Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro-inflammation.

It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro-inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels. Further, along with Pde4b, there was a robust activation of astrocytes and microglia accompanied by significant increases in the inflammatory cytokines (Tnfα, Il-1ß, Mcp-1 and Il-17) and the generalized inflammatory marker Cox-2. At the cellular level, alcohol and inflammatory mediators, particularly LPS, Tnfα and Hmgb1 significantly activated microglial cells (Iba-1 expression) and selectively induced Pde4b expression with a minimal to no change in Pde4a and d isoforms. In comparison, the alcohol-induced decrease in brain cAMP levels was completely inhibited in WT mice treated with the Pde4 specific pharmacologic inhibitor rolipram and in Pde4b-/- mice. Moreover, all the observed markers of alcohol-induced brain inflammation were markedly attenuated. Importantly, glial cell activation induced by systemic endotoxemia (LPS administration) was also markedly decreased in Pde4b-/- mice. Taken together, these findings strongly support the notion that Pde4b plays a critical role in coordinating alcohol-induced, peripheral endotoxemia mediated neuro-inflammation and could serve as a significant therapeutic target.

ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective.

The occurrence of more than 200 diseases, including cancer, can be attributed to alcohol drinking. The global cancer deaths attributed to alcohol-consumption rose from 243,000 in 1990 to 337,400 in 2010. In 2010, cancer deaths due to alcohol consumption accounted for 4.2% of all cancer deaths. Strong epidemiological evidence has established the causal role of alcohol in the development of various cancers, including esophageal cancer, head and neck cancer, liver cancer, breast cancer, and colorectal cancer. The evidence for the association between alcohol and other cancers is inconclusive. Because of the high prevalence of ALDH2*2 allele among East Asian populations, East Asians may be more susceptible to the carcinogenic effect of alcohol, with most evidence coming from studies of esophageal cancer and head and neck cancer, while data for other cancers are more limited. The high prevalence of ALDH2*2 allele in East Asian populations may have important public health implications and may be utilized to reduce the occurrence of alcohol-related cancers among East Asians, including: 1) Identification of individuals at high risk of developing alcohol-related cancers by screening for ALDH2 polymorphism; 2) Incorporation of ALDH2 polymorphism screening into behavioral intervention program for promoting alcohol abstinence or reducing alcohol consumption; 3) Using ALDH2 polymorphism as a prognostic indicator for alcohol-related cancers; 4) Targeting ALDH2 for chemoprevention; and 5) Setting guidelines for alcohol consumption among ALDH2 deficient individuals. Future studies should evaluate whether these strategies are effective for preventing the occurrence of alcohol-related cancers.

The six-year outcome of alcohol use disorders in men: A population based study from India.

BACKGROUND: Despite the large and growing public health problem of alcohol use disorders (AUD) in India there is a dearth of evidence about the longitudinal outcomes in AUD. The aim of this study is to describe the course and outcomes of AUD in a population based sample of men in India. METHODS: A community cohort of 1899 adult (18-49 years at baseline) men who participated in a cross-sectional survey in Goa, India between 2006 and 08, were re-interviewed face to face 6 years later (2012-14). A range of outcomes including social problems (e.g., workplace problems, domestic violence), morbidity (e.g., range of physical and mental health problems), biological parameters (e.g., mean corpuscular volume [MCV], gamma-glutamyl transpeptidase [GGT]) and mortality were measured at follow up. For the association of AUD at baseline with outcomes at follow-up, multivariable logistic regression was used to estimate odds ratios (OR). Analyses were weighted to account for baseline sampling design, age distribution, rural and urban sample sizes, number of adults aged 18-49 years in the household (at baseline), and non-response (at baseline). RESULTS: 1514 (79.7%) were seen at follow-up; a loss to follow up of 20.3%. At follow up, 3.7% of baseline non-drinkers and 15.0% of baseline casual drinkers had AUD. 46.9% of baseline hazardous drinkers and 55.4% baseline harmful drinkers continued to have AUD at follow up. Of those with AUD at baseline, 21.8% had stopped drinking at follow-up. Compared to being abstinent, harmful drinking at baseline was associated with several outcomes at follow-up: workplace/social problems, hypertension, death, tobacco use, suicidality, anxiety disorders, and raised GGT (p<0.002). Hazardous drinking at baseline was associated with tobacco use and raised GGT and MCV (p<0.002) at follow-up. CONCLUSION: Our findings of high persistent and new AUD in the community and the association with a range of long term adverse events are an important addition to the limited evidence about the course and outcomes of AUD in India, which have the potential for informing health policy.

