RESUMO
OBJECTIVES: Exposure to reactive oxygen species (ROS) through cigarette smoking is thought to contribute to the development of systemic lupus erythematosus (SLE). Metabolic enzymes are involved in ROS production. The aim of this study was to evaluate the modifying effect of metabolic polymorphisms on the association of cigarette smoking with SLE risk in a Japanese population. METHODS: We investigated the relationship of the cytochrome P450 (CYP) 1A1 rs4646903 and glutathione S-transferase (GST) M1 deletion polymorphisms to SLE risk with attention to interaction with cigarette smoking among 151 SLE cases and 421 controls in female Japanese subjects. Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for several covariates. RESULTS: Smokers with the CC genotype of CYP1A1 rs4646903 were significantly associated with increased risk of SLE (OR 9.72, 95% CI 2.73-34.6). Similarly, smokers with the combined CYP1A1 rs4646903/GSTM1 'at-risk' genotype were significantly associated with increased risk of SLE (OR 17.5, 95% CI 3.20-95.9). More than 60% of the excess risk for SLE in smokers with the CC genotype and smokers with the combined 'at-risk' genotype was due to an additive interaction. A lack of association of the GSTM1 genotypes with smoking was observed. CONCLUSIONS: Our results suggest that a combination of smoking and either the CYP1A1 rs4646903 genotype or the combined metabolic genotype plays an important role in SLE susceptibility in our Japanese population. Additional studies are warranted to confirm the metabolic polymorphism-smoking interaction suggested in the present study.
Assuntos
Citocromo P-450 CYP1A1/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Lúpus Eritematoso Sistêmico/genética , Fumar/efeitos adversos , Tabagismo/genética , Adulto , Comorbidade , Feminino , Deleção de Genes , Humanos , Modelos Logísticos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Tabagismo/diagnóstico , Tabagismo/epidemiologiaRESUMO
Three previous cohort studies in the USA reported that dairy product consumption was significantly associated with an increased risk of Parkinson's disease (PD) in men, but not in women. We examined the relationship between consumption of dairy products, calcium, and vitamin D and the risk of PD using data from a multicenter hospital-based case-control study in Japan. Included were 249 cases within 6 years of onset of PD based on the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, body mass index, and dietary factors including cholesterol, dietary glycemic index, vitamin E, ß-carotene, vitamin B(6), caffeine, iron, and alcohol. Total dairy product consumption was not materially associated with the risk of PD (P for trend = 0.62). No evident relationships were observed between intake of milk, yogurt, cheese, or ice cream and the risk of PD (P for trend = 0.75, 0.63, 0.59, and 0.35, respectively). There were no measurable associations between consumption of calcium or vitamin D and PD (P for trend = 0.37 and 0.69, respectively). No significant interactions were observed between the dietary exposures and sex regarding PD. Our results suggest that intake of dairy products, calcium, and vitamin D was not related to PD, regardless of sex. However, such null relationships might be a consequence of PD.
Assuntos
Cálcio da Dieta/administração & dosagem , Cálcio/administração & dosagem , Laticínios , Doença de Parkinson/etnologia , Doença de Parkinson/etiologia , Vitamina D/administração & dosagem , Idoso , Cálcio/efeitos adversos , Cálcio da Dieta/efeitos adversos , Estudos de Casos e Controles , Laticínios/efeitos adversos , Feminino , Humanos , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/efeitos adversosRESUMO
BACKGROUND: antioxidant vitamins are expected to protect cells from oxidative damage by neutralizing the effects of reactive oxygen species. However, epidemiological evidence regarding the associations between antioxidant vitamin intake and Parkinson's disease (PD) is limited and inconsistent. We investigated the relationship between dietary intake of selected antioxidant vitamins, vegetables and fruit and the risk of PD in Japan using data from a multicenter hospital-based case-control study. METHODS: included were 249 patients within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, body mass index, dietary intake of cholesterol, alcohol, total dairy products, and coffee and the dietary glycemic index. RESULTS: higher consumption of vitamin E and ß-carotene was significantly associated with a reduced risk of PD after adjustment for confounders under study: the adjusted odds ratio in the highest quartile was 0.45 (95% confidence interval [CI]: 0.25-0.79, P for trend = 0.009) for vitamin E and 0.56 (95% CI: 0.33-0.97, P for trend = 0.03) for ß-carotene. Stratified by sex, such inverse associations were significant only in women. No material relationships were shown between intake of vitamin C, α-carotene, cryptoxanthin, green and yellow vegetables, other vegetables, or fruit and the risk of PD. CONCLUSIONS: higher intake of vitamin E and ß-carotene may be associated with a decreased risk of PD.
