European Resuscitation Council Guidelines for Resuscitation.

Serum gamma-glutamyl transferase (GGT) has been widely used as an index of liver dysfunction and marker of alcohol intake. The last few years have seen improvements in these areas and advances in understanding of its physiological role in counteracting oxidative stress by breaking down extracellular glutathione and making its component amino acids available to the cells. Conditions that increase serum GGT, such as obstructive liver disease, high alcohol consumption, and use of enzyme-inducing drugs, lead to increased free radical production and the threat of glutathione depletion. However, the products of the GGT reaction may themselves lead to increased free radical production, particularly in the presence of iron. There have also been important advances in the definition of the associations between serum GGT and risk of coronary heart disease, Type 2 diabetes, and stroke. People with high serum GGT have higher mortality, partly because of the association between GGT and other risk factors and partly because GGT is an independent predictor of risk. This review aims to summarize the knowledge about GGT's clinical applications, to present information on its physiological roles, consider the results of epidemiological studies, and assess how far these separate areas can be combined into an integrated view.

/pdf/gamma-glutamyl-transferase-g960wl2pzr.pdf

Gamma Glutamyl Transferase

Although the liver plays the major role in drug metabolism [e.g. by oxidative cytochrome P450 (CYP)-dependent phase I and conjugation or phase II reactions], drug metabolising enzymes are also present at other sites. Depending on the particular drug and enzymes involved, these extrahepatic organs and/or tissues can contribute to the elimination of drugs and, thus, should be considered in any discussion of drug disposition. By the use of relatively new techniques in molecular biology, e.g. immunoblotting with antibodies directed to various CYP isoenzymes, the tissue and organ distribution of these drug metabolising enzymes can be determined. In addition, microsomal and cytosolic enzyme activity and capacity can be directly assessed in vitro by incubation of the enzymes with the drugs of interest. Both approaches have demonstrated the presence of 3 CYP families at different extrahepatic sites, such as the mucosa of the gastrointestinal tract, kidney, lung, brain or skin. Enzymes including epoxide hydrolases, hydrolysing enzymes, glutathione S-transferases, UDP-glucuronosyltransferases, sulphotransferases, N-acetyltransferases, and methyltransferases are discussed. Indirect evidence of extrahepatic drug metabolism can be generated from pharmacokinetic studies whenever total body clearance exceeds liver blood flow, or when severe liver dysfunction or anhepatic conditions do not affect metabolic clearance. Indeed, extrahepatic metabolism has been demonstrated for numerous drugs. Therefore, the metabolic profile and sites of enzymatic reactions for each drug should be determined.

Extrahepatic Metabolism of Drugs in Humans

Aims The blood tests used traditionally as markers of excessive drinking are the liver enzymes, gamma glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the red blood cell volume (mean corpuscular volume; MCV). Here we review the nature of these markers’ association with alcohol use, their practical application in detecting, assessing or monitoring drinking and increases in understanding of these markers in the past 10 years. Design Articles were identified via Medline search and perusal of bibliographies. Findings The conventional markers have imperfect sensitivity and specificity, but have an added clinical role in the detection of complications of drinking, and of comorbid conditions that may increase risk of drinking. GGT may in part be a marker of the oxidative stress associated with ethanol metabolism. Markers are more likely to be elevated in those aged more than 30 years and in regular drinkers with a longer drinking history. The markers may be useful in opportunistic case finding, in motivating patients to change drinking and in monitoring treatment response. Increased prevalence of obesity and hepatitis C must be considered in interpretation of liver enzyme results. The liver enzymes are prognostic indicators for several medical conditions and for mortality. Conclusions These conventional tests are widely available and relatively inexpensive. While having limited sensitivity and specificity in detection of excessive drinking, they also provide valuable data on complications of drinking, comorbid conditions that may be affected by drinking and, in some cases, prognosis.

/pdf/traditional-markers-of-excessive-alcohol-use-2bj36ncdb8.pdf

Traditional markers of excessive alcohol use.

