L-Cysteine Containing Vitamin Supplement Which Prevents or Alleviates Alcohol-related Hangover Symptoms: Nausea, Headache, Stress and Anxiety.

AIMS: Alcohol-related hangover symptoms: nausea, headache, stress and anxiety cause globally considerable amount of health problems and economic losses. Many of these harmful effects are produced by alcohol and its metabolite, acetaldehyde, which also is a common ingredient in alcohol beverages. The aim of the present study is to investigate the effect of the amino acid L-cysteine on the alcohol/acetaldehyde related aftereffects. METHODS: Voluntary healthy participants were recruited through advertisements. Volunteers had to have experience of hangover and/or headache. The hangover study was randomized, double-blind and placebo-controlled. Nineteen males randomly swallowed placebo and L-cysteine tablets. The alcohol dose was 1.5 g/kg, which was consumed during 3 h. RESULTS: The primary results based on correlational analysis showed that L-cysteine prevents or alleviates hangover, nausea, headache, stress and anxiety. For hangover, nausea and headache the results were apparent with the L-cysteine dose of 1200 mg and for stress and anxiety already with the dose of 600 mg. CONCLUSIONS: L-cysteine would reduce the need of drinking the next day with no or less hangover symptoms: nausea, headache, stress and anxiety. Altogether, these effects of L-cysteine are unique and seem to have a future in preventing or alleviating these harmful symptoms as well as reducing the risk of alcohol addiction.

Genetic-epidemiological evidence for the role of acetaldehyde in cancers related to alcohol drinking.

Alcohol drinking increases the risk for a number of cancers. Currently, the highest risk (Group 1) concerns oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast, as assessed by the International Agency for Research on Cancer (IARC). Alcohol and other beverage constituents, their metabolic effects, and alcohol-related unhealthy lifestyles have been suggested as etiological factors. The aim of the present survey is to evaluate the carcinogenic role of acetaldehyde in alcohol-related cancers, with special emphasis on the genetic-epidemiological evidence. Acetaldehyde, as a constituent of alcoholic beverages, and microbial and endogenous alcohol oxidation well explain why alcohol-related cancers primarily occur in the digestive tracts and other tissues with active alcohol and acetaldehyde metabolism. Genetic-epidemiological research has brought compelling evidence for the causality of acetaldehyde in alcohol-related cancers. Thus, IARC recently categorized alcohol-drinking-related acetaldehyde to Group 1 for head and neck and esophageal cancers. This is probably just the tip of the iceberg, since more recent epidemiological studies have also shown significant positive associations between the aldehyde dehydrogenase ALDH2 (rs671)*2 allele (encoding inactive enzyme causing high acetaldehyde elevations) and gastric, colorectal, lung, and hepatocellular cancers. However, a number of the current studies lack the appropriate matching or stratification of alcohol drinking in the case-control comparisons, which has led to erroneous interpretations of the data. Future studies should consider these aspects more thoroughly. The polymorphism phenotypes (flushing and nausea) may provide valuable tools for future successful health education in the prevention of alcohol-drinking-related cancers.

Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury.

BACKGROUND & AIMS: The transcription factor nuclear factor-eythroid 2-related factor 2 (Nrf2(-/-)) is essential for protecting cells against xenobiotic and oxidative stress. Increased oxidative stress has been implicated in the pathophysiology of many diseases including ethanol-induced liver disease. Therefore, the role of Nrf2(-/-) in ethanol-induced liver injury was investigated. METHODS: Wild-type and Nrf2(-/-) mice were fed with the ethanol diet, followed by examination of liver pathology, mortality, and ethanol metabolism. RESULTS: Nrf2(-/-) mice displayed a dramatically increased mortality associated with liver failure when fed doses of ethanol that were tolerated by WT mice. Nrf2(-/-) mice showed a significantly reduced ability to detoxify acetaldehyde, leading to an accumulation of the toxic metabolite. Loss of Nrf2(-/-) caused a marked steatosis in livers of ethanol-fed mice, and Srebp1 was identified as a candidate transcription factor responsible for lipogenic enzyme induction. Furthermore, ethanol consumption led to a progressive depletion of total and mitochondrial reduced glutathione, which was associated with more pronounced structural and functional changes to mitochondria of Nrf2(-/-) mice. In addition, ethanol feeding elicited an aggravated inflammatory response mediated by Kupffer cells in Nrf2(-/-) mice as shown by an increased tumor necrosis factor-alpha secretion and activation of the interleukin-6/Stat-3 pathway. Together these changes lead to a vicious cycle of accumulating hepatocellular damage, ultimately leading to liver failure and death of Nrf2(-/-) mice. CONCLUSIONS: Our data establish a central role for Nrf2(-/-) in the protection against ethanol-induced liver injury.

