CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

Cytochrome 1A1 and 1B1 gene diversity in the Zanzibar islands

Amodiaquine (AQ) is a 4‐aminoquinoline widely used in the treatment of malaria as part of the artemisinin combination therapy (ACT). AQ is metabolised towards its main metabolite desethylamodiaquine mainly by cytochrome P450 2C8 (CYP2C8). CYP1A1 and CYP1B1 play a minor role in the metabolism but they seem to be significantly involved in the formation of the short‐lived quinine‐imine. To complete the genetic variation picture of the main genes involved in AQ metabolism in the Zanzibar population, previously characterised for CYP2C8, we analysed in this study CYP1A1 and CYP1B1 main genetic polymorphisms. The results obtained show a low frequency of the CYP1A1*2B/C allele (2.4%) and a high frequency of CYP1B1*6 (approximately 42%) followed by CYP1B1*2 (approximately 27%) in Zanzibar islands. Genotype data for CYP1A1 and CYP1B1 show a low incidence of fast metabolisers, revealing a relatively safe genetic background in Zanzibar’s population regarding the appearance of adverse effects.     

1-Naphthyl isocyanate and 1-naphthylamine as metabolites of 1-naphthylisothiocyanate

Abstract: The importance of the bioactivation of 1-naphthylisothiocyanate was studied. Forty minutes after 1-naphthylisothiocyanate administration to rats, bile was collected over a 2.5-h period; the liver was then excised and homogenized. 1-naphthylisothiocyanate and its metabolites in bile and liver of rats were identified and quantified using coupled gas chromatography-mass spectrometry. Three main compounds were found in all 1-naphthylisothiocyanate-treated animals. They were identified as 1-naphthyl isocyanate, 1-naphthylamine and the parent compound, 1-naphthylisothiocyanate. When rats were given cycloheximide, which attenuates 1-naphthylisothiocyanate toxicity, 30 min before 1-naphthylisothiocyanate (300 mg/kg), 1-naphthyl isocyanate concentration was significantly lower than in rats receiving only 1-naphthylisothiocyanate. The appearance of 1-naphthylamine was also inhibited by cycloheximide, although not to the same extent as 1-naphthyl isocyanate. On the other hand, phenobarbital, which potentiates 1-naphthylisothiocyanate hepatotoxicity, enhanced 1-naphthyl isocyanate and 1-naphthylamine formation. It is suggested that 1-naphthyl isocyanate, 1-naphthylamine and the highly reactive sulfur released from 1-naphthylisothiocyanate might be involved in the hepatotoxic effect of 1-naphthylisothiocyanate.     

Interleukin-1 and interleukin-1 antagonism.

The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and the synthesis of several proteins that, in turn, induce acute and chronic inflammatory changes. IL-1 is also the prototypic "alarm" cytokine in that it brings about increases in a variety of defense mechanisms, particularly immunologic and hematologic responses. Most studies on the biology of IL-1 have been performed in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm the two fundamental properties of IL-1 as being both a mediator of disease as well as of host defense. However, in either situation, over or continued production of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or its effects becomes a target of therapy in many diseases. In this review, the structure, gene expression, synthesis, and secretion of IL-1 are described. In addition, the two IL-1 surface receptors, possible signal transduction mechanisms, various biologic activities, and production of IL-1 during disease states are discussed. Similarities and differences between IL-1, tumor necrosis factor, and IL-6 are presented. Although various agents for reducing the synthesis and/or for antagonizing the effects of IL-1 have been proposed, the recent cloning of a naturally occurring IL-1 receptor antagonist (IL-1ra) has opened new experimental and clinical approaches. The ability of this IL-1ra to block the triggering of IL-1 receptors in animals without agonist effects has reduced the severity of diseases such as hemodynamic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.     

Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis

Cooperative activation of Meis1 and Hoxa9 perturbs myeloid differentiation and eventually leads myeloid progenitors to leukemia, yet it remains to be clarified what kinds of subsequent molecular processes are required for development of overt leukemia. To understand the molecular pathway in Hoxa9/Meis1-induced leukemogenesis, retroviral insertional mutagenesis was applied using retrovirus-mediated gene transfer. The mice that received Hoxa9/Meis1-transduced bone marrow cells developed acute myeloid leukemia (AML), and Trib1, Evi1, Ahi1, Raralpha, Pitpnb, and AK039950 were identified as candidate cooperative genes located near common retroviral integration sites. Trib1 and Evi1 were up-regulated due to retroviral insertions, and coexpression of these genes significantly accelerated the onset of Hoxa9/Meis1-induced AML, suggesting that Trib1 and Evi1 are the key collaborators. Furthermore, Trib1 by itself is a novel myeloid oncogene, enhancing phosphorylation of ERK, resulting in inhibition of apoptosis. These results demonstrate the importance of specific oncogene interaction in myeloid leukemogenesis.     

甲型H1N1与季节性H1N1流感病毒血凝素基因比较分析

目的分析泰安市2008～2009年度季节性流感与2009年度甲型H1N1流感病原学检测结果 ,比较季节性H1N1与甲型H1N1血凝素基因变异情况。方法选择国家级流感监测哨点医院以及暴发疫情的疫点,采集流感样病例的鼻咽拭子标本,通过RealtimePCR进行病毒检测,用MDCK细胞进行病毒分离,通过RT-PCR扩增血凝素HA1片段的基因并测序,利用生物信息学进行序列分析。结果 2008～2009年共检测鼻咽拭子标本283份,分离出流感病毒33株,分离阳性率为11.67%,其中季节性H1N1亚型31株。2009年5月1日～12月31日,检测鼻咽拭子标本996份,流感核酸检测阳性417份,阳性率为41.86%,其中甲型H1N1337份,季节性H1N1亚型1份。6株季节性H1N1病毒均在多个氨基酸位点上发生变异,与疫苗株A/Brisbane/59/2007(H1N1)比较,有11个位点发生了突变,其中5个位点位于抗原决定簇上;测序成功的6株甲型H1N1病毒在多个氨基酸位点发生变异,与疫苗株A/California/07/2009(H1N1)比较,有6个位点发生突变,其中1个位点位于抗原决定簇的B区。结论 2008～2009年度季节性H1N1为优势株,甲流暴发后,甲型H1N1成为绝对优势毒株。季节性H1N1分离株有多处氨基酸替换,抗原决定簇B区变异频繁;甲型H1N1病毒分离株的基因有变异,但关键位点第222位仍为D(天冬氨酸),与疫苗株相比抗原决定簇的关键位点变化不大。     

Glutathione S-transferase M1, T1, and P1 genotypes and rheumatoid arthritis

OBJECTIVE: To determine the effects of genetic polymorphisms of glutathione S-transferase (GST) M1, GSTT1, and GSTP on risk and severity of rheumatoid arthritis (RA) in a Korean population. METHODS: A total of 258 patients with RA and 400 disease-free controls were enrolled. GST genotypes were determined by RFLP-PCR. HLA-DRB 1 typing and further subtyping of all alleles was performed using sequence-specific oligonucleotide probe hybridization after PCR. Severity of RA among cases was assessed by Steinbrocker anatomical stage. Risk was assessed by calculating the age and sex adjusted odds ratio (OR) and 95% confidence intervals (CI). RESULTS: The OR for risk of RA with the GSTM1-null genotype was 1.40 (95% CI 1.02- 1.92, p = 0.04), and 1.86 (95% CI 1.12- 3.09, p = 0.005) among individuals without the shared epitope (SE). Among patients with RA, the OR for risk of severe RA for the GSTM1-null genotype was 2.45 (95% CI 1.04- 5.77, p = 0.02). No association was observed between the GSTT1 or GSTP1 genotypes and either risk or severity of RA. CONCLUSION: These results suggest that the deletion polymorphism of GSTM1 is associated with increased susceptibility for RA, particularly among individuals who are not carriers of the HLA-DRB 1 SE.     

