Three decades of research in
ethanol metabolism have established that alcohol is hepatotoxic not only because of secondary
malnutrition, but also through metabolic disturbances associated with the oxidation of
ethanol. Some of these alterations are due to redox changes produced by the
NADH generated via the liver ADH pathway, which in turn affects the metabolism of
lipids,
carbohydrates,
proteins, and
purines. Exaggeration of the redox change by the relative
hypoxia, which prevails physiologically in the perivenular zone, contributes to the exacerbation of the
ethanol-induced lesions in zone III. Gastric ADH also explains first-pass metabolism by
ethanol; its activity is low in alcoholics and in females and is decreased by some H2 blockers. In addition to ADH,
ethanol can be oxidized by liver microsomes: studies over the last 20 years have culminated in the molecular elucidation of the
ethanol-inducible
cytochrome P450 (P4502E1) which contributes not only to
ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various
xenobiotics. Their activation by P4502E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial
solvents,
anesthetic agents, commonly prescribed
drugs, over-the-counter analgesics, chemical
carcinogens, and even nutritional factors such as
vitamin A.
Ethanol causes not only
vitamin A depletion, but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased
acetaldehyde generation, with formation of
protein adducts, resulting in antibody production,
enzyme inactivation, decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize
oxygen. Moreover,
acetaldehyde promotes GSH depletion,
free-radical-mediated toxicity, and lipid peroxidation. In addition,
acetaldehyde affects hepatic
collagen synthesis; both in vivo (in our baboon model of
alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and lipocytes);
ethanol and its metabolite
acetaldehyde were found to increase
collagen accumulation and
mRNA levels for
collagen. This new understanding may eventually improve
therapy with drugs and nutrients. Encouraging results have been obtained with some "super" nutrients. On the one hand, SAMe, the active form of
methionine, was found to attenuate the
ethanol-induced depletion in SAMe and GSH and associated mitochondrial lesions. On the other hand,
phosphatidylcholine, purified from polyunsaturated
lecithin, was discovered to oppose the
ethanol-induced
fibrosis by decreasing the activation of lipocytes to transitional cells, and possibly also by stimulating
collagenase activity, an effect for which
dilinoleoylphosphatidylcholine, its major
phospholipid species, was found to be responsible.