GENETIC STUDIES CONCERNING THE INDUCTION OF ARYL HYDROCARBON HYDROXYLASE GOVERNED BY THE MURINE AH LOCUS (TOXICOLOGY, MOUSE GENETICS, DRUG METABOLISM)

Three sets of recombinant inbred (RI) mouse sublines were evaluated for three Ah locus-related responses: (1) duration of zoxazolamine-induced paralysis, (2) hepatic Ah receptor levels and (3) hepatic AHH activity following treatment with benzanthracene, 3-methylcholanthrene, beta-naphthoflavone or 2,3,7,8-tetrachlorodibenzo-p-dioxin or corn oil (control). A short duration for the zoxazolamine paralysis response, detectable hepatic Ah receptor levels, and the capacity for hepatic AHH induction are characteristics of the C57BL/6 and C3H/He mouse strains. The DBA/2 mouse strain exhibits a prolonged paralysis response, undetectable cytosolic Ah receptor levels, and more than 10-fold lower capacity for hepatic AHH induction. All of the C57BL/6J x DBA/2J RI sublines segregate with either of the parental strains. It is concluded the difference in the ANN induction process between the C57BL/6 and DBA/2 mice resides in the detectable levels of cytosolic Ah receptor. Four of 26 RI sublines tested, derived from the C57BL/6 and C3H/He strains, exhibit a differential response: these sublines have negligible Ah receptor levels and exhibit a long duration of zoxazolamine-induced paralysis yet are capable of AHH induction. Twenty-two out of 800 (C57BL/6N)(C3H/HeN)F(,2) individuals selected for prolonged zoxazolamine paralysis exhibit this same differential response. This differential response can be explained by the possibility of an Ah receptor-independent pathway for AHH induction. Alternatively, these results could indicate the presence of two regulatory loci in the C57BL/6 and C3H/He strains that control the AHH induction process by affecting the structural composition of the Ah receptor. This possibility is supported by the observation of a charge difference in the Ah receptor between these two mouse strains. The expression of at least two regulatory loci in these sublines could generate various combinations of heterodimeric Ah receptor. The resulting Ah receptor proteins would be responsible for a differential transcriptional activation of two other genes that code for AHH activity and zoxazolamine metabolism. This hypothesis of a differential transcriptional activation mechanism resulting from several possible combinations of Ah receptor subunits would explain the observed data.