Assuntos
Antioxidantes/administração & dosagem , Dieta , Doença de Parkinson/etiologia , Risco , Vitamina E/administração & dosagem , beta Caroteno/administração & dosagem , Idoso , Estudos de Casos e Controles , Inquéritos sobre Dietas , Feminino , Humanos , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Inquéritos e Questionários , VerdurasRESUMO
Patients with idiopathic Parkinson's disease (PD) appear to have reduced capacity for detoxification of certain environmental compounds. The glutathione S-transferases (GSTs) are candidate genes for PD because they are involved in the metabolism of pesticides and cigarette smoke. We investigated the relationship of the seven GST polymorphisms (GSTM1 deletion, GSTT1 deletion, GSTP1 rs1695, GSTO1 rs4925, GSTO1 rs11191972, GSTO2 rs156697 and GSTO2 rs2297235) and PD risk with special reference to the interaction with pesticide use or cigarette smoking among 238 patients with PD cases and 370 controls in a Japanese population. None of the GST polymorphisms were associated with PD. GSTO1 rs4925 and GSTO2 rs2297235 were found to be in strong linkage disequilibrium (D' = 0.98). Cigarette smoking was significantly associated with decreased risk of PD. However, no interaction of smoking with any of the GST polymorphisms was observed. Self-reported pesticide use was not associated with increased risk of PD. There was no evidence of interaction between self-reported pesticide use and either GST polymorphism. Our results suggest that the tested GST polymorphisms did not play an important role in PD susceptibility in our Japanese population. Our study does not give evidence of interaction between the GST polymorphisms and smoking may although this study provided sufficient statistical power to detect modest interaction. As for interaction between GSTP polymorphisms and pesticide use, the power of this study to detect an interactive effect was low due to a small number of pesticide users. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the GST polymorphisms in PD development.
Assuntos
Glutationa Transferase/genética , Doença de Parkinson , Praguicidas/efeitos adversos , Polimorfismo Genético/genética , Fumar , Idoso , Exposição Ambiental/efeitos adversos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Doença de Parkinson/psicologia , Grupos Populacionais , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To assess the association between active and passive smoking and the risk of Parkinson's disease (PD), a case-control study with 249 PD patients and 369 controls was carried out in Japan. METHODS: Information on smoking was obtained through a self-administered questionnaire. Adjustment was made for age, sex, region of residence, educational level, and occupational exposure. RESULTS: Ever having smoked cigarettes was associated with a reduced risk of PD [adjusted odds ratio = 0.38; 95% confidence interval (CI): 0.24-0.59]. Risk for former smokers was intermediate between the high risk for never smokers and the low risk for current smokers. Adjusted odds ratios for former and current smokers were 0.51 (95% CI: 0.32-0.82) and 0.12 (95% CI: 0.05-0.26), respectively. There was an inverse dose-response gradient with pack-years smoked. No significant association was detected for passive smoking exposure. CONCLUSION: Our results appear to confirm data from previous epidemiological studies.