Selective chemical genetic inhibition of protein kinase C epsilon reduces ethanol consumption in mice.

Reducing expression or inhibiting translocation of protein kinase C epsilon (PKCε) prolongs ethanol intoxication and decreases ethanol consumption in mice. However, we do not know if this phenotype is due to reduced PKCε kinase activity or to impairment of kinase-independent functions. In this study, we used a chemical-genetic strategy to determine whether a potent and highly selective inhibitor of PKCε catalytic activity reduces ethanol consumption. We generated ATP analog-specific PKCε (AS-PKCε) knock-in mice harboring a point mutation in the ATP binding site of PKCε that renders the mutant kinase highly sensitive to inhibition by 1-tert-butyl-3-naphthalen-1-ylpyrazolo[3,4-d]pyrimidin-4-amine (1-NA-PP1). Systemically administered 1-NA-PP1 readily crossed the blood brain barrier and inhibited PKCε-mediated phosphorylation. 1-NA-PP1 reversibly reduced ethanol consumption by AS-PKCε mice but not by wild type mice lacking the AS-PKCε mutation. These results support the development of inhibitors of PKCε catalytic activity as a strategy to reduce ethanol consumption, and they demonstrate that the AS- PKCε mouse is a useful tool to study the role of PKCε in behavior.

CaMKII inhibition in the prefrontal cortex specifically increases the positive reinforcing effects of sweetened alcohol in C57BL/6J mice.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is required for synaptic plasticity and has been proposed to be a primary molecular component of the etiology of alcohol addiction. Chronic alcohol intake upregulates CaMKIIα protein expression in reward-related brain regions including the amygdala and nucleus accumbens, and CaMKIIα activity in the amygdala is required for the positive reinforcing effects of alcohol, suggesting this system promotes consumption in the early stages of alcohol addiction. Alternatively, the medial prefrontal cortex (mPFC) is known to inhibit limbic activity via CaMKII-dependent excitatory projections and may, therefore, enable top-down regulation of motivation. Here we sought to remove that regulatory control by site-specifically inhibiting CaMKII activity in the mPFC, and measured effects on the positive reinforcing effects of sweetened alcohol in C57BL/6J mice. Infusion of the CAMKII inhibitor KN-93 (0-10.0 µg) in the mPFC primarily increased alcohol+sucrose reinforced response rate in a dose- and time-dependent manner. KN-93 infusion reduced response rate in behavior-matched sucrose-only controls. Importantly, potentiation of operant responding for sweetened alcohol occurred immediately after infusion, at a time during which effects on sucrose responding were not observed, and persisted through the session. These results suggest that endogenous CaMKII activity in the mPFC exerts inhibitory control over the positive reinforcing effects of alcohol. Downregulation of CaMKII signaling in the mPFC might contribute to escalated alcohol use.

The alcohol deprivation effect: marked inhibition by anticatalase gene administration into the ventral tegmental area in rats.

