Alcohol and health: a drink a day won't keep the doctor away.
We should not advise patients to start drinking alcohol for its alleged cardiovascular benefits. The negative effects of alcohol are well established, and the evidence of alcohol's benefits comes mainly from epidemiologic studies that were not well controlled for other influences, such as lifestyle factors. Moreover, we have other means of lowering cardiovascular risk that are safe and proven. Those who are healthy and whose drinking history shows little risk of developing alcohol dependency may continue to drink moderate amounts. Heavy drinkers should be advised to quit.
Cleve Clin J Med . 2003 Nov;70(11):945-6
Alcohol consumption and risk of laryngeal cancer.
Epidemiological studies consistently showed that alcohol drinking increases the risk of laryngeal cancer. This risk increases with the amount of alcohol consumed: in recent studies conducted in North America, Europe, Japan and Korea the multivariate relative risks for the highest levels of consumption ranged between 2 and 10, and were 1.94 for 50g/day and 3.95 for 100g/day in a meta-analysis of 20 studies. Further, the risk increases by concomitant tobacco smoking, each agent approximately multiplying the effect of the other. In the absence of smoking the risks are small for moderate alcohol consumption. After stopping drinking, some fall in risk becomes apparent in the long term. The role of age at starting and stopping drinking is still unclear. In various studies, the most commonly used alcoholic beverage appears to be the most associated with laryngeal cancer risk, suggesting that no meaningful difference exists for different types of alcoholic beverages. The supraglottis is more closely related to alcohol consumption, as compared to the glottis/subglottis. Alcohol drinking may influence laryngeal cancer risk particularly through its direct contact or solvent action, perhaps by enhancing the effects of tobacco or other environmental carcinogens.
Oral Oncol . 2005 May 28
History of cirrhosis and risk of digestive tract neoplasms.
Background: Cirrhosis is strongly related to liver cancer. Data on the possible association between cirrhosis and risk at other cancer sites are scanty. Patients and methods: We analysed data from a network of case-control studies conducted in Italy between 1983 and 1997, including patients with cancers of the oral cavity and pharynx (520), oesophagus (405), stomach (731), colon (943), rectum (613), liver (425), gallbladder (63) and pancreas (395). The controls were 4297 patients admitted to hospitals for acute non-neoplastic conditions. Results: After strict allowance for alcohol drinking, tobacco smoking and history of hepatitis, the multivariate odds ratios for a history of cirrhosis were 4.7 [95% confidence interval (CI) 2.2-9.8] for neoplasms of the oral cavity and pharynx, 2.6 (95% CI 1.2-5.7) for the oesophagus, 1.0 (95% CI 0.4-2.5) for the stomach, 1.0 (95% CI 0.4-2.4) for the colon, 1.7 (95% CI 0.7-4.1) for the rectum, 20.5 (95% CI 12.3-34.2) for the liver, 2.1 (95% CI 0.3-16.8) for the gallbladder and 0.9 (95% CI 0.3-3.0) for the pancreas. Conclusions: Our study confirms and further quantifies the increased risk of liver cancer in cirrhotic patients and is compatible with an increased risk of oral, pharyngeal and oesophageal cancers.
Ann Oncol . 2005 Sep;16(9):1551-1555
Expression of aldehyde dehydrogenase 2 in the normal esophageal epithelium and alcohol consumption in patients with esophageal cancer.
Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.
Front Biosci . 2005 Sep 1;10:2319-24
Alcohol drinking and risk of localized versus advanced and sporadic versus familial prostate cancer in Sweden.
