Chlorophenoxyacid herbicides induce microsomal cytochrome P-450 IVA1 (P-452) in rat liver.
Induction of the cytochrome P-450 mixed-function oxidase and specifically the cytochrome P-450 IVA1 isoenzyme by seven phenoxyacid herbicides in rat liver have been studied. Liver microsomes from rats orally treated with the herbicides at 3 dose levels showed a significant increase in total cytochrome P-450 content with 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) being the most potent inducer. Benzphetamine N-demethylation, as a marker of cytochrome P-450b (P-450 IIB1) activity, was not affected by any of the herbicides studied, whereas cytochrome P-450c (P-450 IA1), as assayed by ethoxyresorufin-O-deethylation activity, was significantly increased (up to 2.2-fold) by some of the herbicides. The 12-hydroxylation of lauric acid was significantly induced (3-8-fold) by all seven herbicides, 4-chlorophenoxyacetic acid (CPA) and 2,4,5-trichlorophenoxypropionic acid (2,4,5-TP) being the weakest and 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. By comparison, lauric acid 11-hydroxylase activity was not or only marginally increased by phenoxyacid herbicide pretreatment. Our results suggest that the phenoxyacid herbicides act as mixed inducers of the cytochrome P-450 mixed function oxidase system, preferentially inducing the cytochrome P-450 IVA1 isoenzyme.
Bacher
M A
MA
Department of Biochemistry, University of Surrey, Guildford, U.K.
Gibson
G G
GG
D000818:Animals; D002733:Chlorophenols / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006016:Glycolates / Q000494:pharmacology*; D006540:Herbicides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009929:Organ Size / Q000187:drug effects; D051381:Rats
D002733:Chlorophenols; D006016:Glycolates; D006540:Herbicides; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases