In late years.

In late years, biochemical tools have played a major part in shaping our concepts of alcohol-related pathology and in guiding our efforts to obstruct and treat alcoholism and medical disorders associated with it. A typical illustration of the evolution that has taken place is provided through one organ primarily affected by dint of alcohol, namely the liver. The greatest in quantity severe form of alcohol-induced liver disease is cirrhosis, which is now the fourth greatest in number frequent cause of death among bodily forms 25 to 64 years of age who live in urban areas (New York City Department of Health 1986)

BIOCHEMICAL STUDIES

Alcohol-induced liver injury formerly was attributed exclusively to malnutrition associated with alcoholism. In the 1950 however, by dint of using biochemical research techniques, researchers established that alcohol also put forthed some direct effects on the liver (Lieber et al. 1959) Studies directioned over the subsequent three decades in human proffers and subhuman primates showed that the couple the initial liver lesion--the fatty liver (Lieber et al. 1965)--and the ultimate stage of cirrhosis (Lieber and DeCarli 1974) can be produc on alcohol in the absence of dietary deficiencies and calm in the presence of enriched diets (Lieber and Rubin 1968) This recognition of the inherent toxicity of alcohol shifted the emphasis of treatment from correcting nutritional deficiencies to controlling alcohol consumption.

Biochemical techniques also became the essential tool for elucidating the disease mechanisms of many other medical disorders associated with alcoholism (Lieber 1982a, 1990a). by the and of this approach, impairments in carbohydrate, lipid (fat), and protein metabolism were linked to alterations produc when alcohol is oxidized at the liver enzyme alcohol dehydrogenase. More new advances were related to the discovery of the cytochrome P-450-dependent microsomal alcohol-oxidizing order (MEOS) (Lieber and DeCarli 1968) involved in the metabolism of alcohol and the progressive growth of tolerance. Normally functioning at a gentle level, MEOS is induced, or activated, on the presence of alcohol.

MEO involves a specific form of the enzyme cytochrome P-450 known as P450IIE1. This enzyme has a unique capacity for increasing the toxicity of chemicals taken into the visible form [i]or[/i] frame Consequently, its induction provided an explanation for the increased susceptibility of heavy drinkers to the damage caused from industrial solvents, anesthetics, chemical carcinogens, commonly used medications, and equable over-the-counter analgesics and vitamins (Lieber 1990b)

The induction of this pathway also may be derived in energy wastage and leads to increased formation of acetaldehyde, the breakdown consequence of alcohol. Acetaldehyde, in bend causes injury through a variety of mechanisms (Liebr 1988): formation of combination consequences with proteins, enzyme inactivation, decreased DNA repair, and serious alterations of cellular ingredients Acetaldehyde also has been establish to play a key character in the production of scar tissue, common of the basic pathologic features of alcoholic cirrhosis (Savolainen et al. 1984; Moshage et al. 1990) Furthermore, acetaldehyde has been incriminated in processe leading to, or favoring, alcohol support and, possibly, some of the manifestations of the fetal alcohol syndrome (Karl et al. 1988)

METABOLIC AND GENETIC

STUDIES

Since it is now clear that many pathologic complications of alcoholism, and perhaps alcoholism itself, are linked to the metabolism of alcohol, elucidation of the metabolic pathways and their genetic determinants has become crucial to understanding and managing alcoholism and its complications. Inherited abnormalities of metabolism have been invoked to explain one of the variability in susceptibility to put drugs into toxicity. For instance, the antihypertensive mix with drugs debrisoquine sulfate and a score of related commonly prescribed amalgamates have toxic effects in certain bodily substances who harbor a mutant gene that arises in a deficiency of the appropriate form of cytochrome P-450 (Gonzalez et al. 1988) If a similar mechanism exists involving the gene for P450IIE1, this might explain the unusual susceptibility to alcohol of a subset of the population.

Clear-cut genetic differences have been demonstrated already for the alcohol dehydrogenase (ADH) pathway and for the disposition of acetaldehyde. A corresponding genetically determined enzyme deficiency eventuates in intolerance to alcohol (Goedde et al. 1985) and may thereby "protect" against the growth of cirrhosis. The comprehensive review in this issue of Alcohol Health & Research World by dint of Crabb (see pp. 197-203) of techniques of molecular cloning and other advances in this field vividly illustrates the technological progres achieved and the fact that a resolution of the manner in which the carcass handles alcohol and how this is genetically determined is now within our grasp. Elucidation of in what way different individuals may vary in that esteem will enhance our understanding of the medical complications of alcoholism and perhaps of the propensity to unravel alcoholism itself.