BACKGROUND: It is unknown whether the association of alcohol consumption with prostate cancer risk varies between localized and advanced cases, or between sporadic and familial cases.METHODS: We assessed recent alcohol drinking in a population-based case--control study of Swedish men, including 1499 cases and 1130 controls. Drinking status and average volume, frequency, and type of alcohol consumed were evaluated. Unconditional logistic regression was performed to estimate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for associations between alcohol consumption and prostate cancer risk.RESULTS: Prostate cancer cases were more likely than controls to be current or former, rather than never, drinkers. However, there was no association between recent total alcohol, beer, wine, and liquor consumption and risk of overall prostate cancer, nor advanced, sporadic, or familial prostate cancer. The OR for risk of overall disease among men who drank more than 135 g of total alcohol per week versus non-drinkers was 1.2 (95% CI: 0.9, 1.5), p(trend)=0.12. There was a marginal positive association between alcohol intake and risk of localized disease.CONCLUSIONS: We detected no association between recent alcohol consumption and risk of advanced, sporadic, or familial prostate cancer, and a borderline positive association with localized disease.
Cancer Causes Control . 2005 Apr;16(3):275-84
Alcohol in hepatocellular cancer.
Hepatocellular cancer accounts for almost half a million cancer deaths a year, with an escalating incidence in the Western world. Alcohol has long been recognized as a major risk factor for cancer of the liver and of other organs including oropharynx, larynx, esophagus, and possibly the breast and colon. There is compelling epidemiologic data confirming the increased risk of cancer associated with alcohol consumption, which is supported by animal experiments. Cancer of the liver associated with alcohol usually occurs in the setting of cirrhosis. Alcohol may act as a cocarcinogen, and has strong synergistic effects with other carcinogens including hepatitis B and C, aflatoxin, vinyl chloride, obesity, and diabetes mellitus. Acetaldehyde, the main metabolite of alcohol, causes hepatocellular injury, and is an important factor in causing increased oxidant stress, which damages DNA. Alcohol affects nutrition and vitamin metabolism, causing abnormalities of DNA methylation. Abnormalities of DNA methylation, a key pathway of epigenetic gene control, lead to cancer. Other nutritional and metabolic effects, for example on vitamin A metabolism, also play a key role in hepatocarcinogenesis. Alcohol enhances the effects of environmental carcinogens directly and by contributing to nutritional deficiency and impairing immunological tumor surveillance. This review summarizes the epidemiologic evidence for the role of alcohol in hepatocellular cancer, and discusses the mechanisms involved in the promotion of cancer.
Clin Liver Dis . 2005 Feb;9(1):151-69
Next day effects of a normal night's drinking on memory and psychomotor performance.
AIM: To investigate in social drinkers the effects of a 'normal' evening of drinking alcohol on cognitive performance. METHODS: Aiming for ecological validity, the study required participants to consume their usual quantity of any type of alcoholic beverage in their chosen company (hangover situation). However, the timing of drinking was restricted to the period between 22:00 and 02:00 hours on the night before testing. Testing included memory and psychomotor performance tests; testing was also performed after an evening of abstinence (no hangover situation), following a counterbalanced design using repeated measures, with time of testing (09:00, 11:00 and 13:00 hours) and order of testing (hangover/no hangover; no hangover/hangover) as 'between participant' factors in the analysis. RESULTS: Forty-eight social drinkers (33 women, 15 men) aged between 18 and 43 years were tested, with a 1-week interval between test sessions. The morning after alcohol (mean consumption: 14.7 units for men; 10.4 units for women), free recall was impaired at 09:00 hours and delayed recognition and psychomotor performance were impaired throughout the morning, despite blood alcohol levels of zero or very near zero. CONCLUSION: Memory and psychomotor performance is impaired on the morning after heavy 'social' drinking.
Alcohol Alcohol . 2004 Nov-Dec;39(6):509-13
A physiologically based model for ethanol and acetaldehyde metabolism in human beings.
