Molecular Pharmacology, Vol 8, 651-666, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Genetic Expression of Aryl Hydrocarbon Hydroxylase Induction

III. Changes in the Binding of n-Octylamine to Cytochrome P-450

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

Aryl hydrocarbon hydroxylase induction by polycyclic hydrocarbons is expressed as a simple autosomal dominant trait; in any mouse homozygous or heterozygous for the allele Ah, the monooxygenase activity is generally induced by aromatic hydrocarbons in many tissues regularly containing the inducible enzyme system. Induction of hydroxylase activity by 3-methylcholanthrene administration to C57BL/6N mice is associated with an approximately equal conversion of hepatic type b to type a P-450, as measured by n-octylamine binding to the cytochrome. This conversion of mouse hepatic P-450 from one form to the other may also occur in rat and hamster liver microsomes and in kidney microsomes of the mouse, rat, or hamster. However, there is not a precise correlation in liver or kidney microsomes from control, 3-methylcholanthrene-treated, or phenobarbital-treated mice, rats, or hamsters between the sum of type a plus type b P-450 and the total P-450 concentration, as measured by difference spectra of the reduced P-450—CO complex.

In the AhAh or Ahah mouse but not in the ahah mouse, the hydroxylase is induced by a variety of aromatic compounds: polycyclic hydrocarbons such as 3-methylcholanthrene or benz[a]anthracene, flavones, and 2-phenylbenzothiazoles. Phenobarbital treatment of AhAh Ahah, or ahah mice similarly induces the hepatic aryl hydrocarbon hydroxylase system about 100% and causes identical increases of about 65% in both type a and b P-450. Chlorpromazine administration to Ahah, Ahah, or ahah mice induces the oxygenase activity to levels similar to those stimulated by phenobarbital, but increases hepatic type b P-450 preferentially more than the type a form.

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ACKNOWLEDGMENT We thank Dr. J. L. Gaylor for his valuable critical advice.