Assuntos
Doença de Parkinson/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Japão/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Doença de Parkinson/epidemiologia , Fatores de Risco , Inquéritos e Questionários , Poluição por Fumaça de Tabaco/estatística & dados numéricosRESUMO
Cigarette smoking may be associated with an increased risk of systemic lupus erythematosus (SLE), but the underlying mechanism of this association remains unclear. N-acetyltransferase 2 (NAT2) is highly variable and detoxifies aromatic amines, an important class of carcinogens in tobacco smoke. Individuals who possess homozygous polymorphic alleles have a slower rate of metabolic detoxification of aromatic amines. We investigated the relationship of the NAT2 polymorphism to the risk of SLE with special reference to the interaction with cigarette smoking among 152 SLE cases and 427 controls in a female Japanese population. NAT2 4, NAT2 5B, NAT2 6A and NAT2 7B alleles were detected with polymerase chain reaction-restriction fragment length polymorphism. Individuals carrying the 4/4 genotype are rapid acetylators, whereas those with homozygous non- 4 genotypes have a slow acetylator phenotype. Cigarette smoking was associated with an increased risk of SLE (odds ratio [OR] = 2.26; 95% confidence interval [CI] = 1.46-3.50). The slow acetylator genotype of NAT2 was significantly associated with an increased risk of SLE (OR = 2.34, 95% CI = 1.21-4.52) compared with the rapid acetylator genotype. A gene-environment interaction was suggested, with a combination of the NAT2 slow acetylator genotype and smoking conferring significantly higher risk (OR = 6.44, 95% CI = 3.07-13.52; attributable proportion due to interaction = 0.50, 95% CI = 0.12-0.88), compared with the NAT2 rapid acetylator genotype and no history of smoking. This study suggests that, in this Japanese population, the NAT2 slow acetylator status may be a determinant in susceptibility to SLE.
Assuntos
Arilamina N-Acetiltransferase/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético/genética , Fumar/efeitos adversos , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Japão , Lúpus Eritematoso Sistêmico/etnologia , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans' syndrome. METHODS: Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m(2) to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment. RESULTS: Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans' syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18-30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69+ CD4+ T cells decreased significantly. Serum TNF-alpha levels decreased significantly on day 2. The Th1/Th2 balance of CD4+ T cells gradually shifted towards a Th1 type by 6 months. CONCLUSION: In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.
Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Subpopulações de Linfócitos B/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto , Anemia Hemolítica Autoimune/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Antígenos de Superfície/metabolismo , Subpopulações de Linfócitos B/imunologia , Citocinas/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Rituximab , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Epidemiological evidence for an effect of breastfeeding on asthma continues to be inconclusive. The present prospective study examined the relationship between breastfeeding and the risk of wheeze and asthma in Japanese infants. A birth cohort of 763 infants was followed. The first survey during pregnancy and the second survey between 2 and 9 months postpartum collected information on potential confounding factors. Data on breastfeeding, wheeze, and asthma were obtained from questionnaires in the third survey from 16 to 24 months postpartum. Adjustment was made for maternal age, maternal and paternal history of asthma, atopic eczema, and allergic rhinitis, indoor domestic pets (cats, dogs, birds, or hamsters), family income, maternal and paternal education, maternal smoking during pregnancy, baby's sex, baby's older siblings, household smoking in the same room as the infant, and time of delivery before the third survey. By the third survey, the cumulative incidence of wheeze and asthma was 22.1% and 4.3%, respectively. Neither exclusive breastfeeding for 4 months or more nor partial breastfeeding for 6 months or more were materially related to the risk of wheeze. No measurable association was observed between exclusive breastfeeding for 4 months or more and the risk of asthma. Partial breastfeeding for 6 months or more was inversely related to the risk of asthma although the adjusted odds ratio (OR) was not statistically significant. When infants were stratified according to whether there was a negative or positive allergic history in at least 1 parent, a nearly 40% and 60% decrease, respectively, in the ORs were found for exclusive and partial breastfeeding only in infants without a parental allergic history, although the ORs were not statistically significant. The present prospective study showed no statistically significant relationship between breastfeeding duration and the risk of wheeze or asthma in Japanese infants.
Assuntos
Asma/epidemiologia , Aleitamento Materno/epidemiologia , Alérgenos/imunologia , Asma/imunologia , Feminino , Humanos , Lactente , Japão/epidemiologia , Masculino , Estudos Prospectivos , Sons Respiratórios , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.
