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PubMed2004

ADH1B*1, ADH1C*2, DRD2 (-141C Ins), and 5-HTTLPR are associated with alcoholism in Mexican American men living in Los Angeles.

BACKGROUND: The aim of the present study was to use a candidate gene approach to identify the genetic risk factors for alcoholism in Mexican Americans residing in the Los Angeles area. The genes selected include alcohol metabolizing genes and neurotransmitter genes, which have been shown in the literature to be associated with alcoholism in other ethnic groups. METHODS: Thirteen allelic variants from seven genes were evaluated for their role in alcoholism using alcoholic (n = 200) and nonalcoholic (n = 251) Mexican Americans. Those polymorphic sites include alcohol dehydrogenase (ADH1B, ADH1C), aldehyde dehydrogenase (ALDH2), cytochrome P-450 2E1 (CYP2E1) TaqI, DraI, RsaI, dopamine D2 receptor (DRD2) TaqI A, B, intron 6, exon 7, -141C Ins/Del, serotonin transporter (5-HTTLPR), and GABAA receptor beta3 subunit (GABRbeta3). RESULTS: The results demonstrate that Mexican Americans have extremely low allele frequency for both ALDH2*2 and ADH1B*2 and a relatively high frequency of ADH1C*2 and CYP2E1 c2 alleles. ADH1B*1, ADH1C*2, DRD2 (-141C Ins), and 5-HTTLPR were associated with alcoholism in Mexican Americans (p < 0.05). DRD2 Ins was associated with alcoholism in those alcoholics who carried the ADH1B*2 or ADH1C*1 protective alleles (p = 0.032 in genotype level and p = 0.015 in allele level). DRD2 TaqI A and B alleles were associated with early age of onset for drinking (p = 0.016 for TaqI A1 and p = 0.049 for TaqI B1 allele). CONCLUSIONS: Together, the data reveal unique genetic patterns in Mexican Americans that may be in part responsible for the heightened risk for alcoholism and alcohol-associated health problems in this population.

Adult↗
PubMed2006

Association of V227A PPARalpha polymorphism with altered serum biochemistry and alcohol drinking in Japanese men.

OBJECTIVES: Peroxisome proliferator-activated receptor (PPAR) alpha plays a major role in alcoholic liver disease in rodents. The two-fold objective of our study was to determine the presence of PPARalpha polymorphisms and their frequencies in Japanese populations and then to evaluate the effects of any alleles on metabolic parameters and alcohol drinking. METHODS: Analysis of coding SNP in PPARalpha was performed in 706 Japanese men; from these subjects 655 men were further studied after exclusion criteria were applied. RESULTS: PPARalpha-V227A, which has not been reported in Europe and North America as a major polymorphism, was discovered with the frequency of 0.05. PPARalpha-L162V was found in European and North American populations, but not in Japanese, thus confirming the ethnic differences in PPARalpha allele frequencies. The A227 allele was associated with increased serum concentrations of gamma glutamyltranspeptidase. In non-drinkers, the total cholesterol (TC) levels were significantly lower in those having the PPARalpha-V227A polymorphism. In drinkers, however, it was comparable among V227A polymorphisms, and conversely higher in those having both A227 and aldehyde dehydrogenase 2 (ALDH2) variants when further divided according to the ALDH2 polymorphism. Significant interactions between PPARalpha-V227A polymorphism and drinking were also found for TC, triglyceride levels and AST/ALT ratios. These results suggest that the activity of the A227 allele without drinking may be higher than in wild-type allele, but its activity may become lower during drinking habits. CONCLUSION: PPARalpha-V227A is a major polymorphism in the Japanese population, and its activity may be greater compared to wild-type, but decreased by alcohol drinking.

Alcohol Drinking↗
PubMed2006

Melanosis and squamous cell neoplasms of the upper aerodigestive tract in Japanese alcoholic men.

