferentially induce the cytochrome P-450 IVA1 isoenzyme and peroxisomal beta-oxidation in a pattern similar to the typical inducers of this isoenzyme such as clofibrate. A scheme is presented whereby induction of catalytically competent cytochrome P-450 IVA1 is required for the phenomenon of peroxisome proliferation by these chlorophenoxy acid derivatives