Molecular Pharmacology, Vol 11, 389-398, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Genetic Expression of Aryl Hydrocarbon Hydroxylase by 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Evidence for a Receptor Mutation in Genetically Non-responsive Mice

¹ Department of Pharmacology and Toxicology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Hepatic aryl hydrocarbon hydroxylase activity is induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in all inbred strains of mice tested. The genetically "nonresponsive" strains of mice which fail to respond to the usual aromatic hydrocarbons (e.g., 3-methylcholanthrene) are induced by TCDD; however, the dose required is greater than for the genetically "responsive" strains. The dose of TCDD that elicits half the maximal enzyme activity (ED₅₀) in responsive strains, C57BL/6J, BALB/cJ, and A/J, is approximately 1 nmole/kg, and in the nonresponsive strains, DBA/2J, AKR/J, and SJL/J, the ED₅₀ is at least 10 nmoles/kg. In the above strains, TCDD at 3 nmoles/kg fails to induce hepatic aryl hydrocarbon hydroxylase activity in nonresponsive mice, but elicits 70% or more of the observed maximal enzyme activity in responsive strains. In 14 inbred strains of mice, the phenotypic characteristic of aromatic hydrocarbon responsiveness or nonresponsiveness can be detected equally well by a challenge with 3-methylcholanthrene (0.3 mmole/kg) or TCDD at 3 nmoles/kg. In all nonresponsive strains, a 10-fold higher dose of TCDD induces hepatic enzyme activity. The heterozygous offspring of C57BL/6J and DBA/2J parents are distinguishable from both parental strains by an intermediate sensitivity to TCDD. We conclude from these data that the genetically nonresponsive mice have the structural and regulatory genes necessary for the expression of aryl hydrocarbon hydroxylase. The most likely explanation of the defect in nonresponsive mice appears to be a mutation which results in an induction receptor site with a diminished affinity for inducing drugs, leading to an almost absolute unresponsiveness to 3-methyicholanthrene and a diminished sensitivity to the more potent inducer, TCDD.

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