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 receptor ligands, species differences in sensitivity and the relationship of CYP1A induction to the toxicity, are poorly understood. Ah receptor ligands induce formation of CYP1A1 and 1A2 in mammals and of a different set of enzymes, CYP1A4 and 1A5, in chicks. We examined induction by TCDD of CYP1A4 and 1A5 mRNA and protein in chick embryo liver, heart, kidney, lung, intestine, bursa, spleen, thymus, brain, and muscle by in situ hybridization and immunohistochemistry and verified the histochemical findings by CYP-specific assays, 7-ethoxyresorufin deethylase for CYP1A4 and arachidonic acid epoxygenation for CYP1A5. CYP1A4 alone was extensively induced in the cardiovascular system, in cardiac myocytes, in perivascular cells having the same location as impulse-conducting Purkinje cells, and like CYP1A1, in vascular endothelium in every organ examined. Unlike mammalian CYP1A, CYP1A4 and 1A5 were both substantially induced in kidney proximal tubules as well as liver, and neither enzyme was induced in kidney glomeruli or lung or brain parenchymal cells. The findings demonstrate (a) a route for CYP1A4 to affect cardiac function, (b) that vascular endothelium is a major site of CYP1A induction across species, and (c) that CYP1A induced in heart or endothelial cells cannot affect cardiac or vascular function via generation of arachidonic acid epoxides because the CYP1A enzymes induced in those organs are not arachidonic acid epoxygenases. Further, the specificity of CYP1A induction sites and of the catalytically active enzymes induced at each site support a significant role for CYP1A induction in Ah receptor ligand toxicity and species differences in sensitivity.
Gannon
M
M
Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Gilday
D
D
Rifkind
A B
AB
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D002642:Chick Embryo; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D004790:Enzyme Induction / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D009928:Organ Specificity; D010088:Oxidoreductases / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*
D000072317:Polychlorinated Dibenzodioxins; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C108015:cytochrome P-450 CYP1A5