Chronic alcohol consumption increases the risk for cancer of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon, rectum, and breast. Various factors may contribute to the development (i.e., pathogenesis) of alcohol-associated cancer, including the actions of acetaldehyde, the first and most toxic metabolite of alcohol metabolism. The main enzymes involved in alcohol and acetaldehyde metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are encoded by multiple genes. Because some of these genes exist in several variants (i.e., are polymorphic), and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers. Several mechanisms may contribute to alcohol-related cancer development. Acetaldehyde itself is a cancer-causing substance in experimental animals and reacts with DNA to form cancer-promoting compounds. In addition, highly reactive, oxygen-containing molecules that are generated during certain pathways of alcohol metabolism can damage the DNA, thus also inducing tumor development. Together with other factors related to chronic alcohol consumption, these metabolism-related factors may increase tumor risk in chronic heavy drinkers.

Alcohol metabolism and cancer risk.

Background: Acetaldehyde is a local carcinogen in the digestive tract in humans. Atrophic gastritis leads to microbial colonization of the stomach, which could enhance microbial production of aceta...

Ethanol-derived microbial production of carcinogenic acetaldehyde in achlorhydric atrophic gastritis.

To study the effect of controlled heavy drinking of 60 g ethanol/day for 3 weeks on carbohydrate-deficient transferrin (CDT), a commercial double antibody kit (CDTect) was used. By the end of the third drinking week, a statistically significant increase in the mean CDT level was observed. When compared to AST and gamma-glutamyltransferase, CDT was a more informative marker. However, only in 2 of the 10 volunteers did CDT exceed the upper normal level (20 units/liter) recommended by the manufacturer. This indicates that the sensitivity of CDT to detect heavy drinking is lower than that previously reported. The higher accuracy has in general been obtained in studies comparing healthy controls with a low alcohol consumption to alcoholics with an alcohol consumption higher than that used in the present experiment. Our results suggest that it remains to be established whether CDT, although better than AST and gamma-glutamyltransferase, will provide a clinically useful tool in identifying heavy drinkers in populations covering a wide range of alcohol consumption.

Carbohydrate-deficient transferrin during 3 weeks' heavy alcohol consumption.

Characteristics of Helicobacter pylori alcohol dehydrogenase

Alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori--a possible mechanism behind gastric injury.

By virtue of possessing alcohol dehydrogenase activity, cytosol prepared from Helicobacter pylori produces toxic acetaldehyde from ethanol in vitro. To approach the in vivo situation in the stomach, we have now investigation whether intact H. pylori--without addition of exogenous nicotinamide adenine dinucleotide--also forms acetaldehyde. Furthermore, to assess the energy metabolism of H. pylori, we determined whether the alcohol dehydrogenase-catalyzed reaction can run in the opposite direction with ethanol as the end-product and thereby yield energy for the organism. Intact H. pylori formed acetaldehyde already at low ethanol concentrations (at 0.5% ethanol, acetaldehyde, 64 +/- 21 and 75 +/- 9 mumol/l (mean +/- SEM) for strains NCTC 11637 and NCTC 11638, respectively). H. pylori produced ethanol in concentrations that can be significant for the energy metabolism of the organism. Acetaldehyde production by H. pylori may be an important factor in the pathogenesis of gastroduodenal diseases associated with the organism. The primary function of H. pylori alcohol dehydrogenase may, however, be alcoholic fermentation and consequent energy production under microaerobic conditions.

Katja S. Salmela

Papers

Ethanol-derived microbial production of carcinogenic acetaldehyde in achlorhydric atrophic gastritis.

Carbohydrate-deficient transferrin during 3 weeks' heavy alcohol consumption.

Characteristics of Helicobacter pylori alcohol dehydrogenase

Alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori--a possible mechanism behind gastric injury.

Acetaldehyde and ethanol production by Helicobacter pylori.