GSTT1, GSTM1 and GSTP1 polymorphisms and susceptibility to juvenile idiopathic arthritis

OBJECTIVE: In this study we have analyzed GSTM1, GSTT1 and GSTP1 polymorphisms in patients with juvenile idiopathic arthritis (JIA), to investigate a possible role of these genes as genetic components of the disease. METHODS: A total of 103 individuals (49 oligoarticular, 41 polyarticular and 13 systemic) were analyzed for the three polymorphisms, using a PCR/RFLP methodology. RESULTS: We have observed significantly increased frequencies of individuals with GSTT1 null genotype in JIA patients comparing to controls (37% x 21%; p=0.0183). There was a 2-fold increased risk (OR 2.2, 95% CI 1.2-4.1) associating the disease with the GSTT1 null genotype. Considering the subgroups (oligoarticular, polyarticular and systemic), the results indicated an association between polyarticular and systemic patients and the GSTT1 null genotype. There was a 2-fold increased risk for polyarticular patients (OR 2.4, 95%, CI 1.1-5.4), and a 4-fold increased risk for systemic patients (OR 4.4, 95%, 1.3-14.5). CONCLUSION: The GSTT1 null genotype seems to be involved in polyarticular and systemic JIA.     

HIV-1 Env蛋白与HIV-1感染

人免疫缺陷病毒Ⅰ型(HIV-1)是艾滋病的主要病原体,HIV-1 Env蛋白在病毒的感染、侵入和干扰机体免疫机能等方面发挥着重要作用,它可以干扰细胞正常的信号转导途径、导致合胞体的形成、引发细胞病变。HIV-1感染的细胞类型包括 CD_4~+辅助T细胞、单核巨噬细胞、树突状细胞、朗罕氏细胞、胎盘滋养层细胞、神经元细胞等。HIV-1感染引发的病理变化与免疫系统的变化密切相关,免疫系统的     

Polymorphisms of CYP1A1 and GSTM1 and laryngeal cancer risk: evidence-based meta-analyses

Purpose  Previous evidence implicates CYP1A1 and GSTM1 polymorphisms as risk factors for various cancers. A number of studies have been devoted to the association of CYP1A1 or GSTM1 polymorphism with susceptibility to laryngeal carcinoma, with the results inconsistent and inconclusive. The aim of the present study was to assess the possible associations of laryngeal cancer risk with CYP1A1 genetic variation and GSTM1 null genotype respectively. Methods  The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications, then the extracted data were further analyzed using systematic meta-analyses. Results  The results showed that the overall odds ratio (OR) was 1.32 (95% CI = 1.08–1.61) for CYP1A1 Mspl polymorphism. Using subgroup analysis, the pooled ORs were 1.38 (95% CI = 0.98–1.95) in Asians and 1.29 (95% CI = 1.01–1.65) in Caucasians. For CYP1A1 exon7 polymorphism, the overall OR was 1.38 (95% CI = 0.98–1.95). The overall OR was 1.24 (95% CI = 1.03–1.49) for GSTM1 polymorphism and the pooled ORs were 1.36 (95% CI = 0.75–2.48) in Asians, 1.16 (95% CI = 0.94–1.44) in Caucasians and 1.52 (95% CI = 1.05–2.19) in Turkey population. Conclusions  The data suggest CPY1A1 MspI polymorphism as a risk factor for laryngeal cancer in Caucasians but not in Asians. However, the results suggest a marked correlation of GSTM1 polymorphism with laryngeal cancer risk in Turkey population but not Caucasians and Asians. The author Xian-Lu Zhuo works at Guiyang Medical College.     

