Relationship between ALDH2 genotypes and choice of alcoholic beverages]

There are obviously individual differences in the choice for many kinds of alcoholic beverages such as beer, wine, whisky, sake, cocktail and so on. It is generally believed that these differences are related to acquired preferences in taste and smell, in addition to life style. However, the basis of these acquired preferences is not yet understood. It has been shown that around half of Japanese show a marked sensitivity to alcoholic beverages because of aversive reactions due to a catalytic deficiency in ALDH2 isozyme. Therefore, differences in ALDH2 genotypes may possibly influence the choice of alcoholic beverages because the individuals possessing the ALDH2*2 gene may prefer the alcoholic beverages containing lower concentrations of alcohol. A large population survey (320 males, 132 females) was conducted using questionnaires to investigate the relationship between ALDH2 genotypes and the choice of alcoholic beverages. Individuals with the homozygote of ALDH2*1 generally showed more preference for alcoholic beverages containing a higher concentration of alcohol than those with the heterozygote or the homozygote of ALDH2*2. It was noted that the latter groups preferred whisky and water, and sweet cocktails. Also, the choices for beer, whisky, and sake were significantly different between both genders. Our data suggested that individuals with ALDH2*2 prefer beverages with lower concentrations of alcohol due to an aversive reaction after drinking, and that there are obvious gender differences in the consumption as well as the choice for many alcoholic beverages.     

口服大剂量精氨酸对正常人胰岛素分泌功能的影响

目的探讨口服大剂量精氨酸对胰岛β细胞分泌功能的影响。方法糖耐量正常的非肥胖志愿者8例,随机进入4个试验期(间隔至少3 d),分别口服纯净水300 ml、葡萄糖75 g、精氨酸30 g、葡萄糖75 g+精氨酸30 g,检测服药后0、15、30、45、60、120 min的血糖及胰岛素。结果口服纯净水期血糖及胰岛素平稳。其余3期胰岛素曲线变化相似,峰浓度增加(P<0.05),曲线下净增面积增大(P<0.05)。精氨酸期血糖平稳,胰岛素曲线下净增面积小于葡萄糖期及精氨酸+葡萄糖期(P<0.05)。结论糖耐量正常者口服大剂量精氨酸呈不依赖血糖地轻度刺激胰岛素分泌。     

乙醇激活ALDH2对2型糖尿病大鼠睾丸损伤的影响

目的观察乙醇激活乙醛脱氢酶2(ALDH2)对2型糖尿病大鼠睾丸损伤的影响。方法健康♂SD大鼠高糖高脂饮食联合低剂量链脲佐菌素(STZ)(35 mg·kg-1)制备2型糖尿病大鼠模型。成模后,将大鼠随机分为正常对照组、2型糖尿病组、乙醇+2型糖尿病组(n=6)。乙醇+2型糖尿病组大鼠先给予体积分数0.025乙醇喂养1周后,改用体积分数0.05乙醇继续喂养7周;正常对照组和2型糖尿病组大鼠常规喂养8周。8周后,测定血糖、糖化血红蛋白、血清睾酮、睾丸质量系数等指标,观察睾丸组织结构改变,检测睾丸组织ALDH2 mRNA、转化生长因子β1(TGF-β1)mRNA水平和TGF-β1阳性率的变化。结果与正常对照组比较,2型糖尿病组大鼠血糖、糖化血红蛋白和睾丸质量系数均明显升高,血清睾酮水平明显降低,睾丸组织中部分生精小管萎缩,各级生精细胞减少,排列疏松,睾丸间质细胞减少,睾丸组织ALDH2 mRNA水平明显减少,TGF-β1 mRNA水平和TGF-β1阳性率明显升高。给予乙醇干预后,与2型糖尿病组比较,乙醇+2型糖尿病组大鼠血糖、糖化血红蛋白和睾丸质量系数降低,血清睾酮水平升高,病理改变减轻,睾丸组织ALDH2 mRNA水平明显升高、TGF-β1 mRNA水平和TGF-β1阳性率明显降低。结论激活ALDH2可能通过下调TGF-β1的表达,减轻2型糖尿病对睾丸的损伤。     

