Possible mechanism of induction of liver microsomal monooxygenases by phenobarbital

A study has been made of a model of "consecutive" induction of microsomal monooxygenases following treatment with phenobarbital which was administered after maximal induction by 3-methylcholanthrene. It has been found that in this "consecutive" system, notwithstanding the discontinuation of 3-methylcholanthrene, phenobarbital stimulates the further increase of the CO-binding hemoprotein content in the form of P-488. At the same time there is a considerable gain in the content of its high-spin species. An increase has been observed in the velocity of NADPH-dependent reduction of the CO-binding hemoprotein as well as a pronounced elevation in the activity of amino-pyrine N-demethylase. The data presented indicate that the location of the CO-peak of Na2S2O4-reduced hemoprotein is not the criterion of monooxygenase functional specificity; the latter may, possibly, be defined by the relation between the contents of the high-spin and low-spin species of the cytochrome. The possibility has been demonstrated of phenobarbital induction under conditions when the inducer-microsomal hemoprotein primary binding step is not involved, inasmuch as cytochrome P-448 lacks binding sites for phenobarbital. In this connection it is assumed that in the mechanism of phenobarbital induction of microsomal monooxygenases the activation of a portion of the genome and subsequent protein synthesis are effected by the substrate itself and not by the products of its primary metabolism in the microsomes.