Polymorphisms In Metabolizing Enzymes Research Articles

Melanocortin receptor 1 variants and melanoma risk – a study on two European populations

Benzene has been implicated as an environmental risk factor in leukaemia and other haematological diseases. Relationships between urban benzene exposure, oxidative DNA damage and polymorphisms in metabolism enzymes were examined in 40 volunteers living and working in Copenhagen. Personal exposures to benzene, toluene and methyl tert-butyl ether (MTBE) were monitored during a 5-day period. DNA damage was measured by 7-hydro-8-oxo-2′-deoxyguanosine (8-oxodG) in lymphocyte DNA and urine and by comet assay with use of fapyguanine glycosylase (FPG) and endonuclease III (ENDO). Excretion of the benzene metabolites trans,trans-muconic acid (ttMA) and S-phenylmercapturic acid (S-PMA) were measured in urine. Polymorphisms in glutathione-S-transferases T1 (GSTT1), M1 (GSTM1) and P1 (GSTP1) and NAD(P)H:quinone oxidoreductase (NQO) were determined. Median exposures to benzene, toluene and MTBE were 2.5, 18.7 and 0.86 μg/m3. No significant correlations between external benzene exposure and any of the biomarkers were found. However, a significant correlation between S-PMA excretion and 8-oxodG in lymphocytes was found (Rs=0.39). Men were found to excrete significantly more ttMA than the women did and ttMA excretion in men was found to be significantly associated with external benzene exposure (R=0.53, P=0.025). In addition, ttMA and S-PMA excretion was significantly higher in subjects with the NQO+/−genotype compared with subjects with the wild type (P=0.004 and P=0.011, respectively). Even though there are some limitations in this study due to the low range of benzene exposure and biomarker concentrations as well as a small number of subjects, these results could suggest that even at ambient concentrations exposure to benzene could have genotoxic effects in susceptible individuals.

Statistical Methods for Detecting Genetic Interactions: A Head and Neck Squamous-Cell Cancer Study

Tobacco smoke and occupational exposures to chemicals such as polycyclic aromatic hydrocarbons (PAHs) are, aside from alcohol, the major risk factors for development of head and neck squamous-cell cancer (HNSCC). In this study, new statistical methods were applied. We employ new statistical methods to detect genetic interactions perhaps of higher order, that might play a role in developing HNSCC. The underlying study comprises 312 HNSCC cases and 300 controls. Single-nucleotide polymorphisms (SNPs) of PAH metabolizing and repair enzymes, somatic p53 mutations, and tobacco smoke were examined. Key statistical tools for our analysis are methods of unsupervised and supervised learning. In unsupervised learning, one performs cluster analyses based on well-known and new distance measures to find differences in the SNP patterns of cases and controls, and to understand the role of p53. Our main goal in supervised learning was to identify SNPs and SNP interactions that are likely to alter the susceptibility to HNSCC. Logic regression, a classification method well suited for SNPs, was employed as well as a Bayesian generalization that allows for incorporating additional expert knowledge. These methods detected several important interactions, such as an association between CYP1B1, tobacco smokes and p53 mutations and some interactions between CYP1B1 and glutathione S-transferases in smokers, which included a three-way interaction between CYP1B1, CYP2E1-70G>T, and GSTP1 (exon 5).

DNA repair, multidrug resistance and metabolic enzyme genes polymorphisms as predictors of clinical outcome in resected non-small cell lung cancer (NSCLC)