阿卡波糖对糖耐量减低人群干预治疗的临床观察

目的:观察应用阿卡波糖干预治疗糖耐量减低(IGT)患者的临床疗效,协助临床控制糖耐量以减低患者向2型糖尿病的转变。方法:对120例糖耐量减低患者随机分为治疗组和对照组各60例,两组均予饮食和运动干预,治疗组加用阿卡波糖,12个月后比较两组患者糖尿病发生率以及体质量指数(BMI)、腰臀比(WHR)、空腹血糖(FPG)、葡萄糖耐量试验(OGTT)2 h后血糖(2HPG)、空腹胰岛素(FINS)和OGTT 2 h后胰岛素(PINS)、胰岛素抵抗指数(IRI)和胰岛素敏感指数(ISI)等指标。结果:干预治疗1年后,对照组患者糖尿病的发病率为8.3%,阿卡波糖组的发病率为5.0%;治疗组BMI、WHR、FPG、2HPG、FINS、PINS以及IRI值均明显低于对照组,而ISI显著高于对照组,差异有统计学意义。结论:阿卡波糖能够降低IGT人群糖尿病的发病率,明显改善IGT患者的代谢紊乱因素。     

Effects of chronic ethanol ingestion on pharmacokinetics of procainamide in rats

Blood level studies were carried out in rats to determine the effects of chronic ethanol ingestion on the distribution pharmacokinetic parameters and tissue steady-state partition coefficients of procainamide. The ethanol-treated rats received 4g/kg of ethanol daily for 28 days in Treatment A and 4 g/kg of ethanol for an initial 7 days, followed by 8 g/kg of ethanol for the subsequent 21 days in Treatment B; the control rats received isocaloric sucrose in the respective groups. As determined from two-compartment analysis of the blood level data, both ethanol treatments significantly decreased the distribution clearance (CLd; k12Vdc) and the apparent first-order rate constant for drug transfer from the central compartment to the tissue compartment (k12) of procainamide without affecting the total body clearance of drug (CL) or the apparent volumes of distribution of drug in the body at steady state (Vdss) and at pseudo-equilibrium (Vd beta). Additionally, the apparent volume of distribution of the drug in the central compartment (Vdc) was 57-62% greater due to both ethanol treatments. Furthermore, the steady-state partition coefficients of the drug were found to be significantly lower in heart and kidneys and greater in fat of the ethanol-treated rats (Treatment B) as compared with those in the control rats. Possible mechanisms are proposed to account for these various effects in light of the known effects of chronic ethanol ingestion on the chemical composition of cell membranes of tissues and organs.     

Effects of ethanol ingestion on alpha-adrenoceptor-mediated circulatory responses in man.

The acute effects of ethanol on pressor responses to graded intravenous infusions of noradrenaline (24, 48, 90 ng kg-1 min-1) and methoxamine (0.2, 0.4, 0.8, 1.6, 2.0 mg/min, 1 min each) were each investigated in eight normal male subjects. The effects of ethanol on blood pressure, heart rate and plasma catecholamine responses to lower body negative pressure were also examined in six normal male subjects. Each subject acted as his own control by participating twice, once after consumption of ethanol (1.0 ml/kg, 20% v/v, in orange juice) and once after an equivalent volume of orange juice. Ethanol consumption significantly reduced the diastolic blood pressure response to infusion of noradrenaline. This occurred despite a significantly greater increase in plasma noradrenaline concentrations during infusion after ethanol. The systolic and diastolic blood pressure responses to infusion of methoxamine were both significantly reduced after ethanol. During lower body negative pressure, prior consumption of ethanol resulted in a greater fall in systolic blood pressure and a smaller rise in diastolic blood pressure. Plasma noradrenaline responses to lower body negative pressure were significantly increased after ethanol. It is concluded that acute ethanol ingestion depresses alpha-adrenoceptor-mediated vasoconstriction, with resulting impairment of blood pressure control.     

