CYP2E1 Genotype Research Articles

Importance of genetic polymorphisms of drug-metabolizing enzymes for the interpretation of biomarkers of exposure to styrene

The objective of this study was to test the infiuence of genetic polymorphisms for metabolic enzymes (CYP2E1, mEH, GSTM1 and GSTT1) implicated in the biotransformation of styrene in humans on the interpretation of urinary biomarkers of exposure. Thirty workers from a fibreglass-reinforced plastics factory took part in the study. Ambient styrene concentration was determined during the whole workshift by passive sampling. Urine was collected at the end of the shift for the determination of mandelic acid (MA) and phenylglyoxylic acid (PGA) (major biotransformation pathway), N-acetyl-S-(1-phenyl-2-hydroxy)ethyl-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxy)ethyl-L-cysteine (M2) (minor metabolic pathway) and creatinine. The average airborne styrene concentration of 18.2 ppm (range: 0.9-68.9 ppm) was very close to the current threshold limit value (TLV-TWA) recently adjusted by ACGIH from 50 to 20 ppm. There was a better correlation between external and internal exposure as estimated by urinary MA + PGA (r=0.92; p<0.0001) compared with urinary M1 + M2 (r=0.74; p<0.0001). To investigate to what extent genetic polymorphisms in metabolic enzymes could explain interindividual variations observed in the concentration of urinary biomarkers related to a given external exposure, two 'metabolic indexes' (derived from the ratio between the sum of urinary metabolites for a specific pathway and ambient styrene concentration) were calculated for each worker and compared for different allelic combinations. Monovariate analyses showed that GSTM1 polymorphism was clearly the most significant parameter infiuencing urinary concentrations of mercapturic acids. Based on GSTM1 allelic status, two different biological exposure indexes (BEIs) for M1 + M2 in post-shift urinary samples corresponding to a 20 ppm styrene concentration are proposed (GSTM1null: 1330 µg g-1 creatinine, GSTM1+: 2878 µg g-1 creatinine). Multivariate regression analyses were also performed and revealed that the presence of the rare CYP2E1*1B allele linked to TaqI polymorphism (A1/A2) was associated with increased urinary concentrations of metabolites from both pathways. Two previously described polymorphisms for the EPHX gene were also tested but seemed not really relevant for interpretation of biomarkers. In conclusion, while CYP2E1 genotyping, particularly assessment of the CYP2E1*1B allelic status, is useful for a more accurate interpretation of the concentration of urinary biomarkers, GSTM1 genotyping is absolutely necessary when considering a biological monitoring programme based on determination of urinary mercapturic acids.

Influence of genetic susceptibility on the urinary excretion of 8-hydroxydeoxyguanosine of firefighters

OBJECTIVESOxidative DNA damage has been implicated in carcinogenesis. The DNA damage can be assessed from the urinary excretion of the DNA-repair product 8-hydroxydeoxyguanosine (8-OH-dG). The factors were investigated that influenced...

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).It is possible that the ALDH2*1, and c2 and/or C alleles may correspond to the higher blood ethanol and acetaldehyde elimination rates after the intravenous administration of 0.2 g/kg of ethanol.

CYP2E1 Expression in Human Lymphocytes From Various Ethnic Populations

Background: Monitoring CYP2E1 levels in alcoholic individuals holds inherent appeal because such determinations might indicate individuals at increased risk for alcoholic liver disease. We previously demonstrated that lymphocyte CYP2E1 expression reflects in vivo activity of the hepatic enzyme. Methods: To further validate this approach, the current investigation compared lymphocyte CYP2E1 content and chlorzoxazone pharmacokinetics in 51 alcoholic and nonalcoholic White, Navajo, and Mexican American subjects. After an oral dose of chlorzoxazone, blood samples were collected and lymphocytes isolated. Results: Alcoholics exhibited a 2-fold clevation in lymphocyte CYP2E1 messenger ribonucleic acid (mRNA) and protein compared to nonalcoholics. Chlorzoxazone clearance rates were 1.9-fold higher and area under the concentration curve (AUC) values 1.8-fold lower in alcoholic individuals compared to nonalcoholics. Furthermore, chlorzoxazone clearance rates correlated (r= 0.55, p < 0.01, n= 38) with lymphocyte CYP2E1 mRNA content, and transcript levels further correlated (r= 0.52, p < 0.001, n= 38) with CYP2E1 protein content. To compare phenotype with genotype, restriction fragment length polymorphism analyses on deoxyribonuclcic acid samples were performed to identify polymorphisms in the CYP2E1 gene. No subjects were homozygous for rare alleles c2 or C. Nonetheless, 27% of the Navajos and 15% of the Mexican Americans were heterozygous for the c2 allele. Two White subjects appeared heterozygous (c1/c2) when RsaI was used to characterize CYP2E1 genotype but homozygous (c1/c1) at the PstI locus. Fifteen percent of Mexican American subjects, 20% of Navajo subjects, and 6% of White subjects were heterozygous for the C allele. Neither CD nor c1/c2 genotypes were associated with alcoholism. Conclusions: Human lymphocyte CYP2E1 mRNA levels may be useful predictors of alcohol-mediated alterations in hepatic CYP2E1 activity. Moreover, ethnicity does not appear to play a major role in the levels of expression of lymphocyte CYP2E1.