22121 Background: Early stage NSCLC is considered a potentially curable disease following complete resection. Gene expression profiles can identify patients (pts) with a higher risk of recurrence. We hypothesized those differents polymorphisms profiles could help to predict disease outcome. Methods: NSCLC paraffin-embebed samples were obtained from 58 pts who underwent curative pulmonary resection. We analyze 17 polymorphisms: 8 DNA repair polymorphisms: XRCC5(T/C), XRCC5(A/G), XPA(T/C), XPC(Gln939Lys), ERCC1(Lys259Thr), ERCC2(Lys751Gln), ERCC5(Asp1104His) and ERCC5(His49His); 7 metabolic enzyme polymorphisms: EPOXH1(His139Arg), EPOXH1(Tyr113His), CYP2C8(Arg139Lys), CYP2C8(Lys399Arg), GSTP1(G/A), GSTT1(C/T), NAT2–1(Arg197Gln); and 2 multidrug resistance polymorphisms: MDR1(Ile1145Met), MDR1(G412G). The analysis were performed using real-time polymerase chain reaction allelic discrimination TaqMan assay. Results: 58 primary lung cancer cases were included between January 1997 to December 2001. 56 males, 2 females. Median age was 65. Histology: 44.8% adenocarcinoma and 50% squamous cell carcinoma. Stage: I 36.9%, II 25.9% and III 15.5%. 56% relapsed. The presence of ERCC1 (34.5 vs 71 m wild type (WT); p=0.022), XPC (39.6 vs 73.9 m WT; p=0.035), XRCC5(A/G)(12.5 vs 66.9 m WT; p=0.006) or CYP2C8 (Arg139Lys) (26.8 vs 70.8 WT m; p=0.009) polymorphism were associated with worse time to progression (TTP). A metabolic enzyme polymorphisms (NAT 2–1) better outcome (87.6 vs 43 m WT, p=0.008). For survival (OS) pts with XRCC5(A/G) (31.5 vs 65.9 m WT, p=0.054), ERCC1 (38.5 vs 71.5 m WT; p=0.017) and MDR-1(Ile1145Met) (34.7 vs 69.7 m WT; p=0.021) showed worse results. In multivariate analysis stage (p=0.001), sex (p=0.003), XRCC5 (A/G) (p=0.006), ERCC1 (p=0.004), NAT 2–1 (p=0.006) for TTP and stage (p=0.008) and sex (p=0.054) for survival were identified as an independent prognostic factors. Conclusions: we report associations between some DNA repair, metabolic enzyme and multidrug resistance polymorphisms and clinical outcome in resected NSCLC pts. No significant financial relationships to disclose.

The side‐effects after Taxotere® Treatment Affected by Polymorphism of Metabolic Enzymes in Taiwanese Breast Cancer Patients

Breast cancer has been the leading cause of death among Taiwanese women as well as women all over the world. Taxotere® has demonstrated the benefits versus other chemotherapy drugs. Nevertheless, there are different degrees of side effects with the chemotherapy medication. When these side effects occur, they must be cautiously treated, otherwise, they may be fatal. Therefore, this research is to explore the associations of genetic polymorphisms of metabolic enzymes and the side effects of Taxotere® in Taiwanese breast cancer. Breast cancer patients initiating Taxotere® treatment were genotyped for metabolic enzymes to identify variability of side effects. Fifty‐nine Taiwanese women treated for breast cancer were recruited. The polymorphisms of gene for metabolic enzymes were determined using restriction fragment length polymorphism of polymerase chain reaction products and the restriction enzymes. Based on this study, therefore, it is clinically beneficial for physicians to evaluate in advance the likelihood of the occurrence of side effects due to the application of Taxotere® by screening the genetic polymorphisms of their patients.

Meat Intake, Heterocyclic Amine Exposure, and Metabolizing Enzyme Polymorphisms in Relation to Colorectal Polyp Risk

