Effect of various inducers on electron transport system associated with drug metabolism by liver microsomes

Abstract

The metabolism of a wide variety of drugs and other compounds is catalyzed by liver microsomal enzyme systems involving cytochrome P-450 and NADPH-cytochrome c reductase. The sequence of events in these reactions is presumably as follows: The drug substrate reacts with the oxidized form of cytochrome P-450 to form a complex which is reduced either directly by NADPH-cytochrome c reductase or indirectly via an unidentified electron carrier. The reduced cytochrome P-450-substrate complex then reacts with oxygen to form an “active oxygen” complex, which decomposes with the formation of the oxidized drug and oxidized cytochrome P-450. Since the rate of reduction of the cytochrome P-450-substrate is considerably slower than the rate of oxidation of the complex under steady-state conditions, most of the cytochrome P-450-substrate complex is in the oxidized form. The rate of electron flux through the system, however, may be modified by altering the amount of cytochrome P-450-substrate complex, or the rate at which it is reduced. Inducers of drug metabolism may be classified according to their effects on the various components of the system. Phenobarbital-like inducers cause increases in NADPH-cytochrome c reductase and cytochrome P-450, and thus increases in the amount of cytochrome P-450-substrate complex and its rate of reduction. Polycyclic hydrocarbons, such as methylcholanthrene, induce the formation of a variant of cytochrome P-450, which has different affinities for the various drug substrates than does the usual form. This kind of inducer does not increase either NADPH-cytochrome c reductase or the rate of cytochrome P-450 reduction; indeed in some experiments they decrease the rate of cytochrome P-450 reduction per cytochrome P-450. In female rats, spironolactone and perhaps other anabolic steroids increase NADPH-cytochrome c reductase activity and the rate of cytochrome P-450-substrate reduction, but have little or no effect on the amount of cytochrome P-450. The relationship between the electron flux and drug metabolism in liver microsomes depends on the substrate. For example, the demethylation of ethylmorphine and NADPH oxidation (or cytochrome P-450 reduction) approaches the theoretical 1:1 relationship, whereas, the rate of hydroxylation of hexobarbital may be considerably less than the substrate induced rate of NADPH oxidation (and cytochrome P-450 reduction).