Melanosis is frequently observed in the upper aerodigestive tract of Japanese alcoholic men, and the prevalences of squamous cell dysplasia and SCC in the upper aerodigestive tract of Japanese alcoholic men are high. This study evaluated associations between melanosis and both neoplasms of the upper aerodigestive tract and factors contributing to the development of melanosis in Japanese alcoholic men. Endoscopic screening of 643 Japanese alcoholic men (aged 50-79 years) was combined with oropharyngolaryngeal inspection and esophageal iodine staining, and ALDH2 genotyping was carried out in 425 of them. Melanosis was frequently (20.8%) observed in the upper aerodigestive tract. The palate was the most common site of melanosis (11.2%), followed by the pharynx (9.5%), and by the esophagus (7.0%). The incidence of melanosis was higher in those with esophageal dysplasia (31/126, 24.6%), esophageal SCC (19/42, 45.2%), and oropharyngolaryngeal SCC (8/14, 54.1%) than in cancer- and dysplasia-free controls (69/437, 15.8%). The presence of melanosis was associated with a higher risk of esophageal dysplasia, esophageal SCC, and oropharyngolaryngeal SCC (OR 1.69, 4.03, and 6.61, respectively). Multivariate analysis showed that older age, heavier smoking, and heterozygosity for inactive ALDH2 were positively associated with the presence of melanosis. The presence of melanosis indicates a high risk for neoplasms in the upper aerodigestive tract of Japanese alcoholic men. Melanosis and neoplasms have the same causes, including older age, heavy smoking, and high acetaldehyde exposure.

Aged↗
PubMed1993

Mapping of MYF5, C1R, MYHL, TPI1, IAPP, A2MR and RNR onto sheep chromosome 3q.

Five new loci, myogenic factor 5 (MYF5), complement 1 receptor (CIR), myosin-like heavy chain (MYHL), islet amyloid polypeptide (IAPP), and alpha-2-macroglobulin receptor (A2MR), were mapped onto sheep chromosome 3q by Southern hybridization to a panel of chromosomally characterized sheep x hamster cell hybrid lines. The location of the triose phosphate isomerase (TPI1) gene and one of the nucleolar organizer regions (RNR) on sheep 3q was confirmed by Southern analysis. This study provides further evidence for the existence of a large conserved chromosomal segment comprising much of sheep chromosome 3q, cattle chromosome 5, and human chromosome 12. The distal evolutionary breakpoint on human chromosome 12, producing the chromosomal segment U23 in cattle marked by aldehyde dehydrogenase (ALDH2), also produces a separate segment in sheep. Neither ALDH2 nor pancreatic lipase (PLA2), which is also distally located on human chromosome 12, were mapped onto sheep chromosome 3q.

Amyloid↗
PubMed2006

SPINK1 gene mutations and pancreatitis in Japan.

SPINK1 can inhibit up to 20% of trypsin activity, and may constitute one major mechanism to protect the pancreas from autodigestion. In 2000, Witt et al. first recognized the association between mutations in the SPINK1 gene and chronic pancreatitis (CP), but the significance of SPINK1 gene mutation in pancreatitis and its relation to alcohol consumption remains unclear in Japan. The aim of the present paper was to clarify the incidence of SPINK1 mutations in CP patients with various etiologies in Japan and, in addition, to examine the relationship between alcohol metabolism and the polymorphisms in the key enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2). A total of 156 patients with CP, and 165 healthy volunteers, all Japanese, were examined for the SPINK1 mutations by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. In Japan, the prevalence of [N34S; IVS1-37T > C] and [-215G > A; IVS3 + 2T > C] was significantly higher in patients with idiopathic CP (10.6% and 12.8%, respectively) than normal subjects (0.6% and 0%). The frequency of the [-215G > A; IVS3 + 2T > C] mutation in Japan was significantly higher than that reported in other populations. Concerning alcoholic CP, the [-215G > A; IVS3 + 2T > C] mutation was found in only a small number of patients (3.9%). On analysis of ADH2 and ALDH2 gene polymorphisms an association was found between ADH2*2 allele and alcoholic CP, and the ADH2*2/2*2 genotype had a tendency to increase the risk of developing pancreatic pseudocyst. In conclusion, in Japan the [-215G > A; IVS3 + 2T > C] mutation in the SPINK1 gene may form a unique genetic background for pancreatitis.