Assuntos
Glutationa Transferase/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Interpretação Estatística de Dados , Predisposição Genética para Doença , Variação Genética , Genótipo , Glutationa Transferase/fisiologia , Humanos , Neoplasias Pulmonares/etnologia , Polimorfismo Genético , Fatores de Risco , Fumar/efeitos adversos , População Branca/estatística & dados numéricosRESUMO
The relation between cytochrome P4501A1 (CYP1A1) gene polymorphisms and the risk of gallbladder cancer was examined. To clarify individual differences in susceptibility to gallbladder carcinogenesis, we investigated the frequency of the Mspl and Ile-Val polymorphisms of the CYP1A1 gene, in 52 patients with gallbladder cancer (32 females, 20 males) and 104 healthy controls (64 females, 40 males). We then examined the relationship between the CYP1A1 polymorphisms and the development of gallbladder cancer in members of both sexes. A statistical difference in the frequencies of the MspI and Ile-Val polymorphisms or their alleles (ml, m2 and Ile, Val) was not observed in the male patients and controls. Among females, however, the frequencies of genotypes C and Ile/Val were significantly higher (p < 0.05) in the patients than in their controls. Moreover, the frequency of the hetero genotype Ile/Val was statistically higher (p < 0.05) in the female patients than in the male patients. This study demonstrated a significant over-representation of genotypes C and Ile/Val in female patients with gallbladder cancer. Females with genotypes C and/or Ile/Val may have a high genetic susceptibility to the development of gallbladder cancer.
Assuntos
Citocromo P-450 CYP1A1/genética , Neoplasias da Vesícula Biliar/genética , Polimorfismo Genético , Alelos , Estudos de Casos e Controles , Citocromo P-450 CYP1A1/química , Primers do DNA/química , DNA de Neoplasias/metabolismo , Feminino , Neoplasias da Vesícula Biliar/enzimologia , Genótipo , Humanos , Incidência , Isoleucina/química , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Valina/químicaRESUMO
Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.
Assuntos
População Negra/genética , Frequência do Gene , Predisposição Genética para Doença , Neoplasias/genética , Polimorfismo Genético , População Branca/genética , Sistema Enzimático do Citocromo P-450/genética , Bases de Dados Factuais , Ligação Genética , HumanosRESUMO
Glutathione S-transferases (GSTs) are a superfamily of detoxification enzymes that may play an important role in human carcinogenesis. While the genetic polymorphisms GSTM1 and GSTT1 have drawn particular interest in relation to cancer susceptibility, previous studies of colorectal cancer are inconsistent regarding their role. We examined the relation between GSTM1 and GSTT1 genotypes combined and colorectal adenomas, and the interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in Japanese men. Neither GSTM1 nor GSTT1 was related to colorectal adenomas, nor were the null genotypes of GSTM1 and GSTT1 combined. The lack of an association with GSTM1 and GSTT1 genotypes combined persisted even when the analysis was done separately for proximal and distal colorectal adenomas. A three- to fivefold significant increase in the odds of colorectal adenomas was observed among men with a high exposure to cigarette smoking across the genotype groups, and a statistically significant increasing trend was noted within each genotype group. The present findings do not support the role for GSTM1 and GSTT1 genotypes in the development of colorectal adenomas.
Assuntos
Adenoma/enzimologia , Biomarcadores Tumorais/genética , Neoplasias Colorretais/enzimologia , Glutationa Transferase/genética , Proteínas de Neoplasias/genética , Fumar/efeitos adversos , Adenoma/etiologia , Neoplasias Colorretais/etiologia , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Regressão , Risco , Fumar/metabolismoRESUMO
We examined the relation of serum lipids and apolipoprotein E genotype to colorectal adenomas among 205 cases and 220 controls with normal colonoscopy in Japanese men. With adjustment for body mass index, cigarette smoking, alcohol use, and other covaiates, odds ratios of proximal and distal adenomas associated with the presence of an allele varepsilon4 were 0.59 (95% confidence interval 0.23-1.45) and 0.99 (0.50-1.98), respectively. While serum total and LDL cholesterol were unrelated to both proximal and distal adenomas, serum triglycerides were positively related to distal adenomas. The findings suggest that altered lipid metabolism may be differentially associated with tumorigenesis in the proximal and distal colorectum.
