Mechanisms of monooxygenase induction and inhibition.

The mechanisms of monooxygenase induction and inhibition have been discussed from the standpoint of historic development, from the current concepts about the molecular mechanism of enzyme induction, and from the various possibilities by which inhibitors can interact with the complex cytochrome P-450 monooxygenase system. In detail the main features and phenomena of induction and of the induced new enzyme protein are briefly described, whereby general principles are emphasized. The current knowledge on the mechanism of induction is exemplified by a description of the inducing action of TCDD on mouse hepatoma cells. A special example of increase in the molecular activity towards 7-ethoxycoumarin-0-deethylation is given by the action of sulmazole on mouse liver cytochrome P-450. It possesses properties similar to that of cobaltous chloride in that it decreases the amount of cytochrome P-450 in the microsomal protein but at the same time increases the molecular activity to about a four-fold level. The mechanisms of inhibition of the microsomal monooxygenase are explained in general terms by outlining the various modes of inhibitory action that lead to a decrease in enzyme activity.