Distribution and Kinetic Properties of Alcohol and Aldehyde-Dehydrogenase in the Rat Testis

The distribution of both alcohol (ADH) and aldehyde-dehydrogenase (ALDH) was studied in the rat testis. Testicular ADH was mainly localized into the interstitial tissue. Testicular ALDH activity was distributed between the interstitial tissue and the seminiferous tubules with greater activity measured in the former component. The apparent K_m for ADH in the whole testis was greater than that measured in the interstitial tissue. A low K_m value was determined for ALDH in the seminiferous tubules, compared to a higher mean K_m value for this enzyme in the interstitial tissue of the testis. The study shows that interstitial tissue possesses both ADH and ALDH, which are essential for the respective metabolism of ethanol and acetaldehyde, and that the seminiferous tubules possesses greater affinity for the metabolism of acetaldehyde than that of the interstitial tissue.     

Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33 mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200 μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1 > ALDH2 > ADH3 ≈ ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained unchanged. The ADH activity was also significantly reduced in hemorrhoids. ADH4 and ALDH3A1 were uniquely expressed in the squamous epithelium of anus at anorectal junctions. The allele frequencies of ADH1C*1 and ALDH2*2 were significantly higher in colorectal cancer and that of ALDH2*2 also significantly greater in hemorrhoids. In conclusion, ADH and ALDH isozymes are differentially expressed in mucosal cells of rectum and anus. The results suggest that acetaldehyde, an immediate metabolite of ethanol, may play an etiological role in pathogenesis of large bowel diseases.     

Expression and activities of class IV alcohol dehydrogenase and class III aldehyde dehydrogenase in human mouth

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for the oxidation of ingested ethanol in humans. To study these two enzymes in surgical specimens of attached gingiva and tongue, we have examined the isozyme patterns by agarose isoelectric focusing and determined the enzyme activities. Class IV μ-ADH, class III χ-ADH, and class III ALDH₃ were detected in the oral mucosa tissues. Gingival μ-ADH exhibited a pH optimum for ethanol oxidation at 10 and the K_m value for ethanol (pH 7.5) was estimated to be 27 mM. At pH 7.5 and 30°C, the ADH activities in the gingiva and tongue samples were determined to be 90.0 ± 5.8 (mean ± SE; n = 24) and 50.6 ± 5.1 (n = 3) nmol/min/g tissue (at 33 mM ethanol), and 138 ± 11 and 55.1 ± 4.7 nmol/min/g tissue (at 500 mM ethanol), respectively. The ALDH activities at 20 mM acetaldehyde were determined to be 169 ± 19 and 50.3 ± 8.1 nmol/min/g tissue for the gingiva and tongue, respectively. We conclude that ethanol can be significantly metabolized in human attached gingiva and lingual mucosa by μ-ADH. The result also suggests that, due to lacking activity of low K_m ALDH₂ and ALDH₁, cytotoxic metabolite acetaldehyde may be involved in the etiology of alcohol-related oral injury.     

INVOLVEMENT OF GENETIC POLYMORPHISM OF ALCOHOL AND ALDEHYDE DEHYDROGENASES IN INDIVIDUAL VARIATION OF ALCOHOL METABOLISM

The involvement of genetic polymorphism at the alcohol dehydrogenase2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci in determiningblood acetaldehyde levels and the rate of ethanol eliminationafter ethanol intake was investigated. Sixty-eight healthy subjectsingested 0.4 g of ethanol per kg of body weight over 10 min.Blood acetaldehyde levels scarcely increased in the subjectshomozygous for ALDH2^*I, regardless of their ADH2 genotypes (ADH2^*1/^*1,ADH2^*1/^*2 and ADH2^*2/^*2). The acetaldehyde levels in the subjectswith the ALDH2^*1/^*2 heterozygote increased to 23.4 µMon average, and no significant differences were observed betweenthe three ADH2 genotype groups. Subjects homozygous for ALDH2^*2showed very high levels of blood acetaldehyde, and the averagevalue was 79.3 µM. The values of Widmark's ß₆₀(mg/ml/hr)and ethanol elimination rate (mg/kg/br) showed significant differencesamong the three ALDH2 genotypes, and in decreasing order thevalues were ALDH2^*1/^*1, ALDH2^*1/^*2, ALDH2^*2 However, no significantdifferences were seen among the ADH2 genotypes.     