Carrier Proteins↗
PubMed1989

Cytosolic aldehyde dehydrogenase (ALDH1) variants found in alcohol flushers.

Although mitochondrial aldehyde dehydrogenase (ALDH2) has been thought to play a major role in acetaldehyde detoxification, and the high incidence of 'alcohol flushing' among Orientals is attributed to the inherited deficiency of ALDH2, the role of cytosolic aldehyde dehydrogenase (ALDH1) cannot be ignored. On the premise that alcohol flushing in Caucasians could be related to ALDH1 abnormalities, we examined the enzyme properties and electrophoretic mobilities of ALDH1 partially purified from red blood cells of nine unrelated alcohol flushers. One exhibited very low activity (10-20% of control level), and another exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these two samples were also distinguishable from the control samples. Immunological quantitation indicated that the amounts of ALDH1 protein in these two samples were not reduced in parallel with their enzyme deficiency. In the first case, the two characteristics, i.e. very low enzyme activity and alcohol flushing, were inherited by her daughter.

Alcoholic Intoxication↗
PubMed1995

Alcohol-metabolizing enzyme polymorphisms and alcoholism in Japan.

The liver enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. Cytochrome P450IIE1, an ethanol-inducible isozyme of liver microsomal P450, is also important in ethanol metabolism. Genetic polymorphisms in the 5'-flanking region of the human cytochrome P450IIE1 gene have recently been reported. We hypothesized that the polymorphisms of ADH, ALDH, and P450IIE1 modify the susceptibility to development of alcoholism. We determined the genotypes of the ADH2, ALDH2, and P450IIE1 loci of 96 Japanese alcoholics and 60 healthy male subjects, using leukocyte DNA by the restriction fragment-length polymorphism by polymerase chain reaction. The alcoholics had significantly higher frequencies of the ADH2(1) and ALDH2(1) alleles than did the healthy subjects. No significant difference in the frequency of the P450IIE1 genotype was observed between the alcoholics and the healthy subjects. In conclusion, genetic polymorphisms of the ADH and ALDH genes, but not of the P450IIE1 gene, influence the risk of developing alcoholism in Japanese.

Adult↗
PubMed1995

Hormonal and chemical influences on the expression of class 2 aldehyde dehydrogenases in rat H4IIEC3 and human HuH7 hepatoma cells.

We studied the effect a variety of hormones and chemical stimuli on the activity of low Km aldehyde dehydrogenase (ALDH) in rat H4IIEC3 hepatoma cells and ALDH activity in human HuH7 hepatoma cells. The low Km enzyme in H4IIEC3 cells reflects ALDH2 activity, and the ALDH activity in HuH7 likely represents ALDH5. Of the steroid hormone family, thyroid hormone, progesterone, and dihydrotestosterone increased low Km ALDH activity approximately 50%, whereas dexamethasone and estradiol had little effect. Insulin decreased the activity of low Km ALDH. None of these hormones affected the activity of ALDH in HuH7 cells. Among second messengers, 8-bromo-cAMP and A23187 increased low Km ALDH activity; HuH7 ALDH activity again was unchanged. Exposure of the cells to 22 mM ethanol reduced low Km activity by approximately 20%, whereas hydrogen peroxide, tumor necrosis factor-alpha, and interleukin-1 beta had little effect. Ultraviolet light increased the HuH7 ALDH activity. Retinaldehyde or retinolc acid reduced the HuH7 ALDH activity, but had no effect on low Km ALDH activity. These data suggest that low Km ALDH2 can be regulated by hormones and may not be constitutive as previously thought, and that the HuH7 ALDH is regulated differently.

Alcoholism↗
PubMed1996

Association of restriction fragment-length polymorphisms in the alcohol dehydrogenase 2 gene with alcoholic brain atrophy.