BACKGROUND: Animals that have chronically consumed alcohol and are subsequently deprived of it markedly increase their intake above basal levels when access to alcohol is reinstated. Such an effect, termed the alcohol deprivation effect (ADE), has been proposed to reflect (i) an obsessive-compulsive behavior, (ii) craving, or (iii) an increased reinforcing value of ethanol (EtOH). It has been reported that acetaldehyde, a highly reinforcing metabolite of EtOH, is generated in the brain by the action of catalase. Recent studies show that the administration of an anticatalase (shRNA)-encoding lentiviral vector into the brain ventral tegmental area (VTA) of naïve rats virtually abolishes (85 to 95%) their EtOH intake. It is hypothesized that the antireinforcing effect of the anticatalase vector will also inhibit the ADE. METHODS: Two-month-old Wistar-derived UChB alcohol drinker rats were offered free access to water and 10 and 20% EtOH for 67 days. Thereafter, the animals were deprived of EtOH for 15 days and were subsequently offered access to the EtOH solutions. At the start of the deprivation period, animals were microinjected a single dose of an anticatalase (or control) vector into the VTA. EtOH intake was measured on the first hour of EtOH re-exposure as well as on a 24-hour basis for 7 days. RESULTS: A marked ADE was observed when EtOH intake was measured on the first hour or 24 hours following EtOH re-exposure, compared to the corresponding controls. The administration of the anticatalase vector reduced ADE by 60 to 80% (p < 0.001) on the first hour and by 63 to 80% (p < 0.001) on the initial 24 hours of EtOH re-exposure (first and second ADE, respectively) without changing the total fluid intake, indicating a specific effect on EtOH drinking. CONCLUSIONS: Ethanol intake associated with ADE--a binge-like drinking behavior--is markedly inhibited by the administration of an anticatalase vector into the VTA, which blocks the conversion of EtOH into acetaldehyde, strongly suggesting that the marked increased EtOH intake that follows an alcohol deprivation period is mediated by acetaldehyde and its reinforcing metabolite.

Gamma-glutamyltransferase in alcohol use disorders: Modification of decision limits in relation to treatment goals?

Serum gamma-glutamyltransferase (GGT) is recommended as a marker for alcohol use disorders by the Swedish National Guidelines for Addiction, although it has a low sensitivity and specificity. GGT is inexpensive and easily accessible but additional knowledge is required on how to use the marker in patients with various levels of alcohol intake. Levels of GGT were obtained from 37 male social drinkers (< 100 grams pure alcohol weekly) and 18 former alcohol-dependent males with long-term (6 +/- 5 years) abstinence. Reproducibility was calculated through repeated blood samplings. Mean serum activity of GGT, in former alcohol-dependent males, was 0.26 microkat/L with an intra-class correlation coefficient of 0.85. In social drinkers, these figures were 0.34 microkat/L and 0.92, respectively. In treatment of males, with the goal of abstinence, upper reference limit is suggested to be 0.40 microkat/L. Goals of non-harmful drinking (< 100 grams weekly) suggest higher limits (0.62 microkat/L). Thirty percent increase of GGT should be suggestive of relapse.

[Anti-alcoholic and anti-narcotic action of Methylobacteriim extorquens UCM B-3368].

The paper deals with action efficiency of microbial biomass on characteristic indicators at alcohol and morphine organism intoxication. The investigated microbial biomass affects the regulatory biochemical and physiological systems in experimental animals, normalizes activity of alcohol dehydrogenase and aldehide dehydrogenase, as well as the content of dophamine, disturbed under the effect of alcohol and morphine. Thus, the organism intoxication decreases. Except for the specific action, the above microbial biomass can be a source of protein, aminoacids, vitamins, microelements. So, the microbial preparation, made on its basis, can be used for the treatment of alcohol and morphine dependence in a form of biologically active dope. Thus the microbial drug intended for treatment of alcohol and opium dependence has been developed. One of its action mechanisms is based on the microorganisms capacity to transform alcohols and aldehides, owing to availability of alcohol and aldehide dehydrogenase, other its action mechanisms are at the stage of investigation.

Hazardous drinking is associated with an elevated aspartate aminotransferase to platelet ratio index in an urban HIV-infected clinical cohort.