Most colorectal cancers arise from adenomatous polyps or certain hyperplastic polyps. Only a few studies have investigated potential genetic modifiers of the associations between meat intake and polyp risk, and results are inconsistent. Using data from the Tennessee Colorectal Polyp Study, a large colonoscopy-based study, including 1,002 polyp cases (557 adenoma only, 250 hyperplastic polyp only, 195 both polyps) and 1,493 polyp-free patients, we evaluated the association of colorectal polyp risk with carcinogen exposure from meat and genetic polymorphisms in enzymes involved in heterocyclic amine (HCA) metabolism, including N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP1A2), and aryl hydrocarbon receptor (AhR). Data on intake levels of meats by preparation methods, doneness preferences, and other lifestyle factors were obtained. Fourteen single nucleotide polymorphisms in the AhR, CYP1A2, NAT1, and NAT2 genes were evaluated. No clear association was found for any polymorphisms with polyp risk. However, apparent interactions were found for intake of meat and HCAs with AhR, NAT1, and NAT2 genotypes, and the interactions were statistically significant for the group with both adenomatous and hyperplastic polyps. Dose-response relationships with meat or HCA intake were found only among those with the AhR GA/AA (rs2066853) genotype, NAT1 rapid, or NAT2 rapid/intermediate acetylators but not among those with other genotypes of these genes. This dose-response relationship was more evident among those with both AhR GA/AA and the NAT1 rapid acetylator than those without this genotype combination. These results provide strong evidence for a modifying effect of metabolizing genes on the association of meat intake and HCA exposure with colorectal polyp risk.

Genetic polymorphisms of alcohol metabolising enzymes: their role in susceptibility to oesophageal cancer

Alcohol is a major risk factor for susceptibility to oesophageal cancer in the South African population. The role of polymorphisms in alcohol metabolising enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) in predisposition of this population to oesophageal cancer is unknown. Alcohol metabolising enzymes exhibit polymorphisms that result in variant alleles with either increased or decreased activity. The role of these polymorphisms in increased risk of oesophageal cancer was investigated in 238 patients and 268 controls from Black and Mixed Ancestry South Africans, using the PCR/RFLP technique. The ADH3*2/*2 genotype was significantly associated with increased risk for oesophageal cancer amongst Black subjects (odds ratio, 2.19; p=0.004). The low activity ALDH2*2 allele was significantly associated with increased risk for oesophageal cancer amongst the Black subjects (odds ratio, 2.35; p=0.0084). It was observed that ADH variants, ADH2*1 and ADH3*2, were associated with increased risk for oesophageal cancer, possibly due to the tolerance of the carriers of these alleles to alcohol consumption compared to those with high activity alleles (ADH2*2 and ADH2*3) which are associated with higher production of the unpleasant acetaldehyde intermediate.

In Response to “Drug Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort”

In Response to “Drug Metabolizing Enzyme Polymorphisms Predict Clinical Outcome in a Node-Positive Breast Cancer Cohort”

Pharmacogénétique des médicaments immunosuppresseurs: Impact et intérêt clinique en transplantation

The domain of solid organ transplantation is characterized by the use of variable drug combinations with drug-drug interactions, and the presence of two genomes, that of the transplanted organ and that of the receiver, which can be involved in the pharmacogenetics of these drugs. This paper is a literature review of the impact of the genetic polymorphisms of the metabolic enzymes, efflux transporters and therapeutic targets of the main immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus and mycophenolate) on the dose-concentration and concentration-effect relationships of these drugs. The polymorphisms of metabolic enzymes have significant effects on the pharmacokinetics of all these drugs, but the clinical trials for validating treatment individualization based on these genetic differences are still lacking. It should be noted that the influence of the donor's genome has seldom been studied and has been found to be significant in liver transplant recipients. The influence of efflux transporter genes polymorphisms, in particular of P-glycoprotein and MPR2, is controversial. As for the polymorphisms of the drug targets genes, either they have not been reported (calcineurin, mTOR), or their influence has only been the subject of a few preliminary studies (IMPDH2). The pharmacogenetics of immunosuppressants is thus still an open field for investigations and potential therapeutic progress.

