Study on inhibition of cytochrome P-450-dependent mixed function oxidation by ethanol

Abstract

The cytochrome P-450 in liver microsome catalyzes the drug oxidation by using oxygen and NADPH. We have investigated the mechanism on the inhibition of cytochrome P-450-dependent mixed function oxidation by ethanol.
NADPH oxidation decreased with increasing ethanol concentration in liver microsomes. Ethanol induced a reverse type I binding spectrum, and competitively inhibited the binding of hexobarbital to liver microsome due to the displacement of the endogeneous substrate.
The NADPH-dependent reduction of liver microsomal cytochrome P-450 was biphasic and composed of two concurrent first-order reactions. The addition of hexobarbital increased the both rate constant for the fast and slow phase. The rate constant for the fast phase was decreased by the addition of ethanol, but the rate constant for the slow phase remained unchanged. Therefore, the inhibition of mixed function oxidation by ethanol may be due partly to the decrease of NADPH-cytochrome P-450 reductase activity resulting from the decrease of substrates bound to cytochrome P-450 by ethanol.