CHARACTERISTICS OF ALDEHYDE DEHYDROGENASES OF CERTAIN AEROBIC BACTERIA REPRESENTING HUMAN COLONIC FLORA

We have proposed the existence of a bacteriocolonic pathwayfor ethanol oxidation resulting in high intracolonic levelsof toxic and carcinogenic acetaldehyde. This study was aimedat determining the ability of the aldehyde dehydrogenases (ALDH)of aerobic bacteria representing human colonic flora to metabolizeintracolonically derived acetaldehyde. The apparent Michaelisconstant (K_m) values for acetaldehyde were determined in crudeextracts of five aerobic bacterial strains, alcohol dehydrogenase(ADH) and ALDH activities of these bacteria at conditions prevailingin the human large intestine after moderate drinking were thencompared. The effect of cyanamide, a potent inhibitor of mammalianALDH, on bacterial ALDH activity was also studied. The apparentK_m for acetaldehyde varied from 6.8 (NADP⁺ -linked ALDH of Escherichiacoli IH 13369) to 205 µM (NAD⁺ -linked ALDH of Pseudomonasaeruginosa IH 35342), and maximal velocity varied from 6 nmol/min/mg(NAD⁺ -linked ALDH of Klebsiella pneumoniae IH 35385) to 39nmol/min/mg (NAD⁺ -linked ALDH of Pseudomonas aeruginosa IH35342). At pH 7.4, and at ethanol and acetaldehyde concentrationsthat may be prevalent in the human colon after moderate drinking,ADH activity in four out of five bacterial strains were 10–50times higher than their ALDH activity. Cyanamide inhibited onlyNAD⁺ -linked ALDH activity of Pseudomonas aeruginosa IH 35342at concentrations starting from 0.1 mM. We conclude that ALDHsof the colonic aerobic bacteria are able to metabolize endogenicacetaldehyde. However, the ability of ALDHs to metabolize intracolonicacetaldehyde levels associated with alcohol drinking is ratherlow. Large differences between ADH and ALDH activities of thebacteria found in this study may contribute to the accumulationof acetaldehyde in the large intestine after moderate drinking.ALDH activities of colonic bacteria were poorly inhibited bycyanamide. This study supports the crucial role of intestinalbacteria in the accumulation of intracolonic acetaldehyde afterdrinking alcohol. Individual variations in human colonic floramay contribute to the risk of alcohol-related gastrointestinalmorbidity.     

Aldehyde dehydrogenase 2—a potential genetic risk factor for lung function among southern Chinese: evidence from the Guangzhou Biobank Cohort Study

PurposeIn Asia, moderate alcohol users have better lung function. Never users have more inactive aldehyde dehydrogenase 2 (ALDH2) alleles (A) potentially generating confounding because inactive alleles may increase acetaldehyde exposure and reduce lung function.MethodsWe examined the association of ALDH2 genotypes with percentage predicted lung function (forced expiratory volume in 1 second; forced vital capacity) for age, sex, and height among 5641 older Chinese using multivariable linear regression.ResultsALDH2 genotypes were associated with alcohol use and height but not other attributes. Inactive alleles were inversely associated with lung function (percentage predicted forced expiratory volume in 1 second −1.52%, 95% confidence interval [CI], −2.52% to −0.51% for one inactive allele and −2.05%, 95% CI, −3.85% to −0.26% for two inactive alleles compared with two active alleles; and for percentage predicted forced vital capacity −1.25%, 95% CI −2.15% to −0.35% and −1.65%, 95% CI, −3.25% to −0.04%). The association of moderate use with lung function was attenuated after adjusting for ALDH2, in addition to other potential confounders.ConclusionsPrevious findings in Chinese may be confounded by ALDH2. High frequency of inactive ALDH2 alleles in East Asia may exacerbate the effect of environmental acetaldehyde exposure on lung function and potentially on chronic obstructive pulmonary disease.     