OBJECTIVES: The aim of the study was to determine the relationship between alcohol consumption and liver fibrosis as assessed by aspartate aminotransferase to platelet ratio index (APRI) in HIV-infected adults and to explore the relative contributions of alcohol and hepatitis C virus (HCV) to APRI among HIV/HCV-coinfected adults. METHODS: We performed a cross-sectional analysis of data from an observational clinical cohort. Alcohol consumption was categorized according to National Institute on Alcohol Abuse and Alcoholism guidelines. We defined significant liver disease as APRI>1.5, and used multinomial logistic regression to identify correlates of increased APRI. RESULTS: Among 1358 participants, 10.4% reported hazardous drinking. It was found that 11.6% had APRI>1.5, indicating liver fibrosis. Hazardous drinking was associated with increased APRI [adjusted relative risk ratio (RRR) 2.30; 95% confidence interval (CI) 1.26-4.17]. Other factors associated with increased APRI were male gender, viral hepatitis, and HIV transmission category of injecting drug use. Among coinfected individuals, 18.3% had APRI>1.5, and hazardous drinking was not associated with APRI. Among non-HCV-infected individuals, 5.3% had APRI>1.5 and hazardous drinking was associated with increased APRI (adjusted RRR 3.72; 95% CI 1.40-9.87). CONCLUSIONS: Hazardous drinking is an important modifiable risk factor for liver fibrosis, particularly among non-HCV-infected patients. Clinicians and researchers must address alcohol use as the burden of liver disease increases among HIV-positive individuals.

Use of laboratory markers and the audit questionnaire by primary care physicians to detect alcohol abuse by patients.

AIMS: To evaluate how often laboratory markers [Mean corpuscular volume (MCV), Gamma-glutamyl transferase, Aspartate aminotransferase, Alanine aminotransferase, or Carbohydrate-deficient transferrin (CDT)] and the Alcohol Use Disorders Identification Test (AUDIT) are used to detect alcohol abuse in primary health care. METHODS: Cross-sectional self-administered questionnaire survey to all 3193 primary health care physicians in Finland. Response rate was (65.7%). RESULTS: CDT was used at least occasionally by 43.4% of the physicians. Corresponding figures were 53.4% for conventional alcohol laboratory markers (MCV, transaminases) and 67.0% for AUDIT. Almost all the respondents used some laboratory marker to detect alcohol abuse. The use of brief alcohol intervention was associated with the greater likelihood that a physician uses different methods to detect alcohol abuse. The data also indicates that gender, age, and having a specialist licence influence activity in using different methods. CONCLUSIONS: Considering the ambivalences in relation to alcohol issues in health care, the use of CDT and AUDIT are reasonably frequent. This may indicate that tools to facilitate the work may also help in adapting new activities.

Combining the audit questionnaire and biochemical markers to assess alcohol use and risk of alcohol withdrawal in medical inpatients.

AIMS: Alcohol consumption is often under-reported in patients admitted to general hospitals with acute illness. For alcohol-dependent individuals hospital admission results in an enforced period of abstinence with potential alcohol withdrawal symptoms, and possible life threatening complications. Early detection of alcohol use is therefore beneficial to patients and health services. The purpose of this study was to investigate the performance of the alcohol use disorders identification test (AUDIT) questionnaire in the acute medical setting, and the effect of combining routine biological markers-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase, and mean corpuscular volume (MCV) on its performance in the early identification of in-patients with alcohol use disorders and at risk of developing symptoms of alcohol withdrawal. METHODS: Prospective study in consecutive patients admitted to an acute medical admissions ward. All patients were screened using the AUDIT questionnaire and routine blood tests. Patients were then monitored for symptoms of withdrawal using clinical institute withdrawal assessment for alcohol (CIWA-Ar). RESULTS: Of the 874 patients screened using the AUDIT, 98 (11%) screened positive of whom 17 (2% of the 874) experienced clinically significant alcohol withdrawal symptoms, when using serial CIWA-Ar. The AUDIT and serial CIWA-Ar detected all patients who went on to manifest acute withdrawal symptoms. There was no loss of sensitivity at an AUDIT cut-off of 13 or more compared with the lower cut-off of 8 or more. A positive predictive value of 17.3% for an AUDIT score of 8 or more in the detection of withdrawal, increased to 47.1% when found in combination with at least two abnormal biological markers whilst maintaining a sensitivity of 94.1% and specificity of 97.9%. CONCLUSION: These findings confirm that AUDIT is a useful alcohol screen in general medical settings and that its ability to correctly predict which patients will experience alcohol withdrawal is increased when used in combination with biological markers.