Pharmacokinetic models for ethanol metabolism have contributed to the understanding of ethanol clearance in human beings. However, these models fail to account for ethanol's toxic metabolite, acetaldehyde. Acetaldehyde accumulation leads to signs and symptoms, such as cardiac arrhythmias, nausea, anxiety, and facial flushing. Nevertheless, it is difficult to determine the levels of acetaldehyde in the blood or other tissues because of artifactual formation and other technical issues. Therefore, we have constructed a promising physiologically based pharmacokinetic (PBPK) model, which is an excellent match for existing ethanol and acetaldehyde concentration-time data. The model consists of five compartments that exchange material: stomach, gastrointestinal tract, liver, central fluid, and muscle. All compartments except the liver are modeled as stirred reactors. The liver is modeled as a tubular flow reactor. We derived average enzymatic rate laws for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), determined kinetic parameters from the literature, and found best-fit parameters by minimizing the squared error between our profiles and the experimental data. The model's transient output correlates strongly with the experimentally observed results for healthy individuals and for those with reduced ALDH activity caused by a genetic deficiency of the primary acetaldehyde-metabolizing enzyme ALDH2. Furthermore, the model shows that the reverse reaction of acetaldehyde back into ethanol is essential and keeps acetaldehyde levels approximately 10-fold lower than if the reaction were irreversible.
Alcohol. 2005 Jan;35(1):3-12
Oxidation of ethanol to acetaldehyde and free radicals by rat testicular microsomes.
A large number of epidemiological studies evidencing that excessive alcohol consumption is associated with impaired testosterone production and testicular atrophy are available in the literature. One hypothesis to explain the deleterious action of alcohol involves the in situ biotransformation to acetaldehyde, but it strongly suggests the need to learn more about the enzymatic processes governing alcohol metabolism to acetaldehyde in different cellular fractions since limited information is available in the literature. In this article we report studies on the metabolic conversion of alcohol to acetaldehyde and to 1-hydroxyethyl radicals in rat testicular microsomal fractions. The oxidation of ethanol to acetaldehyde in rat testes microsomal fraction was mostly of enzymatic nature and strongly dependent on the presence of NADPH and oxygen. Several compounds were able to significantly decrease the production of acetaldehyde: SKF 525A; diethyldithiocarbamate; esculetin; gossypol; curcumin; quercetin; dapsone; and diphenyleneiodonium. Microsomal preparations in the presence of NADPH were also able to produce both hydroxyl and 1-hydroxyethyl free radicals. Their generation was modulated by the presence of diphenyleneiodonium, gossypol, and deferoxamine. Results show that rat microsomal fractions are able to metabolize alcohol to deleterious chemicals, such as acetaldehyde and free radicals, that may be involved in ethanol toxic effects. Enzymes involved could include CYP2E1, P450 reductase, and other enzymes having lipoxygenase- /peroxidase-like behavior.
Arch Toxicol . 2005 Jan;79(1):25-30
The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role.
Oxidation of ethanol via alcohol dehydrogenase (ADH) explains various metabolic effects of ethanol but does not account for the tolerance. This fact, as well as the discovery of the proliferation of the smooth endoplasmic reticulum (SER) after chronic alcohol consumption, suggested the existence of an additional pathway which was then described by Lieber and DeCarli, namely the microsomal ethanol oxidizing system (MEOS), involving cytochrome P450. The existence of this system was initially challenged but the effect of ethanol on liver microsomes was confirmed by Remmer and his group. After chronic ethanol consumption, the activity of the MEOS increases, with an associated rise in cytochrome P450, especially CYP2E1, most conclusively shown in alcohol dehydrogenase negative deer mice. There is also cross-induction of the metabolism of other drugs, resulting in drug tolerance. Furthermore, the conversion of hepatotoxic agents to toxic metabolites increases, which explains the enhanced susceptibility of alcoholics to the adverse effects of various xenobiotics, including industrial solvents. CYP2E1 also activates some commonly used drugs (such as acetaminophen) to their toxic metabolites, and promotes carcinogenesis. In addition, catabolism of retinol is accelerated resulting in its depletion. Contrasting with the stimulating effects of chronic consumption, acute ethanol intake inhibits the metabolism of other drugs. Moreover, metabolism by CYP2E1 results in a significant release of free