TCDD induces CYP1A4 and CYP1A5 in chick liver and kidney and only CYP1A4, an enzyme lacking arachidonic acid epoxygenase activity, in myocardium and vascular endothelium

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other Ah rec eptor ligands, species differences in sensitivity and the relationship of C YP1A induction to the toxicity, are poorly understood. Ah receptor ligands induce formation of CYP1A1 and 1A2 in mammals and of a different set of enz ymes, CYP1A4 and 1A5, in chicks. We examined induction by TCDD of CYP1A4 an d 1A5 mRNA and protein in chick embryo liver, heart, kidney, lung, intestin e, bursa, spleen, thymus, brain, and muscle by in situ hybridization and im munohistochemistry and verified the histochemical findings by CYP-specific assays, 7-ethoxyresorufin deethylase for CYP1A4 and arachidonic acid epoxyg enation for CYP1A5. CYP1A4 alone was extensively induced in the cardiovascu lar system, in cardiac myocytes, in perivascular cells having the same loca tion as impulse-conducting Purkinje cells, and like CYP1A1, in vascular end othelium in every organ examined. Unlike mammalian CYP1A, CYP1A4 and 1A5 we re both substantially induced in kidney proximal tubules as wed as liver, a nd neither enzyme was induced in kidney glomeruli or lung or brain parenchy mal cells. The findings demonstrate (a) a route for CYP1A4 to affect cardia c function, (b) that vascular endothelium is a major site of CYP1A inductio n across species, and (c) that CYP1A induced in heart or endothelial cells cannot affect cardiac or vascular function via generation of arachidonic ac id epoxides because the CYP1A. enzymes induced in those organs are not arac hidonic acid epoxygenases. Further, the specificity of CYP1A induction site s and of the catalytically active enzymes induced at each site support a si gnificant role for CYP1A induction in Ah receptor ligand toxicity and speci es differences in sensitivity. (C) 2000 Academic Press.