ALDH2 and CYP2E1 genotypes, urinary acetaldehyde excretion and the health consequences in moderate alcohol consumers

Deficiencies in mitochondrial low-Km aldehyde dehydrogenase (ALDH2) activity, and consequently high blood acetaldehyde levels, have been suggested to relate to various diseases in Japanese, including esophageal cancer. In the present study, 200 men aged 35–59 years randomly selected from an occupational population were analyzed for the association of ALDH2 genotypes and cytochrome P450-2E1 (CYP2E1) genotypes with the urinary excretion of acetaldehyde (which is bound to some chemicals in the urine) and with common alcohol-related health consequences. Urinary acetaldehyde excretion was increased, reflecting increased alcohol consumption even in this moderate alcohol-consuming population. Neither the ALDH2 nor the CYP2E1 genotypes showed significant influence on the elevation of urinary acetaldehyde excretion. Neither these genotypes nor urinary acetaldehyde concentration significantly affected blood pressure, serum aspartate aminotransferase and gamma-glutamyl transferase activities, or serum HDL-cholesterol and lipid peroxide concentrations. It was concluded that acetaldehyde accumulates in moderate alcohol consumers irrespective of ALDH2 and CYP2E1 genotype, and that the implications of these genotypes and acetaldehyde accumulation in terms of common alcohol-related health consequences were obscure. The results also suggest that the carcinogenicity of acetaldehyde on esophageal mucosa depends greatly upon repeated exposure to high blood acetaldehyde, even through transient rather than chronic exposure.     

Enantiomeric composition of urinary salsolinol in Parkinsonian patients after Madopar

Summary Urinary salsolinol output had been shown to be lower in Parkinsonian patients than in controls and to increase largely after L-dopa therapy. It had also been established that the R enantiomer of salsolinol is either the predominant or the sole enantiomer present in the urine of healthy subjects.When Madopar was administered to Parkinsonians, the enantiomeric composition of urinary salsolinol showed an S/R ratio around 1. Considering brain and plasma concentrations in dopamine, acetaldehyde and pyruvate, it is suggested that, under physiological conditions, urinary salsolinol should have a central origin in humans. Conversely, urinary salsolinol in Madopar-treated Parkinsonian patients might be predominantly formed at the periphery.     

Cytosolic xanthine oxidoreductase mediated bioactivation of ethanol to acetaldehyde and free radicals in rat breast tissue. Its potential role in alcohol-promoted mammary cancer

Epidemiological evidence links alcohol intake with increased risk in breast cancer. Not all the characteristics of the correlation can be explained in terms of changes in hormonal factors. In this work, we explore the possibility that alcohol were activated to acetaldehyde and free radicals in situ by xanthine dehydrogenase (XDh) and xanthine oxidase (XO) and/or aldehyde oxidase (AO). Incubation of cytosolic fraction with xanthine oxidoreductase (XDh+XO) (XOR) cosubstrates (e.g. NAD⁺, hypoxanthine, xanthine, caffeine, theobromine, theophylline or 1,7-dimethylxanthine) significantly enhanced the biotransformation of ethanol to acetaldehyde. The process was inhibited by allopurinol and not by pyrazole or benzoate or desferrioxamine and was not accompanied by detectable formation of 1HEt. However, hydroxylated aromatic derivatives of PBN were detected, suggesting either that hydroxyl free radicals might be formed or that XOR might catalyze aromatic hydroxylation of PBN. No bioactivation of ethanol to acetaldehyde was detectable when a cosubstrate of AO such as N-methylnicotinamide was included in cytosolic incubation mixtures. Results suggest that bioactivation of ethanol in situ to a carcinogen, such as acetaldehyde, and potentially to free radicals, might be involved in alcohol breast cancer induction. This might be the case, particularly also in cases of a high consumption of purine-rich food (e.g. meat) or beverages or soft drinks containing caffeine.     

Implication of the placenta in acetaldehyde-induced intrauterine growth retardation

Acetaldehyde (AcH) the proximal metabolite of ethanol was administered to pregnant CF rats intraperitoneally in single and triple doses (50, 75 and 100 mg/kg) on days 10, 11 and 12 of gestation and fetuses along with placentae were collected on day 21. Placentae were subjected to histological sectioning and the volume fractions of various zones of placenta were calculated using Weibels point counting techniques. There was no correlation between fetal weight and placental weight, but the fetal weight showed a positive correlationship with the percentage volume fraction of the labyrinthine zone suggesting that the reduction in the labyrinthine zone volume is probably responsible for intrauterine growth retardation following acetaldehyde maternal treatment.     

Blood acetaldehyde response to ethanol ingestion during the reproductive cycle of the female rat

Acetaldehyde could mediate a number of the toxic effects of alcohol both in females and their offspring. Thus, we assessed the blood acetaldehyde response to ethanol (3 g/kg) at various stages of the female reproductive cycle. Blood levels were low throughout the various phases of the estrous cycle and during most of pregnancy. By contrast, a 4-fold rise in maternal blood acetaldehyde occurred at the end of pregnancy (day 20), continued to increase during lactation (17-fold at day 14) and returned to non-pregnant values after weaning or after pup removal at birth. Both enhanced rate of ethanol oxidation and decreased activity of the low Km aldehyde dehydrogenase in liver mitochondria contributed to the increased acetaldehyde levels. Acetaldehyde was detectable in fetal blood, but only a small fraction of the high maternal values in pregnancy reached the fetus through the umbilical vein. Chronic alcohol administration resulted in decreased fetal size and striking enlargement of the placenta with possible implications for abnormal fetal development. Thus, the high maternal acetaldehyde levels at the end of pregnancy may exert deleterious effects on many maternal organs, including those (such as placenta) which are required for normal fetal development.     

