Abstract

The murine Ah locus has two structural genes, P 1-450 and P 3-450, that are members of the 2,3,7,8-tetrachlorodibenzo- p-dioxin-inducible P-450 gene family and are closely linked on mouse chromosome 9. Transcriptional activation of both genes in liver is controlled by the Ah receptor. Inducible P 1-450 mRNA is correlated with aryl hydrocarbon hydroxylase activity, whereas inducible P 3-450 mRNA is correlated with acetanilide 4-hydroxylase activity. This report shows that inducible P 3-450 mRNA is also highly correlated with estradiol 2-hydroxylase activity. Both P 1-450 and P 3-450 activities are induced by 3-methylcholanthrene in liver; in contrast, P 1-450 but not P 3-450 activity is induced to a significant extent in kidney, lung, and intestine. Constitutive levels of P 3-450 mRNA in liver are at least five times greater than those of P 1-450 mRNA, thus accounting for the much greater “fold inducibility” of aryl hydrocarbon hydroxylase than acetanilide 4-hydroxylase or estradiol 2-hydroxylase. The hepatic P 3-450 induction response occurs at lower inducer concentrations than the P 1-450 induction response, suggesting a difference in affinity of the inducer-receptor complex for regulatory regions of the two genes. Developmentally, P 1-450 inducibility occurs at least 2 weeks earlier in gestation than P 3-450 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.

Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call