Are commonly ordered lab tests useful screens for alcohol disorders in older male veterans receiving primary care?.

Although mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferases (ALT), and the AST/ALT ratio are sometimes used as markers of alcohol disorders, their utility has not been established in older persons. We determined the tests' performance characteristics for (1) at-risk drinking, (2) CAGE positivity, (3) at-risk drinking and CAGE positivity, and (4) a clinician-recorded diagnosis of alcohol abuse/dependence in a study of older male veterans receiving primary care. Participants (n = 587) included patients who had MCV, AST, and/or ALT data collected as part of routine care no more than 12 weeks before or after enrollment. MCV, AST, and ALT test results were obtained from the VA's database. At enrollment, the Timeline Followback and Alcohol Use Disorders Identification Test (AUDIT) were used to identify at-risk drinkers (> or = 15 drinks per week or AUDIT score > or = 8), and the CAGE questionnaire was administered to identify participants with a history abuse/dependent drinking (CAGE score > or = 2). Participants' medical records were reviewed to identify subjects with a clinician-recorded diagnosis of alcohol abuse/dependence. The prevalence of abnormal test results for MCV (threshold value = > 98), AST (> 41), ALT (> 41), and the AST/ALT ratio (> 2) was 11%, 4%, 4%, and 5%, respectively. The occurrence of at-risk drinking, CAGE positivity, at-risk drinking and CAGE positivity, and a clinician-recorded diagnosis of alcohol abuse/dependence was 11%, 25%, 5%, and 9%, respectively. Test sensitivity ranged from 3.9% to 25.4% and specificity from 88.5% to 97.1%, whereas positive likelihood ratios varied from 0.72 to 4.01 and negative likelihood ratios from 0.82 to 1.04. Areas under the receiver operating characteristic curve were similar (range = 0.50-0.58) across tests. In conclusion, MCV, AST, ALT, and the AST/ALT ratio are not useful markers of alcohol disorders in older male veterans.

Influence of genetic variations of ethanol-metabolizing enzymes on phenotypes of alcohol-related disorders.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2) play central roles in the metabolism of ethanol and its metabolite, acetaldehyde, in the liver. In ADH2, one nucleotide replacement causes either a super-active beta 2 subunit encoded by the ADH2*2 allele or a less active beta 1 subunit (ADH2*1 allele). In the same way, a G/A replacement at codon 487 of the ALDH2 gene produces an inactive form of the enzyme. Because the geno-types of these genes may explain individual differences in concentration and elimination of ethanol and acetaldehyde in the blood after drinking, they could be used as models to elucidate the contribution of these substances to the development of addiction and various types of organ damage. We have examined the influence of genetic variations of these enzymes on alcohol-related disorders in the Japanese. The results revealed that (1) the less active allele of the ADH2 gene (ADH2*1) is associated with an increased risk for alcohol dependence, alcohol-induced persistent amnestic disorder, alcohol withdrawal syndrome, and cancer of the upper GI tract; (2) the inactive allele of the ALDH2 gene (ALDH2*2) is associated with a decreased risk for alcohol dependence, and an increased risk for alcoholic polyneuropathy and cancer in the same region; and (3) these genetic variations modify clinical features of alcohol dependence. Possible mechanisms of altered risk for these disorders are discussed.

