Developmental and tissue-specific differential regulation of the mouse dioxin-inducible P1-450 and P3-450 genes.
The murine Ah locus has two structural genes, P1-450 and P3-450, that are members of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible P-450 gene family and are closely linked on mouse chromosomes 9. Transcriptional activation of both genes in liver is controlled by the Ah receptor. Inducible P1-450 mRNA is correlated with aryl hydrocarbon hydroxylase activity, whereas inducible P3-450 mRNA is correlated with acetanilide 4-hydroxylase activity. This report shows that inducible P3-450 mRNA is also highly correlated with estradiol 2-hydroxylase activity. Both P1-450 and P3-450 activities are induced by 3-methylcholanthrene in liver; in contrast, P1-450 but not P3-450 activity is induced to a significant extent in kidney, lung, and intestine. Constitutive levels of P3-450 mRNA in liver are at least five times greater than those of P1-450 mRNA, thus accounting for the much greater "fold inducibility" of aryl hydrocarbon hydroxylase than acetanilide 4-hydroxylase or estradiol 2-hydroxylase. The hepatic P3-450 induction response occurs at lower inducer concentrations than the P1-450 induction response, suggesting a difference in affinity of the inducer-receptor complex for regulatory regions of the two genes. Developmentally, P1-450 inducibility occurs at least 2 weeks earlier in gestation than P3-450 inducibility, which occurs near the time of birth. These data thus demonstrate striking differences between the expression of two homologous genes in the same P-450 subfamily, with respect to developmental and tissue specificity and sensitivity to common inducers that interact with the Ah receptor.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002874:Chromosome Mapping; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004147:Dioxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000201:enzymology; D004790:Enzyme Induction; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes; D008099:Liver / Q000201:enzymology; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011247:Pregnancy; D012451:Safrole / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C023738:acetanilide hydroxylase; C020120:estrogen 2-hydroxylase; D012451:Safrole; C015959:isosafrole