Assuntos
Adenoma/sangue , Adenoma/genética , Apolipoproteínas E/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Lipídeos/sangue , Consumo de Bebidas Alcoólicas , Alelos , Índice de Massa Corporal , Colesterol/sangue , LDL-Colesterol/sangue , Colonoscopia , Humanos , Japão , Masculino , Razão de Chances , Fumar , Triglicerídeos/sangueRESUMO
The purpose of this study was to evaluate the prevalence of, attitudes towards, and knowledge about cigarette smoking among senior high school male students with different levels of academic ability. Self-administered anonymous questionnaires were distributed to 2014 students in July 2001. The prevalence of current smokers was 10.9% overall. The percentage of nonsmokers increased with academic ability level in both first and second graders. Students who recognize that cigarette smoking is associated with various diseases were more numerous than those reported in a nationwide Japan survey. Their recognition regarding the deleterious effects of smoking inclined toward diseases of the respiratory system. Correct knowledge concerning the detrimental effects of smoking on 10 selected diseases differed according to academic ability levels. They also thought that environmental tobacco smoke exposure was harmful to nonsmokers' health (86.6%). Although they fully understood the harmful effects of smoking, the percentage of current smokers who wanted to quit smoking (24.7%) was somewhat lower than that of those who did not (30.1%). A considerable number of current smokers, 95 of 219, had not made up their mind to quit smoking. To reduce the numbers of adult smokers, it is important not only to prevent students from starting to smoke or to encourage smokers to quit but also to guide undecided smokers in how to quit.
Assuntos
Fumar/efeitos adversos , Estudantes/psicologia , Adolescente , Avaliação Educacional , Humanos , Japão , Masculino , Morbidade , Abandono do Hábito de Fumar/psicologia , Inquéritos e QuestionáriosRESUMO
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.
Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Polimorfismo Genético , Xenobióticos/metabolismo , Acetiltransferases/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Aldeído Desidrogenase/genética , Sistema Enzimático do Citocromo P-450/genética , Predisposição Genética para Doença , Genótipo , Glutationa Transferase/genética , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2) , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Fatores de Risco , Fumar/efeitos adversosRESUMO
The glutathione S-transferases (GSTs) are widely expressed in mammalian tissues and involved in Phase II detoxification reactions. The GSTs form a supergene family consisting of four distinct families, named alpha (GSTA), mu (GSTM) theta (GSTT) and pi (GSTP). Several of the GST genes are polymorphic in humans and are currently being investigated as possible cancer-risk modifiers. Among the GST genes, we examined GSTP1 polymorphism in exon 5 among male lung cancer patients (n = 86, male Japanese) and male healthy controls (n = 80, male Japanese) by restriction fragment length polymorphism-polymerase chain reaction method. The cancer patients showed frequency of the GSTP1 mutated genotype (individuals having at least one mutant allele, 29.1%) very similar to that of the control subjects (28.8%). After adjusting for smoking status, no association was found between the GSTP1 mutated genotype and lung cancer risk (odds ratio: 0.95; 95% confidence interval: 0.48-1.90). When study subjects were divided into two subgroups based on smoking status, the GSTP1 mutated genotype was not associated with an increased risk of lung cancer among smokers and non-smokers. These results suggest that GSTP1 polymorphism in exon 5 alone may not increase the risk of lung cancer in male Japanese.
Assuntos
Glutationa Transferase/genética , Isoenzimas/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Éxons/genética , Genótipo , Glutationa S-Transferase pi , Humanos , Japão , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Risco , Fumar/epidemiologiaRESUMO
Cigarette smoking has been related to increased risk of colorectal adenomas, but the underlying mechanisms are unknown. Genetic polymorphisms are known for enzymes involved in the activation of polycyclic aromatic hydrocarbons and other tobacco-related carcinogens. Polycyclic aromatic hydrocarbons are activated by cytochrome P4501A1 (CYP1A1) and detoxified by glutathione S-transferases. We investigated the relation of CYP1A1 MspI and GSTM1 genotypes to the risk of colorectal adenomas with special reference to interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in a male Japanese population. Cigarette smoking was strongly associated with increased risk of colorectal adenomas. Overall, neither the CYP1A1 MspI genotype nor the GSTM1 genotype was related to colorectal adenomas. A significant trend for increased risk of colorectal adenomas associated with smoking was observed for each of the CYP1A1 MspI genotypes, and the increasing trends did not differ by MspI genotype. The positive association between smoking and colorectal adenomas did not vary much with GSTM1 genotypes. Among former and current smokers, adenoma risk did not differ according to the combination of CYP1A1 MspI and GSTM1 genotypes. CYP1A1 MspI and GSTM1 genotypes do not seem to modify the risk of colorectal adenomas associated with cigarette smoking.
