The role of microsomal cytochrome b5 in the metabolism of ethanol, drugs and the desaturation of fatty acids.

Liver endoplasmic membrane contains two hemoproteins, cyt. P-450 and cyt. b5. Cytochrome P-450 catalyzes the hydroxylation of lipid-soluble compounds, while the cyt. b5 system is involved in desaturation of fatty acids. NAD(P)H and oxygen are essential components for both systems. Oxidation of ethanol to acetate in the liver, via alcohol and acetaldehyde dehydrogenases, leads to an elevated cellular NADH content. It has been proposed that oxidation of the cytosolic NADH occurs predominantly in the mitochondria via the substrate oxidation-reduction shuttle. In order to investigate the effects of elevated levels of cytosolic NADH on the state of the endoplasmic hemoprotein system, microsomes from a fatty human liver (post-ethanol intake) were isolated and studied. Microsomal cyt. b5 reductase was found to reoxidize cytoplasmic NADH directly and transfer the reducing equivalents readily to the microsomal oxidases. Addition of catalytic amounts of alcohol dehydrogenase, NAD, and ethanol to microsomes resulted in a rapid reduction of microsomal cyt. b5. These results are consistent with the proposal that the catalytic moiety of cyt. b5 reductase is exposed to the aqueous phase of the membrane and directly accepts reducing equivalents from the cytoplasm. Microsomes from fatty human liver showed an increased rate of cyt. b5 dependent desaturation of fatty acids. These findings suggest that ethanol metabolism may selectively affect the activity of one or the other microsomal hemoprotein. Thus, when the desaturase activity is low, drug metabolism by the cyt. P-450 pathway may predominate. Conversely, an increase in the desaturase level may lead to a decreased drug metabolism. This mechanism may underlie the clinical observations of drug intolerance reactions associated with alcohol intake.