Adolescence and the trajectory of alcohol use: basic to clinical studies.

Emerging findings from developmentally focused research indicates subtle but important neurocognitive disadvantages among adolescents with alcohol-use disorders (AUD) as compared to teens without AUD. Even after 3 weeks of abstinence AUD youth display a 10% decrement in delayed memory functions. Neuropsychological testing of youth followed at 4 and 8 years demonstrates that heavy drinking during adolescence is associated with diminished retrieval of verbal and nonverbal material, and poorer performance on tests requiring attention skills. Alcohol withdrawal over the teen years appears to uniquely contribute to deterioration in functioning in visuospatial tasks. Brain imaging studies suggest reduced hippocampal volumes, white matter microstructure irregularities, brain response abnormalities while performing challenging cognitive tasks, and enhanced brain response when viewing alcohol cues (i.e., alcohol advertisements) among adolescents with AUD. Family characteristics such as history of alcoholism and socioeconomic status as well as personal features, including adolescent psychopathology, gender, and age of onset must be carefully considered when investigating the influence of teenage drinking on neurocognition. Further research is needed to understand how age at onset of drinking and duration of abstinence at the time of assessment affect cognitive findings. Longitudinal studies are needed to clarify neuromaturational changes associated with early alcohol exposure and patterns of resiliency. Although the magnitude of alcohol-related effects observed in adolescents' neurocognition is relatively modest, the implications are major given the prevalence of alcohol involvement, and the important educational, occupational, and social transitions that occur during adolescence.

ERK regulation in chronic ethanol exposure and withdrawal.

The extracellular signal regulated protein kinases (ERKs), also known as mitogen-activated protein kinases (MAPK) of 42 and 44 kd, play a crucial role in the induction of various forms of neural plasticity. Ethanol induces long-lasting functional changes that are more severe following repeated exposure and may involve intracellular signal transduction mechanisms. Therefore, we investigated the regulation of the ERK signal transduction pathway in models of continuous and intermittent ethanol exposure and withdrawal. Moderate blood alcohol levels (BALs) reduced ERK activation in most of the brain regions studied. Conversely, during withdrawal, activation of ERK was increased in most areas with some regional variations in the levels and kinetics of induction. The most dramatic effects were observed in the amygdala, the cerebellum, the striatum and the hippocampus. In the amygdala and the cerebellum, the activation of ERK observed during withdrawal was significantly higher after intermittent ethanol exposure than after continuous exposure, suggesting the establishment of a form of sensitization to the effects of withdrawal on ERK regulation. Thus the dysregulation of the ERK pathway could contribute to escalation of withdrawal symptoms induced by repeated withdrawal and possibly to the neuroadaptative changes believed to underlie progression towards addiction.

Prevention of alcohol-related deaths in middle-aged heavy drinkers.