The role of aldehyde dehydrogenase-1 (ALDH1A1) polymorphisms in harmful alcohol consumption in a Finnish population.

Liver cystolic aldehyde dehydrogenase 1 (ALDH1A1) has been previously associated with both alcohol dependence and alcohol consumption behaviour, and has been implicated in alcohol-induced flushing and alcohol sensitivity in Caucasians. The present study tested for association between ALDH1A1 and alcohol consumption behaviour and susceptibility to problem drinking or alcohol dependence in Finnish cohorts of unrelated male subjects recruited from alcoholism clinical treatment facilities ( n = 104) and from the general population ( n = 201). All participants completed the Alcohol Use Disorder Identification Test (AUDIT) and were genotyped for eight single nucleotide polymorphisms (SNPs) within or flanking ALDH1A1 . To test for association between alcohol consumption behaviour and these polymorphisms, we used generalised linear models and haplotypic analysis. Three SNPs were nominally associated (rs348449, p = 0.043; rs610529, p = 0.013; rs348479, p = 0.025) with the quantitative AUDIT score, which evaluates alcohol consumption behaviour. Two-locus (rs610529-rs2288087) haplotype analysis increased the strength of association with AUDIT score ( p = 0.0015). Additionally, rs348449 is highly associated with problem drinking (allelic odds ratio [OR] 7.87, 95 per cent confidence interval [CI] 1.67-37.01) but due to the low minor allele frequency (0.01 and 0.07 in controls and problem drinkers, respectively), more samples are required to validate this observation. Conversely, rs348479 ( p = 0.019) and rs610529 (allelic OR 0.65, 95 per cent CI 0.43-0.98; genotypic OR 0.32, 95 per cent CI 0.12-0.84) are implicated in alcohol dependence status. This study provides further evidence for a role for ALDH1A1 in alcohol consumption behaviour, including problem drinking and possibly alcohol dependence, in our Finnish population.

Measurement of acetaldehyde: what levels occur naturally and in response to alcohol?

The aim of the present paper is to update the status regarding human acetaldehyde levels in blood, breath and saliva during normal ethanol oxidation, i.e. without deficiency in, or inhibition of, aldehyde dehydrogenase activity. The previous conclusion according to which no detectable (<0.5 microM), adequately determined 'free and/or loosely bound' acetaldehyde has not yet been found in venous blood, more or less, still holds. The only new findings within this context consist of low venous blood acetaldehyde levels (1-3 microM on average) observed in some women during the use of oral contraceptives or during the high oestradiol phases of normal menstrual cycle. Breath acetaldehyde levels are about 10-20 and 20-40nM at blood ethanol concentrations of about 10 and 20mM, respectively. Theoretically calculated corresponding blood acetaldehyde levels in pulmonary blood would be about 2-4 and 4-8 microM. The acetaldehyde in the breath most likely reflects pulmonary blood acetaldehyde, microbial and tissue acetaldehyde production in the aerodigestive tract. As well as with breath acetaldehyde, salivary acetaldehyde levels also correlate positively with the blood ethanol concentrations. At blood ethanol concentrations of about 10 and 20 mM the average acetaldehyde concentration in saliva is about 15-25 and 20-40 microM, respectively. Saliva acetaldehyde represents mostly microbial acetaldehyde formation in the oral cavity, but also, to some extent, ethanol oxidation in nearby tissues. More studies are still needed to clarify the proportion of the underlying sources for blood, breath and salivary acetaldehyde at different ethanol concentrations. The problem with rapid acetaldehyde oxidation, which may markedly affect the recovery of low acetaldehyde levels, also needs to be solved.

Acceleration of ethanol and acetaldehyde oxidation by D-glycerate in rats.

