Transcriptional activation of avian CYP1A4 and CYP1A5 by 2,3,7, 8-tetrachlorodibenzo-p-dioxin: differences in gene expression and regulation compared to mammalian CYP1A1 and CYP1A2.
The toxicity, carcinogenicity, and biochemical effects of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) are dependent upon activation of the Ah receptor, a ligand-activated transcription factor. Ah receptor activation leads to the induction of cytochrome P450 (CYP) 1A enzymes, which include CYP1A1 and 1A2 in mammals and CYP1A4 and 1A5 in chickens. CYP1A induction is a major effect of TCDD exposure although its relationship to TCDD toxicity and carcinogenicity are not understood. In these studies we investigated by nuclear run-on transcription assays along with Northern and Western blotting in chick embryo liver, kidney, and heart whether avian CYP1A4 and 1A5, like mammalian CYP1A1 and 1A2, are transcriptionally induced by TCDD and whether the chick CYP1A enzymes exhibit differences analogous to mammalian CYP1A enzymes in organ expression. We report that CYP1A4 and 1A5, like CYP1A1 and 1A2, are transcriptionally induced by TCDD in liver. However, whereas CYP1A1 is not constitutively expressed in liver, CYP1A2 and both CYP1A4 and 1A5 are constitutively expressed. Further, whereas TCDD induces only CYP1A1 and not CYP1A2 in extrahepatic organs, TCDD induces both CYP1A4 and 1A5 in chick kidney. Also, TCDD induced CYP1A4 but not 1A5 in both myocardium and heart vessels whereas CYP1A1 induction has only been found in endocardium. Further, liver CYP1A4 and 1A5 mRNAs had the same half lives and were both superinduced by cycloheximide, whereas mRNA half lives differ for CYP1A1 and 1A2, and cycloheximide superinduces only CYP1A1. We suggest that there are species differences in the effects of TCDD on CYP1A gene expression, organ distribution, and regulation that are likely to be accompanied by differences in CYP1A function and that this diversity may contribute to the large differences in sensitivity to TCDD among species.
Mahajan
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SS
Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.
Rifkind
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AB
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002645:Chickens / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D010088:Oxidoreductases / Q000235:genetics*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis*; D013045:Species Specificity; D015533:Transcriptional Activation
D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D003513:Cycloheximide; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C108015:cytochrome P-450 CYP1A5