Influence of chronic alcohol abuse and liver disease on hepatic aldehyde dehydrogenase activity

Alcohol metabolism results in the production of acetaldehyde, a compound that is much more toxic than ethanol itself. Hepatic aldehyde dehydrogenase (ALDH) is the main enzymatic system responsible for acetaldehyde clearance from the hepatocyte. The objective of this study was to determine the modifications in ALDH activity due to chronic alcohol abuse and liver disease. ALDH activity was determined in samples of liver tissue from 69 alcoholic and 82 nonalcoholic subjects, with and without liver disease. According to the results of liver pathology examination, alcoholic patients were classified into the following groups: controls, with no liver disease (group 1), noncirrhotic liver disease patients (group 2), and cirrhotics (group 3). Nonalcoholic subjects were categorized, using the same criteria, into groups 4, 5, and 6, respectively. ALDH activity was determined spectrophotometrically at two substrate concentrations: 18 mM for total activity and 180 μM for low K_m activity. High K_m activity was calculated by subtracting the low K_m activity value from that of total ALDH activity. Results obtained in each group were expressed as the mean ± SD of mU of g of wet weight. There were no significant differences when the total ALDH activity from the alcoholic and the nonalcoholic patients with a similar degree of liver pathology were compared: group 1, 1257 ± 587 vs. group 4, 1328.1 ± 546.2 (p: NS); group 2, 919.1 ± 452.4 vs. group 5, 753.5 ± 412 (p: NS); and group 3, 430.2 ± 162.4 vs. group 6, 473.2 ± 225.3 (p: NS). On the other hand, total ALDH activity was significantly lower in cirrhotics than in controls, both among alcoholics (p < 0.01) and among nondrinkers (p < 0.05). The low K_m activity was severely reduced in cirrhotics, both alcoholics and nonalcoholics (p < 0.01). High K_m activities in cirrhotic patients were low, compared to controls, both in alcoholics and nonalcoholics, although the difference was nonsignificant. The results of the present study suggests that chronic alcohol abuse does not depress ALDH activity. A reduction in the ALDH activity detected in patients with severe liver disease (cirrhotics) was clearly a consequence of liver damage. This reduction was due mainly to a decrease of the low K_m ALDH activity, but a trend to a decrease in the high K_m ALDH activity was also detected.     

Interaction of the Effects of Alcohol Drinking and Polymorphisms in Alcohol-Metabolizing Enzymes on the Risk of Female Breast Cancer in Japan

Background

Epidemiological studies consistently indicate that alcoholic beverages are an independent risk factor for female breast cancer. Although the mechanism underlying this effect remains unknown, the predominant hypothesis implicates mutagenesis via the ethanol metabolite acetaldehyde, whose impact on the carcinogenesis of several types of cancer has been shown in both experimental models and molecular epidemiological studies. Many of the epidemiological studies have investigated genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) His48Arg and aldehyde dehydrogenase-2 (ALDH2) Glu504Lys, because of the strong impact these polymorphisms have on exposure to and accumulation of acetaldehyde. With regard to breast cancer, however, evidence is scarce.

Methods

To clarify the impact on female breast cancer risk of the interaction of the effects of alcohol consumption and polymorphisms in the alcohol-metabolizing enzymes ADH1B and ALDH2, we conducted a case–control study of 456 newly and histologically diagnosed breast cancer cases and 912 age- and menopausal status-matched noncancer controls. Gene–gene and gene–environment interactions between individual and combined ADH1B and ALDH2 gene polymorphisms and alcohol consumption were evaluated.

Results

Despite sufficient statistical power, there was no significant impact of ADH1B and ALDH2 on the risk of breast cancer. Neither was there any significant gene–environment interactions between alcohol drinking and polymorphisms in ADH1B and ALDH2.