A pilot study on subacute ethanol treatment of ALDH2 KO mice

Aldh (aldehyde dehydrogenase ) 2 knockout (KO) mice have been generated in our laboratory. We evaluated the effects of subacute ethanol treatment on the survival rate, expression of Aldh1, Aldh2, Cytochrome P450 (Cyp) 1A1, Cyp2e1 and Cyp4b1 in wild (Aldh2+/+) mice (C57BL/6) and Aldh2 knock out (Aldh2-/-) mice. Physiological saline (0.3 mL/day) was administered to 4 Aldh2+/+ and 4 Aldh2-/- mice for 8 days as a control. Forty percent ethanol (0.3 mL/day; ethanol 2 g/kg/day) was then administered to 5 Aldh2+/+ and 9 Aldh2-/- mice for 8 days. Three mice of the ethanol administered Aldh2+/+ group and eight mice of the ethanol administered Aldh2-/- group died during the 8 days. The weights of mice were decreased by ethanol exposure to 85% and 74% in Aldh2+/+ and Aldh2-/- group, respectively. The survival rates of the ethanol administered Aldh2+/+ and Aldh2-/- group were 40 and 11%. Liver and pancreas disorder was revealed in the ethanol administered Aldh2+/+ and Aldh2-/- group in the results of serum chemical examination, immunohistochemical staining and western blot analysis. Cyp2e1 is more inducible to ethanol toxicity in Aldh2-/- mice compared with Aldh2+/+ mice when ethanol is administered according to the results of quantitative PCR.     

Effects of chronic ethanol treatment on glucose tolerance, insulin response and circulating metabolites in the pregnant rat

The effects of chronic ethanol treatment on intravenous glucose tolerance and insulin response in non-pregnant and pregnant rats were studied. Basal circulating glucose, insulin, and ketone bodies levels were also determined during the treatment. Basal blood glucose concentration did not change during the ethanol treatment whereas plasma insulin levels were lower at the beginning of gestation and at the 15 and 18 days of pregnancy in ethanol-treated rats. Blood beta-OH-butyrate levels were higher and acetoacetate concentrations unchanged during the ethanol treatment, resulting in augmented beta-OH-butyrate/acetoacetate ratio. Intravenous glucose tolerance was not modified in ethanol-treated rats whilst the associated insulin response was lower in both non-pregnant and pregnant ethanol-treated rats. Data show that ethanol treatment during pregnancy alters glucose-insulin relationships despite being associated with unchanged maternal glycemia.     

Associations of ALDH2 and ADH1B genotypes with response to alcohol in Asian Americans

OBJECTIVE: Individuals with alcohol dependence are less likely to possess variant alleles of the alcohol-metabolizing genes, aldehyde dehydrogenase (ALDH2*2) and alcohol dehydrogenase (ADH1B*2), than non-alcohol-dependent controls. It is hypothesized that the mechanism through which these alleles protect against alcohol dependence is by causing elevations in acetaldehyde, which in turn cause an increased response to alcohol. Previous research has shown that individuals with ALDH2*2 demonstrate enhanced reactions to alcohol compared with those without this genetic variant, but evidence that ADH1B*2 is associated with a greater alcohol response is mixed. This study was designed to determine whether the ADH1B genotype is associated with more intense reactions to alcohol after controlling for the ALDH2 genotype. METHOD: Participants (N = 101) were Asian American college students. Each was evaluated using objective and subjective measures before and after ingestion of alcohol and placebo beverages. RESULTS: Participants with the ALDH2*1/*2 and ALDH2*2/*2 genotypes were more likely to experience vomiting following ingestion of the alcohol beverage than those with the ALDH2*1/*1 genotype. Participants with the ALDH2*1/*2 genotype also had greater pulse-rate increases, observed flushing ratings, and subjective feelings of intoxication 30 minutes after ingestion of alcohol than participants with the ALDH2*1/*1 genotype, despite equivalent blood alcohol concentration (BAC) measurements. Among participants with the ALDH2*1/*1 genotype, there were no additional effects of the ADH1B genotype on any measures of response to alcohol. Among participants with the ALDH2*1/*2 genotype, those with the ADH1B*2/*2 genotype were more likely to experience alcohol-induced vomiting and to report feeling less "great overall" 30 minutes after ingestion of alcohol than those with the ADH1B*1/*2 genotype. CONCLUSIONS: These findings are consistent with the hypothesis that there is an additional effect of ADH1B*2 on level of response to alcohol, but only among individuals with the ALDH2*1/*2 genotype.     