Alcohol abuse can induce brain atrophy, but it only occurs in some alcoholics. To investigate whether genetic polymorphism of alcohol-metabolizing enzymes [including alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH)] was related to alcoholic brain atrophy, we determined restriction fragment-length polymorphisms of the ADH2 and ALDH2 genes in 77 male alcoholics. Computed tomography was used to determine the severity of brain atrophy. Digestion with MaeIII and MboII after polymerase chain reaction amplification showed that the ADH2(1) gene frequency was significantly higher in patients with brain atrophy than in those without brain atrophy (chi 2 = 9.274, p < 0.01), whereas no significant association was observed between brain atrophy and the ALDH2 gene Multivariate analysis (including age, total alcohol intake, liver cirrhosis, and ADH2 genotype) showed that the ADH2(1)/ADH2(1) genotype was associated with alcoholic brain atrophy. These findings suggest that the ADH2(1) allele may be associated with alcoholic brain atrophy.

Adult↗
PubMed1996

Association between alcoholism and the dopamine D4 receptor gene.

A point mutation in the aldehyde dehydrogenase 2 gene (ALDH2(2) allele) is considered to be a genetic deterrent for alcoholism; however, 80 of 655 Japanese alcoholics had the mutant allele. Genotype factors that might increase susceptibility by overriding the deterrent showed a higher frequency of a five repeat allele of the dopamine D4 receptor 48 bp repeat polymorphism in alcoholics with ALDH2(2) than in 100 other alcoholics and 144 controls. Alcoholics with the five repeat allele also abused other drugs more often. These data suggest the involvement of the dopamine system in the development of alcoholism and other addictive behaviour.

Adult↗
PubMed1996

8-Hydroxydeoxyguanosine in human leukocyte DNA and daily health practice factors: effects of individual alcohol sensitivity.

A typical oxidative DNA damage, 8-hydroxydeoxyguanosine (8-OHdG), was evaluated in human polymorphonuclear leukocytes (PMN) and mononuclear leukocytes (MN) by an anaerobic determination method. The mean 8-OHdG values were the lowest level ever reported [PMN, 3.07 +/- 1.45; MN, 2.37 +/- 1.21 8-OHdG/10(6) deoxyguanosine molecules (dG); n = 92]. According to a self-administered questionnaire to 92 healthy male workers, the relationship was investigated between 8-OHdG in leukocytes and daily health practice factors, that is, the frequency of physical exercise, smoking status, alcohol drinking, nutritional balance, and the degree of mental stress. A significant difference was observed only in alcohol drinking in subjects classified by aldehyde-dehydrogenase 2 isozyme (ALDH2) genotype. Habitual alcohol intake appeared to increase 8-OHdG in PMN from ALDH2-deficient subjects. Neither age, body mass index, nor any other factors examined showed any significant correlation with the 8-OHdG levels in leukocytes.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Rapid, accurate genotyping of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 based on the use of denaturing HPLC.

The genotypes of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are related to alcohol dependence and some human disorders. Rapid, accurate genotyping methodologies for specific polymorphisms of these two genes are needed for molecular screening and testing of alcohol-related problems in populations. A polymerase chain reaction (PCR) composed of two separate amplicons was designed to generate sequences containing the polymorphic site of interest in the ADH1B and ALDH2 genes. The PCR amplicons for each sample were subjected to denaturing high-performance liquid chromatography (DHPLC), analysis performed under partially denaturing conditions as determined by profiling the mixture of a unique homozygous control and a tested sample amplicon. A total of 150 genomic DNA samples were tested to validate this assay by blind analysis. Direct DNA sequencing was performed on samples randomly selected from each of the genotype groups detected by DHPLC profiling. The results indicate 100% concordance between the sequencing analysis and the DHPLC detection. The method we present provides a reliable and fast genotyping procedure for molecular screening of alcohol-related problems.

Alcohol Dehydrogenase↗
PubMed2000

Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer.

Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Msp1 polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotype, while others found no risk increase. None of these studies examined the combined effect of CYP1A1 and GST polymorphisms. Either NAT2 or CYP1A2 alone have been slightly associated with colorectal cancer. When CYP1A2 and NAT2 phenotype were combined, a significant increased risk (odds ratio of 2.8) was seen among well done meat consumers with the rapid-rapid phenotype. Two published studies have found that the risk of colorectal cancer can be enhanced (2-3 fold) in alcohol drinkers with heterozygous genotype of ALDH2 in two Japanese populations recently. Findings from three published studies suggested that the mutant genotype of MTHFR inversely slightly associated with colorectal cancer. Although some of genetic polymorphisms discussed here have not shown statistically significant increase/decrease in risk, individuals with differing genotypes may have different susceptibilities to colorectal cancer, based on environmental factors. Further studies are needed to identify risk groups more specific and to determine factors of importance in colorectal cancer development.

