Arachidonic acid metabolism by dioxin-induced cytochrome P-450: a new hypothesis on the role of P-450 in dioxin toxicity.

Rifkind AB, Gannon M, Gross SS
Biochem Biophys Res Commun. 1990 172 (3): 1180-8

PMID: 2123101

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) is a highly potent inducer of cytochrome P-450. The role of the induced P-450 in TCDD toxicity has been obscure as P-450 neither detoxifies TCDD nor activates it to genotoxic or cytotoxic metabolites. We show, using a chick embryo model, that TCDD causes major increases in the NADPH dependent metabolism of arachidonic acid (AA), a predominant cell membrane fatty acid, that it does so with extremely high potency (ED50, 6.3 pmol per egg) and that this metabolism is catalyzed by TCDD-induced cytochrome P-450 species. Thus, TCDD treatment increased by six to ten fold the P-450 mediated hepatic microsomal metabolism of AA to epoxides and monohydroxyeicosatetraenoic acids, products whose diverse biological activities suggest links to TCDD's toxic effects. In contrast only x and x-1 hydroxy AA, inactive products, were significantly formed by the controls. These findings open a new perspective on how P-450 induction could be related to the diverse toxic effects of TCDD. They lead to the novel hypothesis that TCDD-induced cytochrome P-450 metabolizes an endogenous fatty acid to reactive products that in turn mediate or modulate varied manifestations of TCDD toxicity.

MeSH Terms (11)

Animals Arachidonic Acid Arachidonic Acids Chick Embryo Chromatography, High Pressure Liquid Cytochrome P-450 Enzyme System Edema Enzyme Induction Microsomes, Liver Models, Biological Polychlorinated Dibenzodioxins

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