CYP2E1 Expression in Human Lymphocytes From Various Ethnic Populations

Monitoring CYP2E1 levels in alcoholic individuals holds inherent appeal because such determinations might indicate individuals at increased risk for alcoholic liver disease. We previously demonstrated that lymphocyte CYP2E1 expression reflects in vivo activity of the hepatic enzyme. To further validate this approach, the current investigation compared lymphocyte CYP2E1 content and chlorzoxazone pharmacokinetics in 51 alcoholic and nonalcoholic White, Navajo, and Mexican American subjects. After an oral dose of chlorzoxazone, blood samples were collected and lymphocytes isolated. Alcoholics exhibited a 2-fold elevation in lymphocyte CYP2E1 messenger ribonucleic acid (mRNA) and protein compared to nonalcoholics. Chlorzoxazone clearance rates were 1.9-fold higher and area under the concentration curve (AUC) values 1.8-fold lower in alcoholic individuals compared to nonalcoholics. Furthermore, chlorzoxazone clearance rates correlated (r = 0.55, p < 0.01, n = 38) with lymphocyte CYP2E1 mRNA content, and transcript levels further correlated (r = 0.52, p < 0.001, n = 38) with CYP2E1 protein content. To compare phenotype with genotype, restriction fragment length polymorphism analyses on deoxyribonucleic acid samples were performed to identify polymorphisms in the CYP2E1 gene. No subjects were homozygous for rare alleles c2 or C. Nonetheless, 27% of the Navajos and 15% of the Mexican Americans were heterozygous for the c2 allele. Two White subjects appeared heterozygous (c1/c2) when RsaI was used to characterize CYP2E1 genotype but homozygous (c1/c1) at the PstI locus. Fifteen percent of Mexican American subjects, 20% of Navajo subjects, and 6% of White subjects were heterozygous for the C allele. Neither CD nor cl/c2 genotypes were associated with alcoholism. Human lymphocyte CYP2E1 mRNA levels may be useful predictors of alcohol-mediated alterations in hepatic CYP2E1 activity. Moreover, ethnicity does not appear to play a major role in the levels of expression of lymphocyte CYP2E1.

A multiplex-PCR/RFLP procedure for simultaneous CYP2E1, mEH and GSTM1 genotyping

Inter-individual variation in metabolism of environmental toxicants, which is attributed to genetic polymorphism, may be a major risk factor in determining who will develop adverse health effects. This priority research area is the focus of many laboratories, and new techniques need to be developed to enhance the efficiency in generating data. We have developed and validated a new multiplex-polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) procedure for simultaneous genotyping of cytochrome P450 II E1 (CYP2E1), microsomal epoxide hydrolase (mEH), and glutathione S-transferase mu (GSTM1). Enzymes from these three polymorphic genes are involved with the phase I and II metabolism of a variety of environmental toxicants. Therefore, simultaneous characterization of these genes will not only reduce costs but will increase the efficiency of data collection, thereby contributing to health risk assessment efforts.

Meat, metabolic genotypes and risk for colorectal cancer.

Persuasive data exist as to the importance of environmental factors in the pathogenesis of sporadic colorectal cancer. One possibility is that the effect of environmental factors varies between individuals, perhaps on the basis of inherited variation (polymorphism) in genes which influence the activation or inactivation of dietary carcinogens. Thus far, the focus has been on acetylator genes (NAT1, NAT2) and the activation of heterocyclic amines, carcinogens generated by cooking meat for prolonged periods at high temperature. Three case-control studies and one prospective study have shown a consistent trend towards higher risks for cancer with higher intakes of meat in rapid acetylators for NAT1, NAT2 or both genotypes. Other links between meat, cooking methods, metabolic genotypes and risk for cancer might include enhanced activation of polycyclic aromatic hydrocarbons and N-nitroso compounds by variant genotypes of CYP1A1 and CYP2E1, respectively, and modulation by meat of the protective effect of the E4 allele of apolipoprotein E on risk for cancer of the proximal colon.