Conclusions

Our findings do not support the hypothesis that acetaldehyde is the main contributor to the carcinogenesis of alcohol-induced breast cancer.Key words: breast cancer, alcohol drinking, acetaldehyde, polymorphisms in alcohol-metabolizing enzyme genes, case–control study     

Regulation of Alcohol and Acetaldehyde Metabolism by a Mixture of Lactobacillus and Bifidobacterium Species in Human

Excessive alcohol consumption is one of the most significant causes of morbidity and mortality worldwide. Alcohol is oxidized to toxic and carcinogenic acetaldehyde by alcohol dehydrogenase (ADH) and further oxidized to a non-toxic acetate by aldehyde dehydrogenase (ALDH). There are two major ALDH isoforms, cytosolic and mitochondrial, encoded by ALDH1 and ALDH2 genes, respectively. The ALDH2 polymorphism is associated with flushing response to alcohol use. Emerging evidence shows that Lactobacillus and Bifidobacterium species encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) mediate alcohol and acetaldehyde metabolism, respectively. A randomized, double-blind, placebo-controlled crossover clinical trial was designed to study the effects of Lactobacillus and Bifidobacterium probiotic mixture in humans and assessed their effects on alcohol and acetaldehyde metabolism. Here, twenty-seven wild types (ALDH2*1/*1) and the same number of heterozygotes (ALDH2*2/*1) were recruited for the study. The enrolled participants were randomly divided into either the probiotic (Duolac ProAP4) or the placebo group. Each group received a probiotic or placebo capsule for 15 days with subsequent crossover. Primary outcomes were measurement of alcohol and acetaldehyde in the blood after the alcohol intake. Blood levels of alcohol and acetaldehyde were significantly downregulated by probiotic supplementation in subjects with ALDH2*2/*1 genotype, but not in those with ALDH2*1/*1 genotype. However, there were no marked improvements in hangover score parameters between test and placebo groups. No clinically significant changes were observed in safety parameters. These results suggest that Duolac ProAP4 has a potential to downregulate the alcohol and acetaldehyde concentrations, and their effects depend on the presence or absence of polymorphism on the ALDH2 gene.     

Distribution of ADH1B, ALDH2, CYP2E1∗6, and CYP2E1∗7B genotypes in Turkish population

The most well-known metabolic pathways from ethanol to acetaldehyde include alcohol dehydrogenase (ADH) and the microsomal ethanol oxidizing system that involves cytochrome P450 2E1 (CYP2E1). Acetaldehyde is further oxidized to acetate by aldehyde dehydrogenase (ALDH). The genetic variation of ADH1B, ALDH2, and CYP2E1 is different among racial populations and cause difference in elimination rates of alcohol. The aim of this study was to determine the polymorphisms of ADH1B (rs1229984; Arg47His), ALDH2 (rs671; Glu487Lys), CYP2E1*6 (rs6413432; T7632A), and CYP2E1*7B (rs6413420; G-71T) in unrelated healthy Turkish population and compare it with other populations. ADH1B and ALDH2 polymorphisms were analyzed with an allele-specific polymerase chain reaction (PCR) assay, and CYP2E1*6 and CYP2E1*7B polymorphisms were genotyped by PCR-restriction fragment length polymorphism method. ADH1B polymorphism analysis yielded the genotype distribution as 83.9% ADH1B*1/1 and 16.1% ADH1B*1/2, and no individuals with ALDH2*1/2 and ALDH2*2/2 genotypes were found in Turkish population. The genotype frequencies for CYP2E1*6 polymorphism were found as 85.3% for homozygote common, 14.1% for heterozygote, and 0.6% for homozygote uncommon. For CYP2E1*7B polymorphism, the genotype frequencies were determined to be 86.5% G/G, 13.5% for G/T; however, no individuals with homozygote uncommon genotype were detected. According to our study results, the genotype distributions of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B in Turkish population were similar compared with Caucasian and some European populations, whereas differed significantly from East Asian populations. This study may be useful in epidemiological studies of the influence of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B polymorphisms on diseases, including several types of cancer related to alcohol consumption and alcohol dependence.     