乙醇脱氢酶3的遗传多态性对摄入乙醇唾液和全血中乙醛含量的影响

目的　探讨不同乙醇脱氢酶 3(ADH3)基因型对乙醇体内氧化的影响。方法　采用PCR扩增反应测定ADH3基因型 ,将 2 2名健康受试者分为ADH31 -1 ,ADH31 -2 和ADH32 -2 3组。受试者一次po 0 .3g·kg-1 乙醇后 ,采用高效液相色谱荧光法测定 4h内唾液和全血中的乙醛浓度经时过程。结果ADH31 -1 组的乙醛唾液cmax为 (1 2 .5± 2 .3) μmol·L-1 ,AUC为 (1 .4± 0 .4)mmol·min·L-1 ;ADH31 -2 组唾液cmax为 (9.4±1 .7) μmol·L-1 ,AUC为 (1 .1±0 .3)mmol·min·L-1 ;ADH32 -2 组唾液cmax为 (8.7± 2 .2 )μmol·L-1 ,AUC为 (0 .93± 0 .1 9)mmol·min·L-1 。ADH31 -1 组的唾液中乙醛浓度显著高于ADH31 -2 和ADH32 -2 组 ,但全血中的组间差异不如唾液中明显。结论　基因型为ADH31 -1 的个体在摄入乙醇后唾液中乙醛量显著增加 ,提示ADH31 -1 个体酗酒时由乙醛引发病理损害的风险性较大     

吲哚-3-原醇对乙醛所致精密肝切片中星状细胞活化的影响

目的利用精密肝切片(PCLS)技术,研究吲哚-3-原醇(I3C)对乙醛活化肝星状细胞(HSCs)的作用及其机制。方法将200～800μmol.L-1的I3C及700μmol.L-1乙醛与PCLS共同孵育6h,免疫组化法分析肝切片中α-平滑肌肌动蛋白(α-SMA)表达,并检测培养液中谷胱甘肽S-转移酶(GST)和乳酸脱氢酶(LDH)活性、转化生长因子-β1(TGF-β1)含量、基质金属蛋白酶-1(MMP-1)及基质金属蛋白酶抑制物-1(TIMP-1)表达量及组织丙二醛(MDA)和羟脯氨酸(Hyp)含量。结果200～800μmol.L-1I3C可不同程度的减少乙醛激活的HSCs,并可明显降低乙醛升高的培养液中GST、LDH活性和肝组织中MDA和Hyp含量(P<0.05或P<0.01),呈良好的浓度依赖性。I3C给药组与乙醛对照组比较,培养液中TGF-β1含量降低(P<0.01),MMP-1/TIMP-1蛋白表达比值升高(P<0.01)。结论I3C能有效拮抗乙醛所致的HSCs活化,其机制与降低细胞氧化应激和促进基质胶原降解有关。     

乙醛脱氢酶2基因多态性和饮酒习惯与肝癌发生的关系研究

目的 :研究当地饮酒习惯与乙醛脱氢酶 2 (ALDH2 )基因的多态性对肝癌危险性的影响。方法 :在江苏泰兴市选择 1999年 9月 1日～ 2 0 0 0年 12月 31日新发肝癌病人 88例 ,按性别、年龄和居住地1∶1配对 ,进行流行病学调查研究 ,并应用PCR RFLP方法检测研究对象的ALDH2基因型。统计分析采用EpiInfo软件包。结果 :饮大量高度酒能显著增加ALDH2变异基因型携带者患肝癌的危险性 (OR=7 2 0 ,χ2 =6 6 5 ,P <0 0 1)。结论 :ALDH2基因多态性和饮酒习惯与肝癌的发生有关。     

Effects of Fructose and Glucose on Ethanol-Induced Metabolic Changes and on the Intensity of Alcohol Intoxication and Hangover

The effects of fructose and glucose on the metabolic changes induced by ethanol and on the intensity of alcohol intoxication and hangover were studied in 109 healthy male volunteers. After 10 hours of fasting, the subjects were given 1.75 g of ethanol per kg body wt during 3 hours under controlled laboratory conditions. Fructose or glucose were adminstered either simultaneously with ethanol or 12 hours later during the hangover period. The intensity of alcohol intoxication and hangover were estimated 10 times during the experimental period of 20 hours using subjective and objective rating scales. Sequential determinations of blood ethanol, acetaldehyde, glucose, lactate, free fatty acids, triglycerides, ketone bodies and capillary blood acid-base balance were also made during the experiment. Under these experimental conditions neither fructose nor glucose had any significant effect on the intensity of alcohol intoxication and hangover. The sugars also had no significant effect on the rate of ethanol elimination or on the blood acetaldehyde concentration during the course of the experiment. Blood glucose concentration was decreased and blood lactate, free fatty acid and ketone body concentrations were increased during the hangover period in the subjects who had been given only ethanol. These subjects also had a marked metabolic acidosis during hangover. Glucose and fructose significantly inhibited the metabolic alterations induced by ethanol. In this respect fructose was more effective than glucose. The results indicate that both fructose and glucose effectively inhibit the metabolic disturbances induced by ethanol but they do not affect the symptoms or signs of alcohol intoxication and hangover. The results support the view that hangover is not directly related to the metabolic effects of ethanol or to its metabolic products.