BACKGROUND: Alcohol as a cause of death in middle-aged patients is well-known from clinical studies. A similarly important correlation in the general population of urban middle-aged men is highly underestimated. Health screening investigations have shown that mortality related to alcohol is five times more common in nonparticipants than in participants. From the mid-70s, the Malmoe Screening and Intervention Study (MSIS) commenced screening investigations including a large number of residents of Malmoe. One goal was to find intervention programs for individuals in an early development of problem drinking, thereby preventing development of serious complications of endstage alcoholism. Herein, we report on the mortality of heavy drinkers (drinking more than 40 g alcohol/day) who were randomized to an intervention or control procedure and whose median survival was 13 years postentry into the MSIS. METHODS: Health-screened men, aged 45-49 years at the initial screening examination and displaying serum gamma-glutamyltransferase (GT) in the top decentile of the GT distribution, were included. A total of 978 out of 11,257 participants met this criteria. A randomized intervention and control study was performed for four years and consisted of men (n = 667) who were born between 1927-1937 and who had two consecutive high GT values within 3 weeks along with heavy alcohol consumption. Half the individuals were informed of the test results and invited for further assessment by a senior physician (n = 365). The principles for brief intervention (DiClemente et al.,1991; Miller and Sanchez, 1993; National Institute of Alcohol Abuse and Alcoholism, 1999) were applied. The other half of the men (n = 302) were left with the information that they had a high GT value and were followed up with laboratory checkups every 2nd year. Mortality was followed up until 1991 and information on deaths was obtained from hospital and police records, necropsy reports, and death certificates. RESULTS: Long-term follow-up of mortality for 10-16 years (median, 13 years) showed that 124 of the 978 men had died (12.7%). Autopsy was performed in 96.5% of the cases. In 59 men (48%), death was alcohol-related. In the intervention group (n = 365), 38 (10.4%) men were dead and in the control group (n = 302), 42 (13.9%) men had died. There was a statistically significant difference (p = 0.026), with advantage for treatment. Less alcohol-related deaths and deaths occurring later during follow-up were found in the intervention group compared with the control group. The difference between the groups in total mortality, coronary heart disease, and cancer death was not statistically significant. CONCLUSIONS: These findings support previous results from the MSIS study indicating that long-term intervention in urban males with alcohol-induced GT increases may be beneficial in terms of survival.

[Alcohol and drug interactions]. / Alkohol und Medikamenteninteraktionen.

Alcohol metabolism occurs mainly in the liver, where in abstainers the alcoholdehydrogenase (ADH) pathway plays the major role. After chronic alcohol consumption, the microsomal ethanol-oxidizing system (MEOS), involving the ethanol-inducible cytochrome P450 2E1, increases in importance with a four- to ten-fold increase in the contribution to alcohol metabolism. Because of the fact that this enzyme system catalyses not only the metabolism of ethanol but also activates a great number of drugs, it is a very common site of alcohol-drug interactions. Clinically relevant interactions will be discussed. Only a small amount of alcohol is metabolized outside the liver, mainly in the stomach by gastric ADH, which leads to the so-called first-pass metabolism of ethanol. Its significance in alcohol metabolism is reviewed. The only way to prevent severe alcohol-drug interactions is to make medical doctors as well as their patients more aware of these possible secondary effects.

Hangover symptoms in Asian Americans with variations in the aldehyde dehydrogenase (ALDH2) gene.

OBJECTIVE: Hangovers are not experienced by all people and whether they contribute to the development of alcoholism is unclear. One population that might provide some insight into the role of hangover in the etiology of alcohol use disorders is that of individuals of Asian heritage. Certain Asians have lower rates of alcohol use and alcoholism, findings associated with a mutation in the aldehyde dehydrogenase (ALDH2) gene. Asians with ALDH2*2 alleles drink less and are less likely to be alcoholic than Asians without this mutation. Following alcohol ingestion, they exhibit more intense reactions to alcohol and generate higher levels of the metabolite acetaldehyde. This study evaluated hangover symptoms in Asian Americans with variations in the ALDH2 gene. METHOD: Men and women of Chinese, Japanese and Korean heritage (N = 140) were asked about their drinking history and a blood sample was collected for genotyping at the ALDH2 locus. Subjects used a Likert-type scale to estimate their severity of hangover and completed a 13-item hangover scale assessing the frequency of hangover symptoms during the previous 6 months. RESULTS: With abstainers (n = 17) excluded and with the effects of gender and recent drinking history controlled, ALDH2 genotype accounted for a significant amount of additional variability in the estimated severity of hangover score with a similar, but nonsignificant, trend for a five-item subscale score derived from the hangover scale. CONCLUSIONS: These results suggest that Asian Americans with ALDH2*2 alleles may experience more severe hangovers that may contribute, in part, to protection against the development of excessive or problematic drinking in this population.