The aim of the present study was to investigate whether d-glycerate (glycerate) could accelerate ethanol and acetaldehyde (AcH) oxidation in vivo in rats by circumventing the rate-limiting step, that is, the reoxidation of the reduced form of nicotinamide adenine dinucleotide. Male rats belonging to the ANA (Alko, nonalcohol) and AA (Alko, alcohol) rat lines were challenged with 1.2 g ethanol per kilogram with or without glycerate administration (0.1-1.0 g/kg). Blood ethanol, blood AcH, and liver free glycerol concentrations were determined during ethanol intoxication. Glycerate treatment, regardless of the dose, accelerated ethanol elimination by approximately 25% (P < .001) in the ANA animals. Glycerate also accelerated the AcH oxidation, but perhaps not as much as the ethanol oxidation, as indicated by a trend toward elevated AcH levels. In the experiments with the AA rats, glycerate treatment elevated hepatic free glycerol levels by about 50% (P < .05) during alcohol intoxication. The acceleration of ethanol and AcH oxidation in conjunction with elevated glycerol levels by the treatment with glycerate supports the hypothesis that the aldehyde dehydrogenase-mediated AcH oxidation can be coupled with the reduction of glycerate to d-glyceraldehyde catalyzed by the same enzyme. Such a coupling should increase the availability of the oxidized form of nicotinamide adenine dinucleotide and thus accelerate both ethanol and AcH oxidation. Further studies are needed to investigate how the AcH could be even more efficiently oxidized to reduce the harmful effects of ethanol-derived AcH.

Early deprivation increases exploration and locomotion in adult male Wistar offspring.

The aim of the study was to investigate the effects of repeated early maternal deprivation (individual separation in warm or cold environment for 4 h/day) during postnatal days 1-15 on emotional responses in novel situations and voluntary alcohol consumption in adult male Wistar rat offspring. Brain monoamine levels and plasma levels of corticosterone were measured at the end of the experiment. Controls were exposed to a brief (3 min) daily handling procedure. As adults, both groups of early deprived rats showed increased nose poking and locomotion in the exploration test compared to controls. Moreover, separated rats kept in room temperature also showed increased locomotion when tested for an extended period of time. There were no differences in alcohol intake, monoamine levels, or corticosterone levels between early deprived animals and controls. In addition, the dams' retrieval behavior of pups was studied, showing that dams of early deprived pups spent more time in the nest with the pups after the 4-h separation period compared to control dams. Our results indicate that early deprived animals show decreased emotionality in novel settings compared to briefly handled controls. Furthermore, the present study demonstrates that methodological issues within the maternal separation paradigm may be influential factors for behavioral changes in adulthood.

Testosterone, sexuality and antisocial personality in rapists and child molesters: a pilot study.

Morning and afternoon levels of saliva testosterone levels in Finnish imprisoned rapists (n = 10) and child molesters (n = 10) were compared to those in randomly selected control subjects (n = 31). The associations of saliva testosterone with sexual behavior and antisocial personality traits were explored in all groups. The sexual offenders and control subjects did not differ in the between-subjects main effect estimated for the averaged morning and afternoon testosterone levels. Seven rapists and three child molesters met the criteria for antisocial personality disorder (ASP). In the sexual offenders, a summed ASP index was positively correlated with mean saliva testosterone. Sexual activity as estimated from self-reports of sexual intercourse and masturbation was significantly related to testosterone in both rapists and child molesters but not in the control males. The implications of these results are discussed.

Testosterone, 5 alpha-dihydrotestosterone and cortisol in men with and without alcohol-related aggression.