Assuntos
Adenoma/etiologia , Adenoma/genética , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Citocromo P-450 CYP1A1/genética , Glutationa Transferase/genética , Glicoproteínas/genética , Proteínas da Gravidez/genética , Fumar/efeitos adversos , Colonoscopia , Genótipo , Humanos , Isoenzimas/genética , Masculino , Razão de Chances , Polimorfismo Genético , Fatores de RiscoRESUMO
A homozygous mutation at bp 677 in the gene for the methylenetetrahydrofolate reductase (MTHFR) was previously shown to be associated with a decreased risk of colorectal cancer. We examined the relation between the MTHFR genetic polymorphism and risk of colorectal adenoma in Japanese men using 205 cases of colorectal adenomas and 220 controls of normal total colonoscopy. The homozygous mutation was not measurably associated with colorectal adenomas. The findings corroborate the lack of an association between the MTHFR genotype and colorectal adenomas, but do not deny the possibility that the genotype may be involved in the late stage of colorectal carcinogenesis.
Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Polimorfismo Genético/genética , Adenoma/enzimologia , Adenoma/etiologia , Adenoma/patologia , Consumo de Bebidas Alcoólicas , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Homozigoto , Humanos , Japão , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias , Razão de ChancesRESUMO
We have investigated the correlation between DNA adduct levels and aryl hydrocarbon hydroxylase (AHH) activity in peripheral lymphocyte samples obtained from 42 lung cancer patients. DNA adducts and AHH activity were determined by the (32)P-postlabelling technique and the fluorometric method, respectively. The mean +/- SD of DNA adduct level was 0.88 +/- 0.37 (ranged from 0.22 to 1.90) per 10(8) nucleotides. The geometric means of non-induced and 3-methylcholanthrene (MC)-induced AHH activity, as well as AHH inducibility (MC-induced AHH activity/non-induced AHH activity) were 0.029, 0.228 pmol min(-1) 10(-6) cells, and 7.776, respectively. There was no statistically significant correlation between DNA adduct levels and non-induced or MC-induced AHH activity. A tendency of positive correlation was found between DNA adduct levels and AHH inducibility for the all subjects (n = 42, r = 0.25, p = 0.11). Such a positive correlation reached statistical significance in the subjects with squamous cell carcinoma (n = 13, r = 0.70, p < 0.01). In addition, similar correlation of DNA adducts with AHH inducibility was also observed in the GSTM1 present genotype (n = 17, r = 0.44, p = 0.07) and GSTP1-AA genotype (n = 29, r = 0.37, p = 0.05) individuals. These findings suggest that DNA adduct levels are mediated by CYP1A1 enzyme, and AHH inducibility may be a more relevant indicator than specific AHH activity for explaining the variation of DNA adduct levels in lymphocytes.
RESUMO
To determine the predictive value of the expression of p53 and glutathione S-transferase-pi (GST-pi) with respect to chemotherapy response, immunostaining was performed on transbronchial biopsy specimens from previously untreated patients with non-small cell lung cancer. Of the 54 patients, 34 patients (63%) and 37 patients (69%) were positive for p53 and GST-pi, respectively. The response rates in the p53-positive and p53-negative group were 15 and 45%, and those in GST-pi-positive and GST-pi-negative groups were 16 and 47%, respectively. A multiple logistic regression analysis revealed that positive immunostaining for GST-pi was a significant risk factor for clinical chemotherapy resistance. The combination of these two markers was the most important independent factor in predicting a response to chemotherapy in multiple logistic regression analysis. Immunohistochemical expression of p53 and GST-pi was independently related to clinical chemoresistance in patients with non-small cell lung cancer. Combined use of these two biomarkers may be a useful predictor of clinical chemoresistance.