The main pathway for the hepatic oxidation of
ethanol to
acetaldehyde proceeds via ADH and is associated with the reduction of
NAD to
NADH; the latter produces a striking redox change with various associated metabolic disorders.
NADH also inhibits
xanthine dehydrogenase activity, resulting in a shift of
purine oxidation to
xanthine oxidase, thereby promoting the generation of
oxygen-
free radical species.
NADH also supports microsomal oxidations, including that of
ethanol, in part via transhydrogenation to
NADPH. In addition to the classic
alcohol dehydrogenase pathway,
ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of
NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of
cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of
superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by
antibodies against 2E1 in control and
ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of
free radicals. In addition, induction of this microsomal system results in enhanced
acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to
cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-
butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of
cysteine (one of the three
amino acids of GSH) is
methionine.
Methionine, however, must be first activated to
S-adenosylmethionine by an
enzyme which is depressed by
alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of
ethanol-induced liver injury significantly such as the increase in circulating
transaminases, mitochondrial lesions, and leakage of mitochondrial
enzymes (e.g., glutamic
dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of
phosphatidylethanolamine to
phosphatidylcholine. The
methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic
phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated
phospholipids (
polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal
fibrosis and
cirrhosis in the baboon and it abolished an associated twofold rise in hepatic
F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.