Genetic Polymorphisms of Metabolic and DNA Repair Enzymes and Lymphocyte

Genetic Polymorphisms of Metabolic and DNA Repair Enzymes and Lymphocyte

Polymorphisms in Folate, Pyrimidine, and Purine Metabolism Are Associated with Efficacy and Toxicity of Methotrexate in Psoriasis

Methotrexate is the gold standard therapy for moderate to severe psoriasis, but there is marked interpersonal variation in its efficacy and toxicity. We hypothesized that in psoriasis patients, specific common polymorphisms in folate, pyrimidine, and purine metabolic enzymes are associated with methotrexate efficacy and/or toxicity. DNA from 203 retrospectively recruited psoriasis patients treated with methotrexate was collected and genotyped by restriction endonuclease digestion or length polymorphism assays. The reduced folate carrier (RFC) 80A allele and the thymidylate synthase (TS) 3'-untranslated region (3'-UTR) 6 bp deletion were associated with methotrexate-induced toxicity (P=0.025 and P=0.025, respectively). RFC 80A and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) 347G were associated with methotrexate discontinuation (P=0.048 and P=0.038). The TS 5'-UTR 28 bp 3R polymorphism correlated with poor clinical outcome (P=0.029), however, this was not the case when patients with palmoplantar pustular psoriasis were not included in the analysis. Stronger associations between specific polymorphisms and methotrexate-induced toxicity and discontinuation were found in a subanalysis of patients on methotrexate not receiving folic acid supplementation. We have demonstrated preliminary evidence that specific polymorphisms of enzymes involved in folate, pyrimidine, and purine metabolism could be useful in predicting clinical response to methotrexate in patients with psoriasis.

Does CYP1A1polymophism increase the risk for cancer in pollution exposure? A study by gene ontology

Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. Cytochrome P-450 (CYP) 1A1 polymorphism is a widely mentioned for importance of its genetic polymorphisms in risk assessment. However, the reports on the correlation between polymorphism and risk are inconsistent. To study the functional aberration in the human wild and mutate types of CYP1A1 is hard. Here, the author used a new gene ontology technology to predict the molecular function of human CYP1A1. Here, it can be seen that there is no functional difference between wild and mutate types of CYP1A1. Therefore, there should be no difference in effect of wild and mutate types of CYP1A1. This can support the null effect of this polymorphism in clinical findings of the population. This polymorphism might not be an important tool for risk assessment.

Determination of Sequence Variants of Metabolizing Enzymes After Occupational Exposure to Fumes of Bitumen Under High Processing Temperatures

Data concerning the influence of sequence variants of metabolizing enzymes on the effect modulation of current exposure to fumes of bitumen in humans are limited. To assess effect modulation of genetic variants of metabolizing enzymes, 18 single nucleotide polymorphisms (SNPs) in metabolic enzymes were analyzed regarding their impact on the urinary levels of metabolites of polycyclic aromatic hydrocarbons. Based on personal ambient monitoring data for bitumen emissions a group of 180 workers exposed to fumes of bitumen under high processing temperatures during a shift were divided into two exposure groups: 24 with high exposure (> 10 mg/m3) and 156 with low (≤ 10 mg/m3) exposure. Additionally, 55 roadside construction workers without exposure to bitumen but with similar working tasks served as a reference group. SNP determination was performed by real-time PCR using the LightCycler technology based on DNA aliquots from blood samples. The impact of sequence variants on the urinary levels of 1-OH pyrene (1-OHP) and sum of OH-phenanthrenes (OHPhe) was estimated with mixed linear models, adjusted for exposure, smoking, and other factors. Bitumen exposure was a significant predictor of the urinary concentrations of 1-OHP and OHPhe. Both metabolite levels were modulated by the GG variant of the cytochrome P450 SNP CYP3A4 −392A > G , which showed increased levels of 1-OHP (p = 0.013) and OHPhe (p = 0.001). The GG variant of EPHX1 15543A > G showed a significant effect (p = 0.006) only on OHPhe. Selected variants of metabolic enzymes can modulate the metabolite levels under exposure to bitumen. The SNP-related modulation of these biomarkers did not exceed a factor of two and is more pronounced for OHPhe than for 1-OHP.