Acetyltransferases↗
PubMed2000

Polymorphism of drug-metabolizing enzymes in relation to individual susceptibility to industrial chemicals.

Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), N-acetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.

Aldehyde Dehydrogenase↗
PubMed2000

Alcohol and aldehyde dehydrogenase genotypes in Korsakoff syndrome.

BACKGROUND: Previous studies have suggested a genetic predisposition to the development of Wernicke-Korsakoff syndrome (WKS), a neuropsychiatric syndrome commonly associated with alcoholism; however, little is known about this genetic risk factor. METHODS: To test the hypothesis that altered alcohol or aldehyde regulation is related to the development of WKS, the genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-2 (ADH2) were examined in 47 alcoholic subjects with WKS and compared with those of 342 alcoholic subjects without any WKS symptoms and 175 nonalcoholic controls. RESULTS: Although the frequencies of the ALDH2 genotypes and alleles did not differ significantly between alcoholic subjects with WKS and alcoholics without WKS, the ADH2*1/2*1 genotype and ADH2*1 allele were significantly increased in WKS. CONCLUSIONS: These findings suggest that the ADH2*1/2*1 genotype is a risk factor for the development of WKS in alcoholic patients.

Aged↗
PubMed2000

Ethanol patch test: a simple method for identifying the effectiveness of cyanamide in alcoholics.

BACKGROUND: To identify the pharmacological effectiveness of cyanamide, 144 alcoholics treated with cyanamide were subjected to a test that used an acetaldehyde dehydrogenase (ALDH) inhibitor, the ethanol patch test, which is considered to be a good indicator of ALDH2 phenotype. METHODS: We placed 100 microl of 70% ethanol on a lint pad and, as a control, placed the same volume of distilled water on a second pad. The ethanol patch test was performed on 144 alcoholics more than 2 weeks after abstinence from alcohol before and after treatment with cyanamide for 1 week. The dose of cyanamide was increased up to 150 mg until the patch test yielded a positive result. RESULTS: In the ethanol patch test, 36 alcoholics (25.0%) gave a positive result before treatment with cyanamide and might have been ALDH2(1)/2(2) heterozygotes. Among 108 alcoholics who were not positive, the distribution of the cyanamide dose that yielded a positive ethanol patch test result was 30 mg in 42 cases (38.9%), 50 mg in 33 cases (30.6%), 70 mg in 5 cases (4.6%), 100 mg in 6 cases (5.6%), and 150 mg in 2 cases (1.9%). Prevalence of liver cirrhosis was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of less than 50 mg cyanamide than those at doses more than 70 mg (p = 0.029). The prevalence of adverse effects was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of more than 70 mg than at doses of less than 50 mg cyanamide (p = 0.002). CONCLUSIONS: The ethanol patch test is a useful method for identifying pharmacological effectiveness of cyanamide and may reduce the prevalence of side effects in cyanamide-treated alcoholics.

Adult↗
PubMedDate not supplied

[Biomarkers of gentotoxic risk and metabolic polymorphism].

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.

Biomarkers↗
PubMed2001

Genetic and environmental influences on alcohol metabolism in humans.

This manuscript represents the proceedings of a symposium at the 2000 RSA Meeting in Denver, Colorado. The organizer/chair was Ting-Kai Li. The presentations were: (1) Introduction to the Symposium, by Ting-Kai Li; (2) ALDH2 polymorphism and alcohol metabolism, by Shih-Jiun Yin; (3) ALDH2 promoter polymorphism and alcohol metabolism, by David W. Crabb; (4) Use of BrAC clamping to estimate alcohol elimination rates: Application to studies of the influence of genetic and environmental determinants, by Sean O'Connor; and (5) Effect of food and food composition on alcohol elimination rates as determined by clamping, by Vijay A. Ramchandani.

Alcohol Dehydrogenase↗