OBJECTIVE: The present investigation was designed to study steroid hormones, alcohol and aggression interactions in men with a history of alcohol-related aggression (AGG+) and in a cross-sectional control population (AGG-). METHOD: AGG+ (n = 40) and AGG- (n = 44) male volunteers completed the Buss-Perry Aggression Questionnaire and the revised Michigan Alcoholism Screening Test (MAST), after which plasma-free and total testosterone, 5alpha-dihydrotestosterone (DHT) and cortisol were determined. RESULTS: The AGG+ men displayed significantly (p < .05) higher aggression and MAST measures compared with the AGG- men; however, no significant group differences were observed regarding the hormone values. Independently of the steroid hormones, MAST correlated positively with the hostility subscale in both AGG- and AGG+ groups. Free and total testosterone correlated positively with anger and DHT correlated positively with verbal aggression and anger, whereas cortisol correlated negatively with physical aggression and anger in the AGG- group. No significant correlations between steroid hormones and aggression parameters were observed in the AGG+ group. The age factor explained part of the MAST and steroid hormone correlations with aggression. A hormone and MAST independent moderation effect of age upon aggression was also found. CONCLUSIONS: The present study demonstrates an association between alcohol drinking and self-reported sober-state aggression, which implies that the etiology of alcohol misuse and aggressive behavior may involve common biological and/or social factors. These mechanisms, as well as age, androgens and cortisol, all represent factors that, in combination, regulate human aggression.

Effects of Lifelong Ethanol Consumption on Brain Monoamine Transmitters in Alcohol-Preferring Alko Alcohol (AA) Rats.

The purpose of the present study was to examine the combined effects of aging and lifelong ethanol exposure on the levels of monoamine neurotransmitters in different regions of the brain. This work is part of a project addressing interactions of aging and lifelong ethanol consumption in alcohol-preferring AA (Alko Alcohol) line of rats, selected for high voluntary consumption of ethanol. Intake of ethanol on the level of 4.5-5 g/kg/day for about 20 months induced only limited changes in the neurotransmitter levels; the concentration of noradrenaline was significantly reduced in the frontal cortex. There was also a trend towards lower levels of dopamine and 5-hydroxytryptamine (5-HT) in the frontal cortex, and towards a lower noradrenaline level in the dorsal cortex. Aging was associated with a decreased concentration of dopamine in the dorsal cortex and with a declining trend in the striatum. The levels of 5-HT in the limbic forebrain were higher in the aged than in the young animals, and in the striatum, there was a trend towards higher levels in older animals. The data suggest that a continuous intake of moderate amounts of ethanol does not enhance the age-related alterations in brain monoamine neurotransmission, while the decline in the brain level of dopamine associated with aging may be a factor contributing to age-related neurological disorders.

Pubertal testosterone predicts mental rotation performance of young adult males.

Robust sex differences in some spatial abilities that favor males have raised the question of whether testosterone contributes to those differences. There is some evidence for prenatal organizational effects of testosterone on male-favoring spatial abilities, but not much is known about the role of pubertal testosterone levels on adult cognitive abilities. We studied the association between pubertal testosterone (at age 14) and cognitive performance in young adulthood (at age 21-23), assessing male-favoring, female-favoring, and sex-neutral cognitive domains in a population-based sample of 130 male and 178 female twins. Pubertal testosterone was negatively associated with performance in the Mental Rotation Test in young adult men (r=-.27), while among women no significant associations between testosterone and cognitive measures were detected. The significant association among men remained after controlling for pubertal development. Confirmatory within-family comparisons with one-sided significance testing yielded a negative correlation between twin pair differences in testosterone levels and Mental Rotation Test performances in 35 male twin pairs (r=-.32): the twin brother with higher testosterone performed less well on the Mental Rotation Test. That association was evident in 18 pairs of dizygotic male twin pairs (r=-.42; analysis controlling for shared environmental effects). In contrast, the association of differences was not evident among 17 monozygotic male twin pairs (r=-.07; analysis controlling for shared genetic influences). Results suggest that pubertal testosterone levels are related specifically to male-favoring spatial ability and only among men. Within-family analyses implicated possible shared genetic effects between pubertal testosterone and mental rotation ability.

Associations of corticosterone and testosterone with alcohol drinking in F2 populations derived from AA and ANA rat lines.

