CoA-S-C-CH3 Acetyl CoA

Fatty acids

Tricarboxylic ; acid cycle

FIGURE 22-1 Metabolism of ethanol and methanol.

drugs, however, after acute consumption of ethanol because ethanol competes with them for oxidation by the enzyme system (e.g., phenytoin and warfarin). The large increase in the hepatic NADH:NAD+ ratio during ethanol oxidation has profound consequences in addition to limiting the rate of ethanol metabolism. Enzymes requiring NAD+ are inhibited; thus, lactate accumulates, activity of the tricarboxylic acid cycle is reduced, and acetyl coenzyme A (acetyl CoA) accumulates (and it is produced in quantity from ethanol-derived acetic acid; Figure 22-1). The combination of increased NADH and elevated acetyl CoA supports fatty acid synthesis and the storage and accumulation of triacylglycerides. Ketone bodies accrue, exacerbating lactic acidosis. Ethanol metabolism by the CYP2E1 pathway produces elevated NADP+, limiting the availability of NADPH for the regeneration of reduced glutathione (GSH), thereby enhancing oxidative stress.

The mechanisms underlying hepatic disease resulting from heavy ethanol use probably reflect a complex combination of these metabolic factors, CYP2E1 induction (and enhanced activation of toxins and production of H2O2 and oxygen radicals), and possibly enhanced release of endotoxin as a consequence of ethanol's effect on gram-negative flora in the GI tract. Effects of heavy ethanol ingestion on various organs are summarized below; damage to tissues very likely reflects the poor nutritional status of alcoholics (malabsorption and lack of vitamins A and D and thiamine), suppression of immune function by ethanol, and a variety of other generalized effects.

The one-carbon alcohol methanol also is metabolized by ADH and ALDH, with damaging consequences (see below). Competition between methanol and ethanol for ADH forms the basis of the use of ethanol in methanol poisoning. Several drugs inhibit alcohol metabolism, including 4-methylprazole, an ADH inhibitor useful in ethylene glycol poisoning, and disulfiram, an ALDH

inhibitor used in treating alcoholism (see below). Ethanol also can competitively inhibit the metabolism of other substrates of ADH and CYP2E1, such as methanol and ethylene glycol, and therefore is an effective antidote.

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