Fenofibrate – A lipid-lowering drug – Reduces voluntary alcohol drinking in rats

The administration of disulfiram raises blood acetaldehyde levels when ethanol is ingested, leading to an aversion to alcohol. This study was aimed at assessing the effect of fenofibrate on voluntary ethanol ingestion in rats. Fenofibrate reduces blood triglyceride levels by increasing fatty acid oxidation by liver peroxisomes, along with an increase in the activity of catalase, which can oxidize ethanol to acetaldehyde. UChB drinker rats were allowed to consume alcohol 10% v/v freely for 60 days, until consumption stabilized at around 7 g ethanol/kg/24 h. About 1–1.2 g ethanol/kg of this intake is consumed in the first 2 h of darkness of the circadian cycle. Fenofibrate subsequently administered (50 mg/kg/day by mouth [p.o.]) for 14 days led to a 60–70% (p < 0.001) reduction of 24-h ethanol consumption. When ethanol intake was determined within the first 2 h of darkness, the reduction was 85–90% (p < 0.001). We determined whether animals chronically allowed access to ethanol and subsequently treated with fenofibrate, would a) increase liver catalase activity, and b) increase blood acetaldehyde levels after a 24-h ethanol deprivation and the subsequent administration of 1 g ethanol/kg. The oral administration of 1 g ethanol/kg produced a rapid increase in blood (arterial) acetaldehyde in fenofibrate-treated animals versus controls also administered 1 g/kg ethanol (70 μM vs. 7 μM; p < 0.001). Liver catalase activity following fenofibrate treatment was increased 3-fold (p < 0.01). Other hepatic enzymes responsible for the metabolism of ethanol (alcohol dehydrogenase and aldehyde dehydrogenase) remained unchanged. No liver damage was induced, as measured by serum glutamic-pyruvic transaminase (GPT) activity. The effect of fenofibrate in reducing alcohol intake was fully reversible. Overall, in rats allowed chronic ethanol intake, by mouth (p.o.), fenofibrate administration increased liver catalase activity and reduced voluntary ethanol intake. The administration of 1 g ethanol/kg (p.o.) to these animals increased blood acetaldehyde levels in fenofibrate-treated animals, suggesting the possible basis for the reduction in ethanol intake.     

Effect of acute ethanol drinking on alcohol metabolism in subjects with different ADH and ALDH genotypes

The effect of different amounts of orally ingested ethanol on plasma alcohol dehydrogenase (ADH) and erythrocyte aldehyde dehydrogenase (ALDH), as well as on the blood ethanol and acetaldehyde levels, was examined in healthy nonalcoholic subjects. The genotypes at ADH2 and ALDH2 locus were identified in enzymatically amplified blood DNA by hybridization with allele-specific oligonucleotides. While the Japanese subject was found to be genotypically heterozygous for both ADH2 and ALDH2, the Caucasian subjects were genotypically homozygous normal for these alleles. A faster ethanol elimination associated with a higher blood acetaldehyde level was observed in the Japanese subject as compared to Caucasian subjects. However, no significant change in ADH and ALDH enzyme activities was detected as the result of acute ethanol intake.     

A comparison of Val81Met and other polymorphisms of alcohol metabolising genes in patients and controls in Northern Spain

The aim of this paper is to study polymorphism in the TH, ADH1B, ADH1C, ALDH2 and CYP2E1 genes so as to ascertain whether it is associated with excessive consumption of alcohol. The SNPs rs6356 of TH, rs1229984, rs2066702 of ADH1B; rs698, rs1693482 of ADH1C; rs671 of ALDH2; rs72559710, rs55897648, rs6413419, rs3813867, rs2031920, rs6413432 of CYP2E1 were studied in a sample of 172 high-level patients and 150 fully non-drinkers controls. Genotyping was performed using Rt-PCR with Taqman probes. SNPs located at ALDH2 and CYP2E1 showed no heterozygosity. Frequency distribution showed significant differences between the two groups studied for loci TH and ADH1B. The genotype Val/Val of TH locus increased in risk 1.988 times (95% CI: 1.006–3.930) that the subjects carrying the genotype Met/Met; and the genotype ADH1B*1/*1 of ADH1B locus increased in risk 3.811 times (CI: 1.660–8.749) that the subjects carrying the genotype ADH1B*1/*2. Alleles Val and ADH1B*1 may therefore increase the risk of the onset and development of this illness.     