Sulfotransferase 1A1 (SULT1A1) polymorphism and susceptibility to primary brain tumors

Purpose Sulfotransferase 1A1 is a member of sulfotransferase family that plays an important role in the biotransformation of numerous carcinogenic and mutagenic compounds through sulfation. The present study has investigated the association between SULT1A1 polymorphism and primary brain tumor incidence. Methods SULT1A1 genotypes were successfully detected using the PCR-RFLP assay in 60 primary brain tumor patients and 156 hospital-based healthy control individuals with no history of cancer or precancerous disorder. Results There was a significant difference in genotypes distribution (GG vs. GA + AA) between brain tumor patients (GG genotype frequency = 48.3%) and control population (GG genotype frequency = 65.4%; OR = 2.019, 95% CI = 1.103–3.695; P = 0.022). In order to determine the association between SULT1A1 polymorphism and specific types of brain tumors, the patients were classified according to the type of brain tumors they suffer from: glial and non-glial. Results of the statistical analyses of each group of patients in comparison with the control individuals showed a significant difference only between SULT1A1 polymorphism and non-glial brain tumors (OR = 2.615; 95% CI = 1.192–5.739; P = 0.014) but glial tumors (OR = 1.535; 95% CI = 0.688–3.425; P = 0.293). When non-glial tumors were classified as meningiomal and others (pituitary adenoma, craniopharyngioma, acoustic neuroma and hemangioblastoma), statistical analysis showed that this significance is only due to the meningiomal tumors (OR = 3.238; CI = 1.205–8.704; P = 0.015). We also estimated a reduced risk of brain tumor in non-smokers (OR = 1.700; CI = 0.800–3.615) in comparison to smokers (OR = 2.773; CI = 0.993–7.749), but this was not statistically significant. Conclusion Our findings have suggested that there was a significant association between brain tumor and SULT1A1*2 allele (A allele that is also known as His allele) and this allele is an important risk factor in the development of meningiomal brain tumors.     

Inhibition of procarcinogen-bioactivating human CYP1A1, CYP1A2 and CYP1B1 enzymes by melatonin

Abstract:  Administration of melatonin to rodents decreases the incidence of tumorigenesis initiated by benzo[ a ]pyrene or 7,12-dimethylbenz[ a ]anthracene, which requires bioactivation by cytochrome P450 enzymes, such as CYP1A1, CYP1A2 and CYP1B1, to produce carcinogenic metabolites. The present study tested the hypothesis that melatonin is a modulator of human CYP1 catalytic activity and gene expression. As a comparison, we also investigated the effect of melatonin on the catalytic activity of CYP2A6, which is also a procarcinogen-bioactivating enzyme. Melatonin (3–300 μ m ) decreased 7-ethoxyresorufin O -dealkylation catalyzed by human hepatic microsomes and recombinant CYP1A1, CYP1A2 and CYP1B1, whereas it did not affect coumarin 7-hydroxylation catalyzed by hepatic microsomes or recombinant CYP2A6. Melatonin inhibited CYP1 enzymes by mixed inhibition, with apparent K _i values (mean ± S.E.M.) of 59 ± 1 (CYP1A1), 12 ± 1 (CYP1A2), 14 ± 2 (CYP1B1) and 46 ± 8 μ m (hepatic microsomes). Additional experiments indicated that melatonin decreased benzo[ a ]pyrene hydroxylation catalyzed by hepatic microsomes and CYP1A2 but not by CYP1A1 or CYP1B1. Treatment of MCF-10A human mammary epithelial cells with melatonin (up to 300 μ m ) did not affect basal or benzo[ a ]pyrene-inducible CYP1A1 or CYP1B1 gene expression. Consistent with this finding, melatonin did not influence reporter activity in aryl hydrocarbon receptor-dependent pGudluc6.1-transfected MCF-10A cells treated with or without benzo[ a ]pyrene, as assessed in an in vitro cell-based luciferase reporter gene assay. Overall, melatonin is an in vitro inhibitor of human CYP1 catalytic activity, and it may be useful to develop potent analogues of melatonin as potential cancer chemopreventive agents that block CYP1-mediated chemical carcinogenesis.