Molecular Pharmacology, Vol 10, 484-493, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Genetic Expression of Aryl Hydrocarbon Hydroxylase Induction

Presence or Absence of Association with Zoxazolamine, Diphenylhydantoin, and Hexobarbital Metabolism

¹ Section on Developmental Pharmacology, Laboratory of Biomedical Sciences, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20014

An increase in zoxazolamine (2-amino-5-chlorobenzoxazole) metabolism, as determined either by paralysis time or by an enzyme assay in vitro, is associated with aryl hydrocarbon (benzo[a]pyrene) hydroxylase induction among inbred strains of aromatic hydrocarbon-treated, genetically "responsive" mice, does not occur in inbred, genetically "nonresponsive," aromatic hydrocarbon-treated mice, and segregates (p < 0.01) with the Ah locus in the appropriate genetic crosses between "responsive" and "nonresponsive" mice. Hexobarbital metabolism, as determined by sleeping time, is not associated with the Ah locus in either inbred or hybrid mice. The inbred strains used for zoxazolamine and hexobarbital studies were C57BL/6N, BALB/cAnN, C3G/HeN, DBA/2N, and AKR/N. A rise in 5,5-diphenylhydantoin metabolism, as determined by the increased formation of p-hydroxy and 3,4-dihydrodiol derivatives in vitro, is associated with the presence of aryl hydrocarbon hydroxylase induction among aromatic hydrocarbon-treated inbred C57BL/6N, does not occur in aromatic hydrocarbon-treated inbred DBA/2N, but does not segregate (p > 0.10) with the Ah locus among offspring of the appropriate crosses between "responsive" and "nonresponsive" mice. Induction of both diphenylhydantoin hydroxylase and aryl hydrocarbon hydroxylase occurs in the liver of 3-methylcholanthrene-treated Osborne-Mendel rats. Therefore monooxygenation (i.e., ring hydroxylation) of benzo[a]pyrene and zoxazolamine probably involves the same newly synthesized cytochrome P₁-450 regulated by the Ah locus; diphenylhydantoin hydroxylation may be involved with a different P-450 species regulated by an "aromatic hydrocarbon responsiveness" genetic locus other than the Ah locus.

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ACKNOWLEDGMENT We thank Noreen Considine for her valuable technical assistance.

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