Impact of CYP2E1 genotype in renal cell and urothelial cancer patients

Genetic polymorphisms of enzymes involved in carcinogen metabolism have been found to influence susceptibility to cancer. Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several drugs, precarcinogens and solvents to reactive metabolites. In the present study, we investigated the cytochrome P450 2E1 genetic polymorphism in renal cell/urothelial cancer patients from two German regions, Jena and Halle, different with respect to their environmental pollution degree in comparison with healthy controls from the same regions. DNA of peripheral white blood cells was isolated both from 224 renal cell/urothelial cancer patients and 304 controls. We focussed on polymorphisms in the promoter region and intron 6 of the CYP2E1 gene. The polymorphisms were identified as RFLP's by amplification of the appropriate DNA fragment and subsequent digestion with the restriction enzymes PstI, RsaI and DraI. In Jena as well as in Halle, the frequency distributions of the PstI/RsaI, DraI and combined DraI + PstI/RsaI genotypes showed no significant differences between controls and renal cell/urothelial cancer patients. We did not find significant differences between Jena and Halle. 86.2% of all subjects with a homozygote PstI/RsaI genotype also carried a heterozygote DraI genotype, whereas 5.1% of the subjects with a heterozygote PstI/RsaI genotype also carried a heterozygote DraI genotype. Renal cell cancer as well as urothelial cancer risk was not elevated in patients with heterozygote DraI, PstI/RsaI and combined DraI + PstI/RsaI genotypes (odds ratios slightly insignificantly increased). Interestingly enough, an association between these polymorphisms and renal cell cancer risk was found in the female subgroup but not in the male subgroup. The basis of these sex-specifically increased risks are different frequencies concerning heterozygote and homozygote genotypes in controls and cancer patients. In controls, the heterozygote genotype frequency was lower in females than in males. In renal cell cancer patients, the results were quite the contrary. Summing up, our results demonstrate an lack between CYP2E1 genetic polymorphism and renal cell/urothelial cancer risk.

ジメチルホルムアミド曝露者のCYP2E1遺伝子多型による尿中代謝物の生物学的半減期の検討

ジメチルホルムアミド曝露者のCYP2E1遺伝子多型による尿中代謝物の生物学的半減期の検討

Biological monitoring of workers exposed to low levels of 2-butoxyethanol.

(1) To assess the value of urinary butoxyacetic acid (BAA) measurement for the monitoring of workers exposed to low concentration of 2-butoxyethanol (BE); (2) to evaluate the in vivo effect of low occupational BE exposure on the erythrocyte lineage; and (3) to test the possible influence of genetic polymorphism for cytochrome P450 2E1 (CYP 2E1) on urinary BAA excretion rate. Thirty-one male workers exposed to BE in a beverage package production plant were examined according to their external (BE) and internal (BAA) solvent exposure. The effect of this exposure on erythrocyte lineage [red blood cell numeration (RBC), hemoglobin (Hb), hematocrit (Htc), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), haptoglobin (Hp), reticulocyte numeration (Ret) and osmotic resistance (OR)], hepatic [aspartate aminotransferase (GOT), alanine aminotransferase (GPT)] and renal [plasmatic creatinine, urinary retinol binding protein (RBP)] parameters was also investigated. DNA purified from whole blood was used for CYP 2E1 genotyping. Average airborne concentration of BE was 2.91 mg/m3 (0.59 ppm) with a standard deviation of 1.30 mg/m3 (0.27 ppm). There was a relatively good correlation between external and internal exposure estimated by measuring BAA in post-shift urine samples (average 10.4 mg/g creatinine; r = 0.55; P = 0.0012). Compared with a matched control group (n = 21) exposed workers had a statistically significant decrease (3.3%; P = 0.03) in Hct while MCHC was increased (2.1%; P = 0.02). No significant difference was observed either in other erythroid parameters or in hepatic and renal biomarkers. One exposed individual exhibited a mutant allele with increased cytochrome P450 oxidative activity which coincided with a very low urinary BAA excretion. Single determination of BAA in post-shift urine samples can be used to assess exposure to low levels of BE. A slight but significant effect on erythroid parameters suggesting membrane damage was observed in exposed workers. The influence of the genetic polymorphism for CYP 2E1 deserves further investigation for the interpretation of urinary BAA measurements.

CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan.

Nasopharyngeal carcinoma occurs disproportionately among individuals of Chinese descent. The cytochrome P450 2E1 enzyme (CYP2E1) is known to activate nitrosamines and other carcinogens that are possibly involved in the development of this disease. Certain alleles of the CYP2E1 gene are thought to be more highly expressed than others, and their distribution varies between Asian and Caucasian populations. We conducted a case-control study to investigate whether such variations affect the risk of developing nasopharyngeal cancer. Three hundred sixty-four patients with nasopharyngeal carcinoma (96% of 378 eligible patients) and 320 control subjects (86% of 374 eligible subjects) were studied. A risk factor questionnaire was administered to participants to assess factors postulated to be linked to nasopharyngeal carcinoma. Peripheral blood was obtained from all subjects and DNA was purified from nucleated cells. A polymerase chain reaction-based restriction fragment length polymorphism assay that used the restriction enzymes Rsa I and Dra I was used to detect wild-type and variant forms of the CYP2E1 gene. Individuals homozygous for an allele of the CYP2E1 gene that is detected by Rsa I digestion (c2 allele) were found to have an increased risk of nasopharyngeal carcinoma (relative risk [RR] = 2.6; 95% confidence interval [CI] = 1.2-5.7); this effect was limited to nonsmokers (RR = 9.3; 95% CI = 2.7-32) and was not affected by alcohol consumption. Our findings suggest that the CYP2E1 genotype is a determinant of nasopharyngeal carcinoma risk.

CYP2D6, NAT2 and CYP2E1 genetic polymorphisms in nonagenarians.

enzymatic polymorphisms affecting the metabolic disposition of xenobiotics may modulate the rate of activation or deactivation of carcinogens and other toxic environmental chemicals. Hence, these polymorphisms may influence the risk of suffering some types of cancer and other degenerative diseases that are incompatible with extreme longevity. to establish the distribution of three well known enzymatic polymorphisms that affect the CYP2D6, NAT-2 and CYP2E1 genes and the activity of their enzymatic gene products, involved in the disposition of many xenobiotics, in a group of nonagenarians and in much younger controls. the three genotypes were determined in 41 nonagenarians (10 males, mean age 92.2 years, range 90-98) free of known malignancies or neurodegenerative diseases. The control groups comprised 217 healthy volunteers (128 males, mean age 36.3 years; SD, 12.7) for the CYP2D6 and NAT2 genotypes and 137 (116 males, mean age 32 years; SD, 18.8) for the CYP2E1 genotype. after extraction of DNA from white blood cells, polymerase chain reaction and restriction fragment polymorphism methods were used to identify the allelic variants of the three genotypes. we found no qualitative or quantitative difference in the mutations underlying the three genetic polymorphisms studied, nor in the expected enzymatic phenotypes. Instead, a close parallelism exists between advanced age and younger groups. longevity does not seem to be related to any special configuration of these three polymorphic traits. Comparisons with younger controls may be adequate when studying the distribution of these polymorphisms in diseases affecting old people. No genetically determined differences in the activation of drugs metabolized by these enzymes are to be expected in very old people.

Effect of the Cytochrome P‐1450IIE1 Genotype on Ethanol Elimination Rate in Alcoholics and Control Subjects

We studied an influence of genetic polymorphisms in the cytochrome P-450IIE1 (CYP2E1) gene on ethanol elimination rate in alcoholic patients and healthy subjects. The CYP2E1 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism method for 124 alcoholics and 54 healthy subjects. There was no significant difference in the gene frequency of CYP2E1 between alcoholics and healthy control subjects. Blood ethanol concentrations in the 65 alcoholics on admission ranged from 0.32 to 4.22 mg/ml. In the patients with the c1/c2 genotype, the elimination rate was significantly correlated with blood ethanol concentration. In each of the three genotypes of CYP2E1, the patients were divided into three groups based on ethanol concentrations. The average of the ethanol elimination rate in the patients with c1/c2 having blood ethanol levels of > or = 2.5 mg/ml was significantly higher than the rates in the two other groups of c1/c2. When blood ethanol levels were > or = 2.5 mg/ml, the elimination rate in the patients with c1/c2 was significantly higher than that in those with c1/c1. Regardless of the CYP2E1 genotype, the elimination rate in the alcoholics was higher than that in the control subjects when blood ethanol levels were < 1.0 mg/ml. These results suggest the possibility that the c2 allele of CYP2E1 Influences the rate of ethanol elimination at high ethanol levels. The rate of ethanol elimination was independent of liver disorder judged by serum total bilirubin values.