The effects of the ALDH2*1/2, CYP2E1 C1/C2 and C/D genotypes on blood ethanol elimination

The effects of CYP2E1 genotypes on the blood ethanol and acetaldehyde levels were investigated in a pair of Japanese volunteers whose ADH2, ADH3 and ALDH2 genotypes were identical but whose CYP2E1 genotypes were different. In the same way, the effects of ALDH2 and ADH2 on the ethanol elimination kinetics were also studied. The predicting 95% confidence bounds determined on regression analysis of the data suggested that after venous injection of ethanol, the blood ethanol and acetaldehyde concentrations in a volunteer normal homozygous for ALDH2 (ALDH2*1/1) were lower than in a heterozygous one (ALDH2*1/2). Also, the blood ethanol and acetaldehyde concentrations in a volunteer with the c2 and C alleles of CYP2E1 (c1/c2 and C/D) were lower than in one without the c2 and C alleles (c1/c1 and D/D). However, there were no significant differences in the blood ethanol and acetaldehyde concentrations between volunteers with ADH2*1 (ADH2*1/1) and without ADH2*1 (ADH2*1/2).     

Effects of ethanol ingestion on the hepatotoxicity and metabolism of paracetamol in mice

The influence of ethanol on paracetamol-induced liver damage was studied in mice and related to changes in microsomal monooxygenases and plasma paracetamol metabolites in the same group of animals. Paracetamol (400 mg/kg body wt, p.o.) was administered alone or simultaneously with ethanol (3 g/kg, p.o.) to mice fed either a chow diet or pretreated for 4 weeks with a liquid diet containing ethanol (20% of energy). Acute ethanol administration protected against paracetamol hepatotoxicity, but this protection was complete only in mice not fed ethanol previously. Acute ethanol administration also appeared to reduce paracetamol monooxygenation in vivo, but ethanol (50 mM) added to microsomal incubations in vitro had no significant effect on paracetamol activation and covalent binding. The chronic ingestion of ethanol in the diet increased paracetamol-related liver damage, but there appeared to be no induction of paracetamol monooxygenation in these animals. We are unable to confirm current concepts that the potentiation of paracetamol hepatotoxicity by chronic ethanol ingestion and its reduction by acute ethanol administration result solely from contrasting effects of ethanol on cytochrome P-450, and alternative explanations are proposed.     

Influence of ALDH2 polymorphism on ethanol kinetics and pulmonary effects in male and female rats exposed to ethanol vapors

Ethanol is being added in various proportions to fuel in order to reduce greenhouse gas emissions. This is likely to result in involuntary exposure to ethanol vapors. Whether or not such exposure might cause health effects is still unknown. Acetaldehyde, an important metabolite of ethanol detoxified by aldehyde dehydrogenase (ALDH2) is more toxic that ethanol. This study assessed the impact of genetic ALDH2 polymorphism in male and female Sprague-Dawley rats on ethanol kinetics and pulmonary effects following sub-chronic exposure to ethanol vapors. Homozygote rats ALDH2(Q)/2(Q) (fast ALDH2 activity) and ALDH2(R)/2(R) (ALDH2 deficiency) were exposed to 1000 or 3000 ppm, 6 h/day, 5 days/week for 13 weeks. Blood ethanol concentrations (BEC) were measured at various post-exposure times. Cellularity in bronchoalveolar lavages (BAL) and lung histological evaluation were performed at week 13. Results showed that BEC in males were systematically lower than in females, e.g. BEC in ALDH2(Q)/2(Q) males (2 min, 1,000 ppm, day 1) was significantly (p < 0.05) lower (66.8 +/- 10.7 microM) compared to females (87.6 +/- 15.3 microM). BEC for ALDH2(Q)/2(Q) rats were different from ALDH2(R)/2(R) only for males exposed for more than 64 days. Repeated exposures resulted in a significant decrease of BEC, e.g. for ALDH2(Q)/2(Q) males (3,000 ppm) BEC on day 1 and day 85 were 324.6 +/- 102.6 microM and 187.5 +/- 32.1 microM, respectively. BAL and histological evaluation revealed no pulmonary toxicity for all groups. Overall, results showed that 3,000 ppm of ethanol vapors represents no observed adverse effect level (NOAEL) for pulmonary toxicity in the rat.     

