Liver alcoholism and

Bosron WF, Li TK. Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism. Hepatology 1986 6 502-510. 

Psychological Effects Alcohol and Behavior Effects of Chronic Heavy Drinking Alcohol and Brain Functioning Alcohol and the Liver Alcohol and Reproductive Functioning Fetal Alcohol Syndrome Moderate Drinking and Health The Development of Alcohol Abuse and Dependence Traditional Approaches to Etiology "Biopsychosocial" Approaches to Etiology Summary... 

Gamma-glutamyl transferase. This enzyme is located in cell plasma membranes of several tissues, with the highest levels present in liver. Alcohol and other toxic compounds that impair liver cells result in a major increase in the activity of this enzyme in serum. Therefore, it is a good marker of injury to the liver and a diagnostic marker for monitoring the abstinence of alcoholic patients during withdrawal therapy. 

TOXICITY. No toxic effects have been observed. However, oral pharmacologic doses of up to 20 g per day of choline chloride used for periods of several weeks in the treatment of fatty liver, alcoholism, and kweishiorkor have caused some patients to experience dizziness, nausea, and diarrhea. 

Some of the most important aromatic pyrazoles with biological activity are shown in Table 38. Pyrazole itself and several A-unsubstituted pyrazoles are inhibitors and deactivators of liver alcohol dehydrogenase (79JMC356, 79ACS(B)483, B-79MI40414, 82ACS(B)10l). 

Chirazymes. These are commercially available enzymes e.g. lipases, esterases, that can be used for the preparation of a variety of optically active carboxylic acids, alcohols and amines. They can cause regio and stereospecific hydrolysis and do not require cofactors. Some can be used also for esterification or transesterification in neat organic solvents. The proteases, amidases and oxidases are obtained from bacteria or fungi, whereas esterases are from pig liver and thermophilic bacteria. For preparative work the enzymes are covalently bound to a carrier and do not therefore contaminate the reaction products. Chirazymes are available form Roche Molecular Biochemicals and are used without further purification. 

Liver alcohol dehydrogenase (ADH) is relatively nonspecific and will oxidize ethanol or other alcohols, including methanol. Methanol oxidation yields formaldehyde, which is quite toxic, causing, among other things, blindness. Mistaking it for the cheap... 

Retinoids are alcohols and accordingly soluble in ethanol, isopropanol, and polyethylenglycol. Major sources of natural retinoids are animal fats, fish liver oil (retinylesters) and yellow and green vegetables (carotenoids). Ingested retinylesters (RE) are hydrolyzed to retinol by enteral hydrolases in the intestine. ROL and carotenoids are absorbed by intestinal mucosa cells. 

The miscellaneous anticonvulsants are used cautiously in patients with glaucoma or increased intraocular pressure a history of cardiac, renal or liver dysfunction and psychiatric disorders. When the miscellaneous anticonvulsants are used with other CNS depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant effect may occur. 

Figure 8.27 Reduction of aldehyde in SCCO2 by an isolated enzyme, horse liver alcohol dehydrogenase (HLADH) [20c] (a) Reaction scheme (b) fluorinated coenzyme soluble in CO2 and (c) effect of coenzyme on the reaction.

From animal tissue, especially bovine lung and liver (e. g. autolysis of comminuted tissue parts, heating with ammonium sulfate in alkaline solution, filtration and acidification yield heparin as complex with protein, removal of fat with alcohol and treatment with trypsine for the purpose of decomposition of proteins, precipitation with alcohol and various purification methods). 

Adverse consequences of drinking include a variety of social, legal, medical, and psychiatric problems (Babor et al. 1987, 2003). Alcohol is among the top four causes of mortality in 1988, 107,800 deaths, or about 5% of all deaths in the United States, were attributed to alcohol-related causes (Stinson and DeBakey 1992). Approximately 17% of alcohol-related deaths were directly attributable to alcohol, 38% resulted from diseases indirecdy attributable to alcohol, and 45% were attributable to alcohol-related traumatic injury (U.S. Department of Health and Human Services 1994). Alcohol-related mortality declined during the latter part of the twentieth century. For example, the age-adjusted mortality rate from liver cirrhosis in 1993 (7.9 deaths per 100,000 persons) was just over half the rate in 1970 (14.6 deaths per 100,000) (Saadat-mand et al. 1997), and the proportion of automobile fatalities that was related to the use of alcohol fell to a two-decade low of 33.6% in 1993 (Lane et al. 1997). 

High concentrations of endosulfan sulfate were found primarily in the liver, intestine, and visceral fat 24 hours after mice were exposed to a single dose of -endosulfan (Deema et al. 1966). Five days following a single oral administration of " C-endosulfan to rats, the diol, sulfate, lactone, and ether metabolites were detected in the feces (Borough et al. 1978). In sheep, endosulfan sulfate was detected in the feces, and endosulfan alcohol and a-hydroxyether were detected in the urine (Gorbach et al. 1968). 

Alcoholism leads to fat accumulation in the liver, hyperlipidemia, and ultimately cirrhosis. The exact mechanism of action of ethanol in the long term is stiU uncertain. Ethanol consumption over a long period leads to the accumulation of fatty acids in the liver that are derived from endogenous synthesis rather than from increased mobilization from adipose tissue. There is no impairment of hepatic synthesis of protein after ethanol ingestion. Oxidation of ethanol by alcohol dehydrogenase leads to excess production of NADH. 

