Dr. A.C.

Santucci

Drug Use and Abuse

Metabolism of Alcohol
Alcohol Alcohol dehydrogenase Acetaldehyde Aldehyde dehydrogenase Acetyl coenzyme A

Energy + CO2
The major site of alcohol metabolism or breakdown (biotransformation) is in the liver. Alcohol dehydrogenase is the rate-limiting enzyme in the metabolism of alcohol and thus limits the amount of alcohol metabolized. Consequently, it is impossible to speed up alcohol metabolism. Unlike absorption, it proceeds at a steady rate, unaffected by blood concentrations. A 150-pound male, for example, can metabolize about 8 to 12 grams of alcohol an hour - that's about 1/3 to 1/2 ounces, the amount in one bottle of beer or half an ounce of whiskey. Theoretically, therefore, one could drink 24 beers a day at a rate of one per hour and stay sober. In order to become intoxicated, you need to outpace metabolism. Interestingly, in humans metabolic differences for alcohol have been shown between Asians (and some Native Americans whose ancestors are from Asia) and Caucasians (Kalow et al., 1986). Approximately 50% of Asians have lower levels of aldehyde dehydrogenase in their livers. In these cases, alcohol is metabolized rapidly early in the chain of biotransformation, but the process then stalls at the aldehyde dehydrogenase phase allowing an accumulation of alcohol by-products. These by-products cause slight adverse reactions of increased heart rate and facial flushing. Some alcohol is metabolized in the stomach. One study indicates that metabolism in the stomach may account for the effects of drinking between women and men (Frezza et al., 1990). Human males, as oppose to females, show significantly more amounts of alcohol dehydrogenase in their stomach linings, which increase the first-pass metabolism of alcohol. This, therefore, may account for the fact that women are more affected by equivalent doses of alcohol. Moreover, because women must rely primarily on their livers to metabolize alcohol, having lower levels of alcohol dehydrogenase may also account for the fact that women are more susceptible to alcoholic liver disease (e.g., cirrhosis, liver cancer, and fatty livers). This is due to

The information contained in this handout is based on Palfai, T., & Jankiewicz, H. (1997). Drugs and Human Behavior (2nd ed). Madison WI: Brown & Benchmark.

Dr. A.C. Santucci

Drug Use and Abuse

the fact that women who abuse alcohol place increase metabolic demands on their livers to breakdown alcohol. The liver metabolizes alcohol into "empty calories," energy devoid of nutritional value - no vitamins or minerals. When alcohol is taken with food, the body uses the unstorable alcoholic energy first, and synthesizes fat to store the excess energy from the food. Drinking alcohol along with eating is therefore highly conducive to weight gain, since the meal will be stored over a period of about 4 hours while the alcohol is being used. Another significant metabolic pathway in the liver is called microsomal ethanol oxidizing system (MEOS). This consists of the induction of the liver enzyme cytochrome P-450 which biotransforms a number of substances including alcohol, barbiturates, PCBs (polychlorinated biphenyls) found in insulators, oil and lubricants, the steroid hormone testosterone, and bilirubin (the pigment that causes yellowing in jaundice). This accounts for the mechanism of tolerance called "drug disposition" or "metabolic tolerance." For example, the large amounts of alcohol consumed by people who abuse alcohol will induce the production of cytochrome P-450. Thus, these people need more and more alcohol in order to achieve the same BAL (blood alcohol level) and psychological effect. If, however, the increase in cytochrome P-450 is being occupied by breaking down PCBs in lubricants (if the person is an auto mechanic, for example) then the person needs much less alcohol in order to achieve the desired BAL and psychological effect. Similarly, in alcoholic males, the induction of cytochrome P450 will cause an increased metabolism of testosterone when the enzyme is not occupied with breaking down alcohol. Thus, chronic alcoholics experience a decreased libido (sex drive) because of low levels of testosterone. The MEOS system also contributes to the production of acetaldehyde and might contribute to the liver damage seen in heavy drinkers. As said above, there is no way to speed up the metabolism of alcohol, but considerable research (and folklore!) has been devoted to examining drugs which counteract some of the effects of alcohol. These so-called "sobering-up" agents are referred to as amethystic agents, named after the amethyst stone because of its absorption quality. One possible drug is RO15-4513 (remember from our discussion of drug names -- this is a "code name" given by the drug company developing it). This drug works by displacing alcohol from the GABA receptor (the neurotransmitter receptor that mediates some of alcohol's CNS effects). RO15-4513, however, counteracts only some of the effects of alcohol and also causes seizures so its clinical utility is quite limited. Another possible amethystic agent is naloxone, which serves as a non-specific opiate receptor antagonist. Naloxone has been shown to reverse alcohol-induced respiratory depression and coma. Other possible amethystic agents are ibuprofen (an analgesic), lithium carbonate (a drug usually used to treat mania), and thyrotropinreleasing hormone (a hormone which acts on the thyroid to release thyroid hormones). All three have been shown to reduce some of the effects of intoxication. Since alcohol, however, is so well absorbed and distributed throughout the body, it is truly difficult to develop an effective amethystic agent. Moreover, imagine the impact on society if one were to be developed.

The information contained in this handout is based on Palfai, T., & Jankiewicz, H. (1997). Drugs and Human Behavior (2nd ed). Madison WI: Brown & Benchmark.