In our previous studies on alcohol-preferring AA (Alko alcohol) and nonpreferring ANA (Alko nonalcohol) rats, we have observed that the AA rats exhibit lower endogenous levels of corticosterone, higher testosterone levels, and more frequent alcohol-induced testosterone elevations when compared with ANA rats. The objective of the present study was to get more conclusive evidence for the potential role of the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes in alcohol drinking by using the F2 experimental design. Alcohol-preferring AA and alcohol-nonpreferring ANA rat lines were crossbred to form a F1 population from which the final F2 population was derived. Male animals were challenged with a priming alcohol dose after which a 3 weeks' voluntary alcohol drinking period took place. After a washout period of 1 week, one-half of the 40 highest and 40 lowest alcohol drinkers were challenged with a second dose of alcohol and the other half with saline. Serum testosterone and corticosterone levels were measured before and during the test. Higher endogenous testosterone levels were detected in the rats of the high alcohol consumption group compared with the low consumption group. Also supporting the original AA/ANA line differences, a trend for lower endogenous corticosterone levels were measured in the high alcohol consumption group compared with the low consumption group. The alcohol challenge test after the drinking period resulted in a higher frequency (38%) of testosterone elevations in the high drinkers compared with the low drinkers (5%). The present data confirms the validity of the positive connections between testosterone elevation and increased alcohol drinking, as well as between testosterone reduction and decreased alcohol drinking, in AA and ANA rats.

Decreased prevalence of left-handedness among females with male co-twins: evidence suggesting prenatal testosterone transfer in humans?

Studies of singletons suggest that right-handed individuals may have higher levels of testosterone than do left-handed individuals. Prenatal testosterone levels are hypothesised to be especially related to handedness formation. In humans, female members from opposite-sex twin pairs may experience elevated level of prenatal exposure to testosterone in their intrauterine environment shared with a male. We tested for differences in rates of left-handedness/right-handedness in female twins from same-sex and opposite-sex twin pairs. Our sample consisted of 4736 subjects, about 70% of all Finnish twins born in 1983-1987, with information on measured pregnancy and birth related factors. Circulating testosterone and estradiol levels at age 14 were available on 771 and 744 of these twins, respectively. We found significantly (p=.006) lower prevalence of left-handedness in females from opposite-sex pairs (5.3%) compared to females from same-sex pairs (8.6%). The circulating levels of neither testosterone nor estradiol related to handedness in either females or males. Nor were there differences in circulating testosterone or estradiol levels between females from opposite-sex and same-sex twin pairs. Birth and pregnancy related factors for which we had information were unrelated to handedness. Our results are difficult to fully explain by postnatal factors, but they offer support to theory that relates testosterone to formation of handedness, and in a population-based sample, are suggestive of effects of prenatal testosterone transfer.

Association between harmful alcohol consumption behavior and dopamine transporter (DAT1) gene polymorphisms in a male Finnish population.

BACKGROUND: Ethanol-induced dopamine (DA) release in the mesolimbic system may reinforce excessive alcohol intake and the progression of alcohol dependence. Within this reward system, the DA transporter (DAT1) plays a key role in the regulation of dopaminergic neurotransmission through presynaptic DA reuptake. OBJECTIVE: This study investigated whether DAT1 genetic variation was associated with either alcohol consumption behavior or alcohol dependence in a Finnish cohort. METHODS: Eight single nucleotide polymorphisms and a frequently studied 3'-untranslated region 40-bp variable number tandem repeat were genotyped in unrelated male Finnish participants selected from alcoholism clinical treatment facilities (n=104), or through the Finnish Population Register (n=201). All participants completed the Alcohol Use Disorder Identification Test. MAIN RESULTS: We found significant evidence that the synonymous exon 2 rs6350 variant was positively associated with both alcohol consumption behavior (P=0.0004) and problem drinking (G allele, odds ratio: 3.63, 95% confidence interval: 1.22-10.78). A second single nucleotide polymorphism, rs463379 (intron 4), was negatively associated with alcohol dependence (A allele, odds ratio: 0.61, 95% confidence interval: 0.39-0.94). However, two-locus haplotypic analysis of rs6350-rs463379 did not further increase the strength of association with the quantitative Alcohol Use Disorder Identification Test score trait (P=0.0024). CONCLUSION: The present findings suggest that DAT1 genetic variation influences drinking behavior in our Finnish population, where the rs6350 A and rs463379 G alleles provide a protective role against high alcohol consumption and alcohol dependence, respectively. A systematic search for DAT1 variants that affect gene function or expression in the Finnish and other populations is warranted.

The role of social isolation in the effects of alcohol on corticosterone and testosterone levels of alcohol-preferring and non-preferring rats.