Styrene-oxide N-terminal valine haemoglobin adducts in reinforced plastic workers: Possible influence of genetic polymorphism of drug-metabolising enzymes

Styrene is one of the most important organic chemicals used worldwide. In humans, styrene metabolism involves oxidation by cytochrome P450 monooxygenases (CYPs) to styrene-7,8-oxide, an epoxide thought to be responsible for the genotoxic effects of styrene exposure, and detoxification by means of epoxide hydrolase (mEH) and glutathione S-transferases (GSTs). The objective of this study was to investigate if genetic polymorphisms of metabolic enzymes modulate the level of urinary styrene metabolites and styrene oxide adducts with N-terminal valine of human globin (SO-Hb) in 75 workers occupationally exposed to styrene and 77 unexposed controls. The mean air concentration of styrene in the breathing zone of workers (30.4ppm) was higher than the threshold limit value of 20ppm recommended by the American Conference of Governmental Industrial Hygienists (ACGIH), and the biological exposure index adopted by the ACGIH for exposure to styrene prior to the next shift (MA+PGA=400mg/g creatinine) was exceeded, indicating that styrene exposure for this group of workers was higher than recommended. A highly significant correlation was observed between styrene concentration in the breathing zone and the MA+PGA in urine of workers (r=0.85, P<0.001). The levels of SO-Hb adducts in exposed workers were significantly increased as compared with controls, although no difference was observed between subjects stratified as high and medium exposure categories based on MA+PGA excretion. Regarding the effect of the genetic polymorphisms we found that the level of SO-Hb adducts might be modulated by the predicted mEH enzymatic activity in the exposed workers. From our data we conclude that SO-Hb adduct measurement is a complementary method to MA+PG measurement for assessing exposure to styrene at occupational and environmental levels, which reflects a more extensive exposure period.

Re-assessment of the influence of polymorphisms of phase-II metabolic enzymes on renal cell cancer risk of trichloroethylene-exposed workers

Individual differences in susceptibility to trichloroethylene-induced nephrocarcinogenicity may be conferred by genetic polymorphisms of glutathione S-transferases (GST), because enzymes of this group are pivotal for the metabolic activation of trichloroethylene. Because of a potential involvement of N-acetylation in the detoxication of reactive trichloroethylene metabolite(s) to N-acetyl-cysteine derivatives, polymorphisms of the NAT2 gene may also be relevant. The primary collective used for a re-investigation of these questions was that of a hospital-based case-control study by Brüning et al. (Am J Ind Med 43:274-285, 2003) of 134 renal cell cancer cases (20 cases exposed to trichloroethylene) and 401 matched controls. Genetic polymorphisms of GSTT1, GSTM1, GSTP1 and NAT2 were studied. Additional control collectives of non-diseased persons were used for comparison of allele frequencies. No genetic influences on the development of renal cancer due to trichloroethylene were apparent, related to the deletion polymorphisms of GSTT1 and GSTM1, as well as to the NAT2 rapid/slow acetylator states. However, renal cell cancer cases displayed a somewhat higher proportion of the homozygous GSTP1 313A wild type (GSTP1*A), although this was not statistically significant (chi(2) test: P=0.1071, when using only the original controls of Brüning et al. (2003); P=0.0781 with inclusion of the additional controls). The re-investigation does not confirm the working hypothesis of an influence of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 on renal cell cancer development due to high occupational exposures to trichloroethylene.