Effects of captopril on glucose tolerance in elderly patients with congestive cardiac failure

A prospective study was carried out to investigate the effects of the ACE inhibitor captopril on glucose tolerance in 14 elderly patients, aged 76 to 89 years, who had co-incident cardiac failure and stable Type II diabetes mellitus. Patients were maintained on their diet and diabetic therapy and were given 12.5 mg captopril twice daily. Clinical findings, including signs of cardiac failure, body weight and blood pressure, biochemical profile and chest X-ray appearance were documented at each visit. Blood glucose tolerance testing was carried out immediately before starting captopril and again 28 days later. A reduction in symptoms of heart failure occurred in all patients and 5 of them reduced their New York Heart Association grade of heart failure. Significant improvement in glucose tolerance occurred in all patients. Four were able to reduce hypoglycaemic therapy and 1 was able to stop his hypoglycaemic agents. This potentially valuable additional benefit of captopril in improving glucose tolerance has not yet been shown to occur with other ACE inhibitors.     

Effects of ethanol ingestion on amino acid uptake in the dog liver in vivo

The effect of ethanol ingestion on the uptake of labeled amino acids was studied in the in situ autoperfused dog liver. Ethanol was administered orally, as a 15% water solution, in a dose of 4 g/kg body weight/day as the only source of water for 2 days. Amino acid uptake was measured in anesthetized dogs by means of the single-passage, multiple-tracer dilution technique. In control animals, hepatic uptake of 14C-glycine, 3H-alpha-aminoisobutyric acid (3H-AIB) and 3H-L-leucine were 50, 15 and 66%, respectively. In the ethanol-treated dogs, glycine and AIB uptake was reduced by 70 and 63%, respectively. L-leucine uptake was reduced by only 23%. The plasma concentration of the naturally occurring amino acids was significantly increased after ethanol treatment, probably due to a reduced influx into hepatocytes. Simultaneous measurements of hemodynamic parameters showed a significant increase in the portal vein pressure of ethanol-treated animals, whereas the portal vein blood flow and hepatic extracellular volume were unaffected.     

Effects of chronic ethanol ingestion on tissue elimination-phase kinetics of procainamide in rats.

The effects of chronic ethanol ingestion on the pharmacokinetics of procainamide in various tissues were studied. Ethanol-treated rats received ethanol at 4 g/kg/day for an initial 7 days and then at 8 g/kg/day for the subsequent 21 days; control rats received isocaloric sucrose. After a single intravenous dose, the semilogarithmic procainamide concentration-time profiles observed in hearts and kidneys of both groups of rats were similar to the previously reported biexponential profiles of procainamide concentration in blood. This finding indicates a rapid distribution equilibrium of drug in both blood and these highly perfused tissues. The profiles of drug concentration in thigh muscle and fat of both groups of rats exhibited a drug-uptake phase during the initial 25-min period followed by a monoexponential decline in drug concentration. For all tissues, the slopes (beta values) of the curves of the drug concentration versus time were calculated on the basis of elimination-phase data, except for fat of control rats where the predominant elimination phase was not discernible. The beta values in hearts and thigh muscles of ethanol-treated rats were significantly higher than those in the corresponding tissues of control rats. These results are evaluated in light of previously reported effects of the same ethanol treatment on the distribution pharmacokinetics and the steady-state partition coefficients of the drug in these tissues. Possible mechanisms are proposed to account for these effects on the basis of the known diverse effects of chronic ethanol ingestion on the cellular compositions of individual organs and tissues.     

