Dependence of the porphyrogenic effect of 2,3,7,8-tetrachlorodibenzo(p)dioxin upon inheritance of aryl hydrocarbon hydroxylase responsiveness

Experimental porphyria caused by chlorinated aromatic hydrocarbons is associated with decreased uroporphyrinogen decarboxylase activity and induction of the microsomal mixed function oxygenase systems, especially cytochrome P1-450 (P-448). 2,3,7,8-Tetrachlorodibenzo(p)dioxin (TCDD) produces porphyria in mice and is a specific inducer of cytochrome P1-450 and its associated aryl hydrocarbon hydroxylase (AHH) activity. To test the hypothesis that susceptibility to porphyria depends on responsiveness to induction of P1-450, the susceptibility to TCDD-induced porphyria was studied in mice which were genetically responsive (C57BL6J) or nonresponsive (DBA2J) to induction of AHH. To compensate for nonspecific strain differences, mice were obtained by backcrossing the progeny from a C57BL6J × DBA2J mating with DBA2J animals to yield the strain D2(B6D2)F1. These animals were phenotyped for AHH responsiveness by determining the effect of β-naphthoflavone on zoxazolamine paralysis time. It was found that susceptibility to porphyria was inherited together with AHH responsiveness. Increase in urine porphyrin was similar in mice homozygous and heterozygous for AHH responsiveness but depression of uroporphyrinogen decarboxylase activity was intermediate in the heterozygotic group.