Another common liver disease, alcoholic liver damage produced by moderate to heavy alcoholic intake, is also reflected by an elevation of the serum GOT and GPT activities. The serim glutamyl transferase activity is reported to be a sensitive index of alcoholic intake and can serve to monitor persons on alcoholic withdrawal programs (60). The LD-5 isoenzyme arises mainly from liver tissue, but has a short half-life (61), which is about 1/5 and 1/2 of the half life of the transaminases, GPT and GOT respectively. Some authors consider that a normal LD-5 isoenzyme activity in a jaundiced patient is sufficient evidence to exclude primary liver disease and that obstruction is probably responsible for the jaundice (62). In hemolytic jaundice the LDH-1 and 2 isoenzymes are elevated. 

Johansson, V., Johnsson, F., Joelsson, B., Beiglund, M. and Akesson, B. (1986). Selenium status in patients with liver cirrhosis and alcoholism. Br. J. Nutr. 55, 227-233. 

Korpela, H., Kumpulainen, J., Luoma, P.V., Arranto, A.J. and Sotaniemi, E.A. (1985). Decreased serum selenium in alcoholics as related to liver structure and function. Am. J. Clin. Nutr. 42, 147-151. 

Tsukamoto, H., Gaal, K. and French, S.W. (1990). Insights into the pathogenesis of alcoholic liver necrosis and fibrosis, status report. Hepatology 12, 599-608. 

Ward. R. J. and Peters, T.J. (1992). The antioxidant status of patients with either alcohol-induced liver damage of myopathy. Alcohol and Alcoholism 27, 359-365. 

Zinc-containing alcohol dehydrogenases take up two electrons and a proton from alcohols in the form of a hydride. The hydride acceptor is usually NAD(P) (the oxidized form of nicotinamide adenine dinucleotide (NADH) or its phosphorylated derivative, NADPH). Several liver alcohol dehydrogenases have been structurally characterized, and Pig. 17.8 shows the environment around the catalytic Zn center and the bound NADH cofactor. 

Figure 17.8 Catal3ftic zinc center of horse liver alcohol dehydrogenase revealed from an X-ray crystallographic structure (PDB file 20HX) [Al-Karadaghi et al., 1994]. The bound NADH cofactor, a molecule of the inhibitor dimethylsulfoxide (DMSO), and the amino acid residues that coordinate the Zn are shown as sticks shaded according to the elements, and the Zn center is shown as a gray sphere, while the protein is shown in thin gray lines.

Cirrhosis is the result of long-term insult to the liver, so damage is typically not evident clinically until the fourth decade of life. Chronic liver disease and cirrhosis combined were the 12th leading cause of death in the United States in 2002. In patients between the ages of 25 and 64, damage from excessive alcohol use accounted for over one-half of the deaths.2 Alcoholic liver disease and viral hepatitis are the most common causes of cirrhosis in the United States and worldwide. 

Progression of alcoholic liver disease moves through several distinct phases from development of fatty liver to the development of alcoholic hepatitis and cirrhosis. Fatty liver and alcoholic hepatitis may be reversible with cessation of alcohol intake, but cirrhosis itself is irreversible. Although the scarring of cirrhosis is permanent, maintaining abstinence from alcohol can still decrease complications and slow development to end-stage liver disease.22 Continuing to imbibe speeds the advancement of liver dysfunction and its complications. 

Disulfiram works by irreversibly blocking the enzyme aldehyde dehydrogenase, a step in the metabolism of alcohol, resulting in increased blood levels of the toxic metabolite acetaldehyde. As levels of acetaldehyde increase, the patient experiences decreased blood pressure, increased heart rate, chest pain, palpitations, dizziness, flushing, sweating, weakness, nausea and vomiting, headache, shortness of breath, blurred vision, and syncope. These effects are commonly referred to as the disulfiram-ethanol reaction. Their severity increases with the amount of alcohol that is consumed, and they may warrant emergency treatment. Disulfiram is contraindicated in patients who have cardiovascular or cerebrovascular disease, because the hypotensive effects of the disulfiram-alcohol reaction could be fatal in such patients or in combination with antihypertensive medications. Disulfiram is relatively contraindicated in patients with diabetes, hypothyroidism, epilepsy, liver disease, and kidney disease as well as impulsively suicidal patients. 

For a liver alcohol dehydrogenase (LADH) model an NS2O coordination sphere is required. The chelating aldehydes are ideal for the formation of this donor set when combined with bis(pentafluoro-thiophenolato)zinc. Structural data on the complexes with one equivalent of 6-methylpyridine-2-carbaldehyde, 6-methoxypyridine-2-carbaldehyde, 2-(dimethylamino)benzal-dehyde) demonstrate that the coordination sphere for LADH has been reproduced to a close approximation and the corresponding alcohol complexes have also been characterized.354 Other thiophenols have been used to form such complexes but have not been structurally characterized.304... 

ALAD, an enzyme occurring early in the heme pathway, is also considered a sensitive indicator of lead effect (Hemberg et al. 1970 Morris et al. 1988 Somashekaraiah et al. 1990 Tola et al. 1973). Because there is no well-defined blood lead threshold at which inhibition of ALAD does not occur, it allows measurement of the effect on the general population at environmental lead levels and does not require high exposure levels as with occupational workers (Hemberg et al. 1970). However, ALAD activity may also be decreased with other diseases or conditions such as porphyria, liver cirrhosis, and alcoholism (Somashekaraiah et al. 1990). 

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