Acetaminophen metabolism in patients with different cytochrome P-4502E1 genotypes.

Cytochrome P-450 (CYP) 2E1 is the major ethanol-oxidizing enzyme of the nonalcohol dehydrogenase metabolic pathway in the liver. Recently, the presence of genetic polymorphisms of this enzyme was confirmed. In this study, to clarify the influence of CYP2E1 genotype on alcohol metabolism, we analyzed acetaminophen metabolism in subjects with different CYP2E1 genotypes. In normal subjects, a half-life of acetaminophen from blood was the longest in type A (c1/c1) and was the shortest in type C (c2/c2). The elimination rate in type C was more than twice that of type A and type B (c1/c2). In type A, both half-life and elimination rate of acetaminophen were not different between patients with noncirrhotic alcoholic liver disease within 1 week after abstinence and in normal subjects. In one patient with minimal change, there were no differences in both half-life and elimination rate within 1 and 6 weeks after abstinence. On the other hand, in type B, half-life was shorter and the elimination rate was greater in alcoholic noncirrhotic patients within 1 week after abstinence than in alcoholic patients with type A and in normal subjects with type B. In type B, half-lives were shorter, and the elimination rates were greater in patients with alcoholic liver disease within 1 week after abstinence than 4 to 6 weeks after abstinence. These results suggest the possibility that alcohol metabolism in individuals with the c2 gene may be greater than those with the c1 gene, and that the induction of CYP2E1 by ethanol in type B may occur more markedly than that in type A, although the sample number is too small to obtain final conclusions.

Acetaminophen metabolism in patients with different CYP2E1 genotypes: [formula omitted] Div. of Gastroent., Dept. of Int. Med., Kanazawa Med. Univ., Ishikawa, Japan

Acetaminophen metabolism in patients with different CYP2E1 genotypes: [formula omitted] Div. of Gastroent., Dept. of Int. Med., Kanazawa Med. Univ., Ishikawa, Japan

P-130 Different CYP2E1 genotypes and alcoholic liver disease

P-130 Different CYP2E1 genotypes and alcoholic liver disease

Human Lung Carcinogen--DNA Adduct Levels Mediated by Genetic Polymorphisms In Vivo

Cancer risk from exposure to tobacco smoke varies widely from person to person, depending in part on the status of particular genes and acquired susceptibilities. Certain genes determine how cells activate and detoxify carcinogens. Activated carcinogen metabolites may bind to DNA and form DNA adducts (e.g., 7-methyl-2'-deoxyguanosine-3'-monophosphate [7-methyl-dGMP] and polycyclic aromatic hydrocarbons-dGMP [PAHs-dGMP]), many of which can induce genetic mutations. Thus, if individuals have an increased capacity to activate carcinogens, they might form more carcinogen-DNA adducts and subsequently have an increased risk of cancer. Using DNA-adduct detection methods specific for 7-methyl-dGMP and PAH-dGMP, we sought to determine whether an inherited genetic susceptibility to cancer associated with certain carcinogen-metabolizing and detoxifying genes (e.g., cytochrome P450 and glutathione S-transferase) is related to DNA adduct formation in lung tissue. Human lung tissues were collected randomly from 90 autopsy donors who were free of cancer. Levels of 7-methyl-dGMP, a metabolic product of N-nitrosamines, and PAH-dGMP adducts were determined in lung tissue specimens by use of micropreparative DNA purification steps combined with a 32P-postlabeling assay. Genetic polymorphisms (the presence of different genes and/or alleles) were determined for the cytochrome P450 genes, CYP2D6, CYP2E1, and CYP1A1, as well as for glutathione S-transferase M1 (GSTM1). Statistical differences among adduct levels for the study variables, including genotypes, were assessed by the two-sided Student's t test or the Mann-Whitney U test. Higher 7-methyl-dGMP adduct levels were associated with CYP2D6 genotypes (P = .01), consistent with the reports of the increased risk of lung cancer associated with this genotype. Higher adduct levels were also associated with CYP2E1 minor alleles (P = .05). In both cases, the association was attributed mostly to individuals with low serum cotinine levels (P = .004 and P = .05, respectively), suggesting that the effect of the genotypes is mostly in nonsmokers exposed to either passive tobacco smoke or to N-nitrosamine exposures other than tobacco smoke or to N-nitrosamine exposures other than tobacco smoke. Separately, the presence of PAH-dGMP adducts was associated with the GSTM1 null genotype (absence of the gene) (odds ratio = 8.6; 95% confidence interval = 1.03-100). This study finds that the levels of two different carcinogen-DNA adducts vary in lung tissue (an important target tissue) in association with three separate genetic polymorphisms (i.e., CYP2D6, CYP2E1, and GSTM1). CYP2D6 and CYP2E1 genotypes are associated with higher 7-methyl-dGMP levels, while the GSTM1 null genotype is associated with higher numbers of PAH-dGMP adducts. These findings suggest that genetic polymorphisms are predictive of carcinogen-DNA adduct levels and would thus be predictive of an individual's lifetime response to carcinogen exposure.

CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese.

The genotypes of the CYP2E1 and ALDH2 loci of alcoholic (alcohol dependence) and nonalcoholic (healthy) Japanese were investigated to examine the relationship between the polymorphism of CYP2E1 (C1/C2) and ALDH2 (ALDH2*1/ALDH2*2), and the susceptibility to alcoholism. There was no significant difference in C2 gene frequency between alcoholics (0.19) and nonalcoholics (controls) (0.20), whereas there was a significant difference in ALDH2 allele frequency, suggesting that, in Japanese, the C2 genotype of CYP2E1 may have nothing to do with the risk of developing alcohol dependence. However, the ALDH2*1 allele may influence drinking behavior and the development of alcohol dependence. Furthermore, racial interethnic differences in the frequency of the mutated allele of the CYP2E1 gene (C2) were found, like the ALDH2 gene. Japanese healthy controls showed a significantly higher frequency of the C2 allele than did Swedish healthy controls (0.05; reported by Persson et al., FEBS Lett. 319:207-211, 1993).

Analysis of cytochrome P450 2E1 genetic polymorphisms in relation to human lung cancer: Kato S, Shields PG, Caporaso NE, Sugimura H, Trivers GE, Tucker MA et al. Laboratory of Human Carcinogenesis, Division of Etiology, National Cancer Institute, Bethesda, MD 20892. Cancer Epidemiol Biomarkers Prev 1994;3:515–518

Human cancer risk assessment using molecular genetic techniques is a rapidly emerging field. Many studies suggest that both inherited and acquired genetic predispositions play an important role in carcinogenesis. Cytochrome P450 (CYP) 2E1 is involved in the metabolic activation of N-nitrosamines and other low molecular weight compounds. A recently described genetic polymorphism of CYP2E1 [DraI restriction fragment length polymorphism (RFLP)] has been associated with an increased risk of lung cancer in Japanese. We have assessed the allelic frequency of three RFLPs (PstI, RsaI, and DraI) in African-Americans (n = 109), Caucasian Americans (n = 153), and octogenarian Japanese (n = 42), and also in a United States case-control study of lung cancer (histologically confirmed lung cancer, n = 58; controls, n = 56; total, n = 114). The relationship of the CYP2E1 DraI polymorphism to other CYP2E1 polymorphisms (PstI and RsaI RFLP) was examined. The allelic frequency of the DraI C minor allele for all subjects was 0.09 in Caucasians, 0.09 in African-Americans, and 0.31 in Japanese. In the case-control study of lung cancer, no association of the CYP2E1 DraI genotype with lung cancer was found (odds ratio, 1.57; 95% confidence interval, 0.59-4.18). Comparison after discordant CYP2E1 genotypes suggests the presence of different haplotypes in Americans and Japanese. These results indicate that the CYP2E1 DraI RFLP is probably not a cancer risk factor in United States Caucasian or African-Americans, although statistical power is limited given the low frequency of the CYP2E1 DraI C minor alleles.

CYP2E1 genotypes and serum LAP in Japanese alcoholics.

The genotypes of the ALDH2 and CYP2E1 loci of Japanese alcoholic patients were determined to investigate the susceptibility to alcoholic liver injury. In alcoholics with a liver-function disorder, a significant association was observed between the genotypes of the CYP2E1 loci and the serum level of a liver-derived enzyme, LAP. However, there was no significant association between the ALDH2 genotypes and liver dysfunction.