Effects of maternal ethanol ingestion on cerebral neurotransmitters and cyclic-AMP in the rat offspring

• 1.1. To study the effects of maternal alcohol ingestion on brain parameters in offspring, rats were given ethanol for drinking (25% w/v) from the time of mating until sacrifice. Controls drank tap water.
• 2.2. Alcohol ingestion reduced daily food and liquid consumption but total caloric intake was only slightly diminished.
• 3.3. Maternal body weight increased and offspring body weight, size and brain weight were reduced in the animals receiving alcohol.
• 4.4. Brain concentrations of tryptophan, tyrosine and GABA were augmented in ethanol treated mothers at 1 day post-partum.
• 5.5. Comparison of brain parameters in offspring of alcoholic mothers with those of controls showed that tryptophan and 5HT concentrations were augmented in 4 day old neonates, NA was increased in 21 day fetuses and 1 day old neonates, and adenylate cyclase activity was also greater in the brains of 21 day fetuses and the cerebellums of 4 day old neonates.
• 6.6. Neither phosphodiesterase nor cyclic-AMP concentrations differed in offspring of alcoholic and control mothers.
• 7.7. Data showed alterations in brain NA and 5HT systems in the offspring of alcoholic mothers.

     

Effects of ethanol ingestion on the metabolism of a hepatotoxic dose of paracetamol in mice

After administration to mice of a hepatotoxic dose of paracetamol (400 mg/kg body wt, p.o.) peak plasma concentrations of the drug and its glucuronide were approximately 900 microM around one hour. Corresponding levels of the sulphate, mercapturate and cysteine conjugates were approximately 100, 35 and 20 microM, respectively. Urinary excretion accounted for 55% of the administered drug 31 h after dosing. Of this total, 64.7% was paracetamol glucuronide, 17.9% paracetamol cysteine, 10.4% paracetamol sulphate, 0.5% paracetamol mercapturate and 6.5% unchanged drug. One hour after acute ethanol administration (3 g/kg, p.o., concomitantly with paracetamol) plasma levels of the glucuronide, cysteine and mercapturate conjugates were decreased by approximately 50%. There were reductions in the urinary excretion of the glucuronide (-13%) and cysteine conjugates (-24%), but increases in the amounts of mercapturate (+52%), sulphate +11%) and unchanged drug (+81%). Chronic ethanol ingestion (15 g/kg per d for 28 d) caused a transient initial increase in plasma paracetamol cysteine (+32%) and mercapturate (+41%) concentrations, but the only substantial change in urinary excretion was a 29% increase in the amount of paracetamol glucuronide. After chronic ethanol consumption, acute ethanol administration had a transient inhibitory effect on paracetamol mono-oxygenation, but glucuronidation was unaffected (as judged by plasma concentrations). Only paracetamol mercapturate excretion was substantially affected (+64%).     

Effect of carbohydrate intake on serum 3,5,3'-triiodothyronine-response to glucose ingestion and its relation to glucose tolerance in lean non-insulin-dependent diabetic patients

This study was conducted to know the effect of carbohydrate intake on serum 3,5,3'-triiodothyronine (CAS 6893-02-3, T3)-response to glucose ingestion and its relation to glucose tolerance in lean non-insulin-dependent diabetes mellitus (NIDDM) patients. Ten patients, body mass index: 21.8 +/- 2.2 (mean +/- SD) kg/m2, were given a control diet (2012 kcal/day(d); carbohydrate (CHO): 299 g/d) on admission. Several days later, they were given a low-calorie and low-CHO diet (Low-CHO) (1156 kcal/d; CHO: 139 g/d) and 2 weeks later, they received a low-calorie and high-CHO diet (High-CHO) (1154 kcal/d; CHO: 176 g/d) and another 2 weeks later, they were given Low-CHO again for 2 weeks. They received oral 75 g glucose tolerance tests after completion of each diet. sigma dGlucose (mmol/l) decreased from 54.3 +/- 11.9 (control) to 42.5 +/- 7.5 after Low-CHO and reached 34.5 +/- 10.4 after High-CHO but increased to 36.4 +/- 11.1 after the 2nd Low-CHO (F = 7.46, p = 0.0005). sigma dT3 (nmol/l) increased from -0.18 +/- 0.52 (control) to 0.12 +/- 0.67 after Low-CHO and reached 0.92 +/- 0.59 after High-CHO but decreased to 0.36 +/- 0.65 after the 2nd Low-CHO (F = 5.92, p = 0.0022). Serum insulin and body weight remained unchanged throughout the study. Negative correlation between sigma dT3 and sigma dGlucose (r = -0.493, n = 40, p = 0.0012) was found throughout the diet modification. Carbohydrate intake affected serum T3-response to glucose ingestion and the response was closely related to glucose tolerance in lean NIDDM patients.