Urinary 1‐Hydroxypyrene Level Relative to Vehicle Exhaust Exposure Mediated by Metabolic Enzyme Polymorphisms

Polycyclic aromatic hydrocarbons (PAH) are common air pollutants generated from incomplete combustion. The inhalation of exhaust fumes in urban areas has been suggested to be an additional contributing factor. This study investigated the influence of urban traffic exposure, personal lifestyle factors and metabolic enzyme polymorphisms on the urinary 1-hydroxypyrene (1-OHP) level, approximating exposure to PAH. With consents, 95 male taxi drivers exposed to vehicle exhaust in traffic and 75 male office employees received health interviews and provided urine samples. The results showed taxi drivers had higher urinary 1-OHP than the office employees (mean +/- standard deviation were 0.17 +/- 0.10 vs. 0.10 +/- 0.07 mol/mol creatinine, p<0.001). The average urinary 1-OHP level increased from 0.07 micromol/mol creatinine for non-smoking office employees to 0.17 micromol/mol creatinine for those who smoked more than 20 cigarettes daily. The values for taxi drivers with similar smoking statuses were 0.12 and 0.25 micromol/mol creatinine, respectively. Among non-smokers, taxi drivers still had higher 1-OHP level than office employees (0.12 +/- 0.05 vs. 0.07 +/- 0.03 micromol/mol creatinine). The subjects with the m1/m2 or m2/m2 genotype of CYP1A1 MspI or GSTM1 deficiency had significantly higher urinary 1-OHP levels than those with other CYP1A1 MspI and GSTM1 genotypes. Multivariate logistic regression analysis showed that taxi drivers (adjusted odds ratio (OR)=5.1, 95% confidence interval (CI)=1.1-13.6), smokers (OR=5.5, 95% CI=1.6-18.4) and subjects with the m1/m2 or m2/m2 genotype of CYP1A1 MspI (OR=9.7, 95% CI=2.7-35.0) had elevated urinary 1-OHP (greater than the overall median value, 0.11 micromol/mol creatinine). The results of this study suggest smoking contributes to the elevated urinary 1-OHP levels in taxi drivers in addition to taxi driving, and the excess level contributed from traffic exhaust and smoke was regulated by the CYP1A1 MspI genotype. Traffic exhaust exposure, smoking and CYP1A1 MspI genotype contributed to the variation in levels of urinary 1-OHP excretion.

Genetic polymorphisms of folate metabolic enzymes and toxicities of high dose methotrexate in children with acute lymphoblastic leukemia

Dear Editor,Methotrexate (MTX) inhibits several enzymes in folatemetabolic pathway, including dihydrofolate reductase,thymidylate synthase (TYMS), and methylenetetrahydrofo-late reductase (MTHFR), causing defects in DNA and RNAsyntheses and methylation process [1]. Genetic polymor-phisms of genes encoding proteins in folate metabolismaffect their structures and functions. MTHFR C677T andA1298C are associated with decreased enzyme activity andhyperhomocysteinemia [1]. There are 28 nucleotide-tandemrepeat variations in 5’untranslated region of the TYMSgene. The most common variations of this polymorphismare two and three repeats (2R and 3R). TYMS gene with3R polymorphism has a higher expression level than theone with 2R [1, 2]. Reduced folate carrier (RFC) is anessential carrier protein for folate and MTX. RFC G80Apolymorphism affects MTX level in patients treated withhigh dose of MTX. MTX level has been found to besignificantly higher in patients with RFC 80 AA genotypethan other genotypes [1, 3].Our institute normally uses two courses of high-doseMTX (1.5 g/m

分子疫学と尿路上皮がん

Tobacco smoking is the main cause of human urothelial cancer. It has been suggested that genetic susceptibility may contribute to the risk, because only a small portion of smokers develops urothelial cancer. Tobacco smoke contains many carcinogens which are activated or detoxified by phase-I or phase-II enzymes. The concentration of the ultimate carcinogen, which will react with DNA, is determined by the rate of activation and detoxification. Individuals with an increased rate of activation or a decreased rate of detoxification have a slightly higher level of bulky carcinogen-DNA adduct in the urothelial mucosa. Thus metabolic polymorphisms have been recognized as important determinants of carcinogen susceptibility, and recent efforts have shown that inter-individual differences in specific cytochrome P450 enzymes (CYPs), N-acetyltransferases (NAT), glutathione S-transferases (GST) and sulfotransferases (SULT) are often disproportionately represented in epidemiological studies between urothelial cancer cases and controls. It has been revealed that GSTM1 null genotype or NAT2 slow acetylator genotype may be associated with a small increase in urothelial cancer risk. Associations between other polymorphisms of metabolic enzymes and urothelial cancer are not well-known or are inconsistent. To reveal these associations, further well-designed and large-scale studies are needed.

Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside

The chronic nature of rheumatoid arthritis (RA) means that patients require drug therapy for many years. Many RA patients, however, have to discontinue treatment because of drug-related toxic effects, loss of efficacy, or both. The underlying molecular cause for loss of efficacy of antirheumatic drugs is not fully understood, but it might be mediated, at least in part, by mechanisms shared with resistance to anticancer drugs. This Review outlines molecular mechanisms that could be involved in the onset of resistance to, or the loss of efficacy of, disease-modifying antirheumatic drugs in RA patients, including methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, and leflunomide. The mechanisms suggested are based on findings from experimental laboratory studies of specific drug-uptake and drug-efflux transporters belonging to the superfamily of multidrug-resistance transporters, alterations in intracellular drug metabolism, and genetic polymorphisms of drug transporters and metabolic enzymes. We also discuss strategies to overcome resistance and the current clinical studies aiming to predict response and risk of toxic effects. More in-depth knowledge of the mechanisms behind these features could help facilitate a more efficient use of disease-modifying antirheumatic drugs.

Pharmacogenetics and Smoking Cessation with Nicotine Replacement Therapy

Nicotine replacement therapies (NRTs), including transdermal patch, gum, lozenge, nasal spray and inhaler, are widely used for the treatment of tobacco dependence; however, only one-quarter to one-third of smokers who utilise NRTs to quit smoking are able to maintain long-term abstinence from tobacco use. Pharmacogenetic studies of NRT may be useful to identify subgroups of smokers who respond more favourably to specific NRTs, and to determine the optimal dose and duration of NRT. To date, pharmacogenetic studies have examined genes coding for nicotine metabolising enzymes, as well as proteins in neurotransmitter pathways that mediate the effects of nicotine. Initial findings suggest that polymorphisms in nicotine metabolising enzymes, and selected genes in the dopaminergic and opioidergic pathways, may have predictive validity for NRT response; however, independent replication is necessary before translation to clinical practice. Larger-scale investigations that incorporate pathway-based or genome-wide analysis, as well as intermediate measures of nicotine dependence (i.e. 'endophenotypes'), may be necessary to capture the complexity of pharmacogenetic effects.

Genetic polymorphism of metabolic enzymes modifies the risk of chronic solvent-induced encephalopathy

In the present study, we investigate whether genetic polymorphism in enzymes involved in the metabolism of organic solvents influences susceptibility to chronic solvent encephalopathy (CSE), which is one of the major effects of long-term exposure to organic solvents. Polymorphisms in the genes encoding CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1 and GSTP1 enzymes were determined in a group of male CSE patients (N=97) and controls (N=214). The selection of the patients was based on a standard diagnostic protocol, including interviews, neuropsychological tests and questionnaires directed to somatic, cognitive and mood symptoms and exposure, in combination with well-defined decision rules. As controls, healthy workers of similar socio-economic background, without memory problems and with no known exposure to organic solvents, were included in the study. Comparing patients and controls, higher frequencies of the variant *5B allele of the CYP2E1 gene (OR: 5.8; 95% CI: 1.8-18.8) and of the variant GSTP1*C allele (OR: 0.40; 95% CI: 0.17-0.94) were found. Homozygous carriers of the exon 4 EPHX1 Arg139 variant allele had a lower risk (OR: 0.25; 95% CI: 0.06-1.13). The present study indicates that genetic polymorphism of CYP2E1, EPHX1 and GSTP1 modify the risk of developing CSE.