In vitro inhibition of 10-formyltetrahydrofolate dehydrogenase activity by acetaldehyde

Alcoholism has been associated with folate deficiency in humans and laboratory animals. Previous study showed that ethanol feeding reduces the dehydrogenase and hydrolase activity of 10-formyltetrahydrofolate dehydrogenase (FDH) in rat liver. Hepatic ethanol metabolism generates acetaldehyde and acetate. The mechanisms by which ethanol and its metabolites produce toxicity within the liver cells are unknown. We purified FDH from rat liver and investigated the effect of ethanol, acetaldehyde and acetate on the enzyme in vitro. Hepatic FDH activity was not reduced by ethanol or acetate directly. However, acetaldehyde was observed to reduce the dehydrogenase activity of FDH in a dose- and time-dependent manner with an apparent IC₅₀ of 4 mM, while the hydrolase activity of FDH was not affected by acetaldehyde in vitro. These results suggest that the inhibition of hepatic FDH dehydrogenase activity induced by acetadehyde may play a role in ethanol toxicity.     

Population pharmacokinetics of multiple alcohol intake in humans

The objective of this study was to determine population-based pharmacokinetics parameters for ethanol following multiple intake and to identify the factors influencing the pharmacokinetics. Three different solutions of alcoholic liquor (ethanol 55.39 ± 0.45 g) with different dissolved oxygen concentrations were administered, and blood alcohol concentration was determined in 59 healthy subjects using a breath analyzer. Samples (n = 2955) were collected at various time points. Population pharmacokinetic modeling was performed to describe the pharmacokinetics of ethanol. The influence of individuals' demography and dissolved oxygen concentration was investigated, and Visual Predictive Check and bootstrapping were conducted for internal evaluation. The developed model was used to perform simulations to visualize the effects of covariates on individuals. A one-compartment model with Michaelis–Menten elimination kinetics described the multiple ethanol intake data. Population pharmacokinetic estimates of V_max and K_m were 3.256 mmol min⁻¹ and 0.8183 mmol L⁻¹, respectively. V_d/F was estimated to be 77.0 L, and K_a was 0.0767 min⁻¹. Body weight, age, and the dissolved oxygen concentration were confirmed to be significant covariates. The mean estimates from the developed population pharmacokinetic model were very similar to those from 500 bootstrap samples, and Visual Predictive Check showed that approximately 94% of the observed data fit well within the 5th–95th percentile. A one-compartment model with nonlinear elimination kinetics for multiple ethanol intake was developed and the significant covariates were determined. The robustness of the developed model was evaluated by bootstrap and Visual Predictive Check. The final model and implanted covariates explained well the variability and underlying mechanism of ethanol PK.     

Microbes and mucosa in the regulation of intracolonic acetaldehyde concentration during ethanol challenge