radicals which, in turn, diminishes reduced glutathione (GSH) and other defense systems against oxidative stress which plays a major pathogenic role in alcoholic liver disease. CYP1A2 and CYP3A4, two other perivenular P450s, also sustain the metabolism of ethanol, thereby contributing to MEOS activity and possibly liver injury. CYP2E1 has also a physiologic role which comprises gluconeogenesis from ketones, oxidation of fatty acids, and detoxification of xenobiotics other than ethanol. Excess of these physiological substrates (such as seen in obesity and diabetes) also leads to CYP2E1 induction and nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH), with pathological lesions similar to those observed in alcoholic steatohepatitis. Increases of CYP2E1 and its mRNA prevail in the perivenular zone, the area of maximal liver damage. CYP2E1 up-regulation was also demonstrated in obese patients as well as in rat models of obesity and NASH. Furthermore, NASH is increasingly recognized as a precursor to more severe liver disease, sometimes evolving into "cryptogenic" cirrhosis. The prevalence of NAFLD averages 20% and that of NASH 2% to 3% in the general population, making these conditions the most common liver diseases in the United States. Considering the pathogenic role that up-regulation of CYP2E1 also plays in alcoholic liver disease (vide supra), it is apparent that a major therapeutic challenge is now to find a way to control this toxic process. CYP2E1 inhibitors oppose alcohol-induced liver damage, but heretofore available compounds are too toxic for clinical use. Recently, however, polyenylphosphatidylcholine (PPC), an innocuous mixture of polyunsaturated phosphatidylcholines extracted from soybeans (and its active component dilinoleoylphosphatidylcholine), were discovered to decrease CYP2E1 activity. PPC also opposes hepatic oxidative stress and fibrosis. It is now being tested clinically.
Drug Metab Rev . 2004 Oct;36(3-4):511-29
CYP2E1: from ASH to NASH.
The pathology of the liver in alcoholic steatosis and alcoholic steatohepatitis (ASH) is remarkably similar to that of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), suggesting some common pathogenic mechanism. Studies carried out over the last three decades of possible mechanisms involved revealed one common link, namely the induction of cytochrome P4502E1. Its substrates include fatty acids, ketones and ethanol. These substances, when present chronically in large amounts, induce the activity of the enzyme which thereby contributes to the disposition of these substrates. This reaction, however, is associated with the release of free radicals which can cause lipid peroxidation and liver injury, including mitochondrial damage. Mitochondrial damage in turn exacerbates the oxidative stress. CYP2E1 can also convert various xenobiotics to toxic metabolites. When unchecked, this toxicity eventually results in inflammation and fibrosis, culminating in cirrhosis. Prevention of this disorder is based on limiting the substrates that induce the system, such as excessive fatty acid associated with obesity and excessive alcohol consumption. No effective pharmacologic treatment is presently available but there is ongoing research on possible inhibitors of CYP2E1, innocuous enough to be suitable for chronic human consumption and sufficiently effective to attenuate the CYP2E1 induction to avoid the consequences of its excessive activity while maintaining its physiologic role.
Hepatol Res . 2004 Jan;28(1):1-11
Oxidative stress and antioxidant status in patients with alcoholic liver disease.
BACKROUND: Alcoholic liver diseases (ALD) are very common in lower socio-economical strata due to heavy drinking habits and multiple nutritional deficiencies. Ethanol causes liver damage by many mechanisms. The generation of lipid peroxidation by free radicals has been proposed as a mechanism for ethanol induced hepatotoxicity. These free radicals are destroyed by anti-oxidants. Many anti-oxidants are present in the diet, e.g., vitamin E, vitamin C etc. However, poor nutrition or malabsorption leads to deficiency of these vitamins. This may impair the anti-oxidative defense leading to ethanol induced oxidative stress and then to liver damage. METHODS: Oxidative stress and antioxidant defense were assessed in patients with alcoholic liver disease. Serum malondialdehyde (MDA) concentrations were measured as an index of lipid peroxidation, i.e., oxidative stress; and serum vitamins E and C concentrations were measured as an index of antioxidant status. RESULTS: Serum MDA concentrations were increased with the increase in severity of the disease. Concentrations of serum vitamins E and C were decreased in patients with alcoholic liver disease as compared to controls. CONCLUSIONS: Our observations may be due to increased demands of the same or increased utilization.
Clin Chim Acta . 2005 May;355(1-2):61-5