NAD+ and NADH mainly are used by enzymes that catalyze substrate oxidation involving energy metabolism, histone deacetylation, and cell death. Under normal physiological conditions, the ratio of cytosolic free NAD+ to NADH is approximately 700:1, whereas that of the mitochondria has been reported to be 7–8 to 1 (Stubbs et al. 1972; Veech et al. 1969). Increased NADH/NAD+ ratios (e.g., because of depletion of NAD+) in both the cytosol and mitochondria of hepatocytes influence the direction of several reversible reactions, leading to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The increase in the ratio of NADH/NAD+ also results in derangement of carbohydrate metabolism, cell death, modulation of the mitochondrial permeability transition (MPT) opening, and modulation of gene expression.