— Aims: The bacteriocolonic pathway for ethanol oxidationleads to high intracolonic levels of carcinogenic acetaldehyde.The respective roles of colonic mucosal cells and gut florain the regulation of intracolonic acetaldehyde concentrationare not known. Disulfiram inhibits hepatic acetaldehyde oxidationand may have an effect on colonic mucosal cells. On the otherhand, metronidazole treatment leads to overgrowth of acetaldehyde-producingaerobic flora in the large intestine. The aim of this studywas to characterize by means of disulfiram and metronidazolethe contribution of colonic mucosal cells and intracolonic microbesto the regulation of intracolonic acetaldehyde concentrationduring ethanol oxidation in rats. Methods: Forty male Wistarrats were used. Three groups of 10 rats each received metronidazole,disulfiram, or both for 5 days, and a fourth group of 10 ratsserved as controls and did not receive any premedication. Faecalsamples were taken for the ALDH (aldehyde dehydrogenase) determinationbefore the injection of ethanol, after which all rats receivedethanol (1.5 g/kg) 2 h prior to taking samples from blood, liver,colonic mucosa and colonic contents. Results: Disulfiram decreasedsignificantly hepatic and colonic mucosal ALDH activities, andresulted in increased blood and intracolonic acetaldehyde levels.In disulfiram-treated rats, mean intracolonic acetaldehyde levelwas 8-fold higher than that in the blood. Metronidazole inhibitedonly colonic mucosal high K_M ALDH and increased intracolonic,but not blood, acetaldehyde levels. Faecal ALDH activity wasnot detectable in any of the groups. Conclusions: This studydemonstrates that during ethanol challenge, intracolonic acetaldehydelevel is regulated not only by intracolonic microbes, but alsoby colonic mucosal cells.     

Is ADH1C genotype relevant for the cardioprotective effect of alcohol?

The cardioprotective effect of ethanol has been suggested to be linked to one of the ethanol metabolizing enzymes (ADH1C), which constitutes a high V_max and a low V_max variant. This has been demonstrated in some studies, while others have not been able to replicate the findings. The aim of the present study was to investigate the relation between the different ADH1C genotypes, death from coronary heart disease (CHD) and alcohol in a material larger than the previously published studies. Eight hundred CHD deaths as well as 1303 controls were genotyped for the high V_max (γ1) and the low V_max (γ2) ADH1C variant. Information of alcohol use was available for all subjects. Multiple logistic regression analyses was used to study if the decreased risk of death from CHD in alcohol consuming subjects was more pronounced in subjects homozygous for the γ2 allele (γ2γ2 subjects) compared to γ1γ1 and γ1γ2 subjects. The odds ratio (OR) for death from CHD in alcohol consumers compared to abstainers was similar in the genotype groups, i.e., 0.62 (95% CI: 0.43–0.88) in γ1γ1 subjects and 0.62 (95% CI: 0.42–0.91) in γ2γ2 subjects. Also when stratifying the results by gender and when dividing alcohol consumers into different alcohol consumption groups, there was no difference in the OR between the different genotype groups. This study, which included the largest study group published so far, failed to find any link between the ADH1C genotype and the cardioprotective effects of alcohol.     

酒精代谢酶基因型在日本双生子中的分布

目的为预防酒精相关性疾病发生,调查了酒精代谢酶控制基因在日本双生子中的分布。方法以饱和酚法提取ＤＮＡ,应用限制性片段长度多态性分析技术检测了９２个日本双生子的酒精脱氢酶２（ＡＤＨ２）和乙醛脱氢酶２（ＡＬＤＨ２）基因型,根据基因型差异筛选敏感个体。结果ＡＤＨ２和ＡＬＤＨ２基因分布符合Ｈａｒｄｙｗｅｉｎｂｅｒｇ等式。ＡＤＨ２基因的３种基因型分别是ＡＤＨ２１／ＡＤＨ２１（１．１％）、ＡＤＨ２１／ＡＤＨ２２（４４．６％）和ＡＤＨ２２／ＡＤＨ２２（５４．３％）。ＡＬＤＨ２的基因型分别为ＡＬＤＨ２１／ＡＬＤＨ２１（４１．３％）、ＡＬＤＨ２１／ＡＬＤＨ２２（３９．１％）和ＡＬＤＨ２２／ＡＬＤＨ２２（１９６％）。ＡＤＨ２和ＡＬＤＨ２基因频率分别为０．２５５、０．７４５和０６０９、０３９１。结论异常纯合的ＡＤＨ２基因和纯合的ＡＬＤＨ２基因占优势。个体携有ＡＤＨ２１／ＡＤＨ２２和ＡＬＤＨ２１／ＡＬＤＨ２１、ＡＤＨ２２／ＡＤＨ２２和ＡＬＤＨ２１／ＡＬＤＨ２１者可视为敏感个体。     

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.