AIMS: Alcohol has been reported to affect the hypothalamic-pituitary-gonadal axis (HPG-axis) and hypothalamic-pituitary-adrenal axis (HPA-axis) as expressed by increased or decreased corticosterone and testosterone levels. Both hormones have also been related to the aetiology of alcohol drinking and the development of alcoholism. Our aim has been to study these interrelations in animal models of alcohol drinking by using social isolation as a model of anxiety. METHODS: The effects of alcohol on serum testosterone and corticosterone concentrations were investigated in alcohol-preferring (AA) and alcohol non-preferring (ANA) rat lines. Animals were tested in mornings and afternoons with 0.75 and 1.5 g alcohol/kg. Half of the animals were kept in single cages, while the control animals were housed in groups of four individuals. RESULTS: The group-caged ANA rats displayed higher control corticosterone levels than the corresponding AA rats during morning sessions (P = 0.007). The AA rats displayed elevated corticosterone levels (AM: P = 0.047) and the ANA rats displayed reduced control corticosterone levels (PM: P = 0.016) in the single cage situation compared with the group-cage situation. Corticosterone concentrations were not affected by low doses and increased (P < 0.05) by high doses of alcohol in all test groups except for isolated AA rats during afternoon sessions. In general, more significant reductions in testosterone levels following alcohol administration were found in the ANA line. In group-caged AA rats, alcohol reduced testosterone levels, while no such effect was observed in isolated AA rats. CONCLUSIONS: We suggest that social isolation, representing stress, may constitute a situation in which the HPA and HPG axes are connected together in promoting alcohol drinking.

Increased plasma fatty acid ethyl ester levels following inhibition of oxidative metabolism of ethanol by 4-methylpyrazole treatment in human subjects.

BACKGROUND: Recent experimental evidence suggests that fatty acid ethyl esters (FAEE), nonoxidative metabolites of ethanol, mediate ethanol-induced organ damage. A direct association between pancreas-specific toxicity and increased levels of FAEE following inhibition of the oxidative metabolism of ethanol by 4-methylpyrazole (4-MP) has previously been shown in studies with rats. METHODS: We obtained plasma samples from 32 healthy human volunteers who drank ethanol following 4-MP or placebo ingestion to determine whether in vivo inhibition of oxidative metabolism of ethanol causes a shift to nonoxidative metabolism of ethanol and the subsequent production of increased levels of FAEE. Plasma FAEE were isolated by solid-phase extraction and quantified by gas chromatography-mass spectrometry (GC-MS). RESULTS: Plasma FAEE levels in subjects receiving 4-MP treatment before ethanol consumption were elevated compared with plasma FAEE concentrations taken from control subjects who received a placebo before ethanol ingestion. Increased FAEE levels in the 4-MP treatment group occurred after peak blood ethanol, and peak FAEE levels were achieved. There was a correlation between the blood ethanol and the plasma FAEE levels, and the correlation persisted in the presence or absence of 4-MP. The peak FAEE values were greater in men than in women, with or without 4-MP treatment. CONCLUSIONS: Our results indicate that the in vivo inhibition of the oxidative metabolism of ethanol using 4-MP results in an increased circulating concentration of FAEE, products of the nonoxidative metabolism of ethanol.

Testosterone and alcohol use among adolescent male twins: testing between-family associations in within-family comparisons.

We examined associations of testosterone (T) and alcohol use in adolescent twin brothers, conducting both between- and within-family analyses. The twins completed semi-structured interviews, provided two saliva samples to assay T, and reported their drinking patterns and pubertal development. We adjusted T levels for diurnal/seasonal effects and association with pubertal maturation. In analyses of twins as individuals, higher T levels characterized boys reporting ever drinking, more frequent intoxication, high density drinking, more alcohol symptoms, and diagnosed alcohol dependency on interview. Adjusting for pubertal development, only associations with symptom count and diagnosis remained significant. The association with frequent intoxication replicated among drinking-discordant twin brothers, effectively ruling out between-family confounds, but that association was not significant after adjustment for pubertal development. The phenotypic correlation between T and pubertal maturation is largely genetic, inviting study of the magnitude and meaning of linkages between testosterone and symptoms of alcoholism on follow-up in early adulthood.