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.     

Association of CYP1A1 and GSTM1 Polymorphisms With Oral Cancer Susceptibility: A Meta-Analysis

Our meta-analysis was aimed to evaluate the association of CYP1A1 and glutathione-S-transferase M1 (GSTM1) polymorphisms with oral cancer susceptibility.The related articles were searched in PubMed, Embase, and CNKI databases. Fifty eligible studies were included in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the relationship of CYP1A1 (rs4646903 and rs1048943) and GSTM1 polymorphisms with oral cancer risk. A random-effects model or fixed-effects model was employed depending on the heterogeneity.In overall analysis, CYP1A1 rs4646903 polymorphism was associated with the risk of oral cancer (CC vs TT: OR 1.65, 95% CI 1.33–2.05; CC vs TC+TT: OR 1.77, 95% CI 1.48–2.11; C vs T: OR 1.17, 95% CI 1.07–1.28), whereas rs1048943 showed no obvious association with oral cancer susceptibility. Moreover, subgroup analysis by ethnicity demonstrated that rs4646903 and rs1048943 both related with increased risk of oral cancer in Asians. Moreover, the analysis based on source of control suggested that rs4646903 could increase the risk for oral cancer in both population- and hospital-based populations, whereas no remarkable relationship of rs1048943 with oral cancer susceptibility was observed. For GSTM1 gene, null genotype appeared to be a risk factor for oral cancer (null vs present: OR 1.23, 95% CI 1.12–1.34), which was also proved in the subgroup analysis.The results demonstrated that CYP1A1 rs4646903 and null genotype of GSTM1 polymorphisms might serve as risk factors for oral cancer.     

Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7 and 1A1 genes

AIM: To investigate the relationship between single nucleotide polymorphisms in the uridine-diphosphoglucurono-syltransferase (UGT) UGT1A7 and UGT1A1 genes and patients suffering from colorectal cancer (CRC). METHODS: A case-control study was designed in order to investigate the genotypes of the UGT1A7 and UGT1A1 genes, which were identified by the polymerase chain reaction-restriction fragment length polymorphism (RFLP) method, for 268 CRC patients and 441 healthy controls. RESULTS: The results of simple logistical regressions revealed odds ratios (ORs) of 1.97 (P<0.001),1.91 (P<0.001),and 2.03 (P<0.001) for patients who carried the UGT1A7*1/*3 genotype,UGT1A7*3 allele,and variant-211 UGT1A1 allele.The interaction of UGT1A7*3 allele and variant-211 UGT1A1 allele produced an additive effect on the risk for the development of CRC [observed OR (2.34) greater than expected OR (1.59)]. For the 268 patients, the results of simple logistical regressions indicated that the OR of developing metastases was 4.90 (P<0.001) and 4.89 (P<0.001) for the individuals possessing UGT1A7*3 allele and variant-211 UGT1A1 allele, respectively. The results of multivariate logistical regressions confirmed these findings (OR = 2.51, P= 0.01; and OR=2.71,P=0.01,respectively).The interaction of these two variants resulted in an additive effect on the risk for metastases amongst patients [observed OR (6.83) greater than expected OR (4.56)]. CONCLUSION: In conclusion, carriage of the UGT1A7*3 allele, as well as variant-211 UGT1A1 allele represents a risk factor for the development of, and a determinant for, metastases associated with CRC patients.     

Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bear-ing UGT1A1*28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1*28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UG-T1A1*28 (TA 7/7), while UGT1A1*6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1*28 polymorphism (TA 6/7) as well as the UG-T1A1*6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinote-can dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1*28 and UGT1A1*6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinote-can. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1*28 and UGT1A1*6 polymorphisms.     

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.     

COL1A1-shRNA表达质粒构建及抑制COL1A1表达的有效序列的筛选

目的: 构建和筛选对大鼠肝星状细胞前Ⅰ型胶原α1链(COL1A1)mRNA有抑制作用的COL1A1短发夹RNA (shRNA)的表达质粒.方法:从NCBI网站获得大鼠的COL1A1 cDNA序列, 根据Whitehead研究所的siRNA设计软件设计3条理论上最佳的siRNA序列, 相应的双链DNA被插入pGPU6/GFP/Neo质粒中, 即pGPU6/GFP/Neo-shRNA-A、pGPU6/GFP/Neo-shRNA-B和pGPU6/GFP/Neo-shRNA-C. 为得到高效沉默COL1A1-siRNA, 以脂质体LipofectAMINE2000, 将1、2、3、4 μg DNA质粒转染至HSC-T6细胞中, 并观察转染效果. 将最佳沉默siRNA导入HSC-T6细胞, RT-PCR分析各组的COL1A1 mRNA表达水平.结果: 靶向COL1A1 mRNA的3个shRNA重组质粒载体pGPU6/GFP/Neo-shRNA-A、pGPU6/GFP/Neo-shRNA-B和pGPU6/GFP/Neo-shRNA-C经测序分析, shRNA编码序列与设计的片段完全一致, 经酶切凝胶电泳证实载体构建成功. 1、2、3、4 μg组转染效率分别为16.7%、20.3%、23.5%和22.3%, 以2 μg siRNA为最佳剂量, pGPU6/GFP/Neo-shRNA-A、pGPU6/GFP/Neo-shRNA-B和pGPU6/GFP/Neo-shRNA-C对COL1A1 mRNA的抑制率分别为16.6%, 63.3%和80.3%. 结论:筛选出的pGPU6/GFP/Neo-shRNA-C表达质粒能高效地抑制转染细胞COL1A1 mRNA的表达, 从而为肝纤维治疗提供新的方法和材料.     

甲型H1N1流行性感冒33例确诊病例临床分析

目的 总结甲型H1N1流行性感冒(流感)确诊患者的临床特征,以期为今后的甲型H1N1流感防治工作积累经验.方法 将2009年5月15日-6月22日在北京地坛医院隔离治疗并达到出院标准的33例甲型H1N1流感确诊患者纳入研究,采用SPSS11.0软件进行统计学分析.结果 33例患者中有25例在发病前1周曾前往美国、加拿大、日本等甲型H1N1流感流行国家旅行.12例有明确密切接触史患者的潜伏期为1-6 d.患者的主要临床症状有发热(66.7%)、咳嗽(60.6%)、咳痰(42.4%)、咽痛(36.4%).24例(72.7%)患者实验室检查结果均正常,仅少数患者出现轻度异常.33例患者均达到出院标准,病毒核酸检测连续2次阴性距出现首发症状的时间为2～16 d,住院时间为3～16 d.结论 新型甲型H1N1流感具有症状轻微、病程较短、预后良好等临床特征,如无严重基础疾病,患者均能治愈.     

Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert's syndrome

BACKGROUND/AIMS: UDP-glucuronosyltransferases (UGTs) are important enzymes involved in glucuronidation of various exogenous and endogenous compounds. Studies were undertaken on the variability of three UGT enzyme activities in human livers. Enzyme activities were associated with genetic polymorphisms in UGT1A1 (UGT1A1*28) and UGT1A6 (UGT1A6*2). UGT1A1*28 is associated with Gilbert's syndrome, a deficiency in glucuronidation of bilirubin leading to mild hyperbilirubinemia, whereas UGT1A6*2 may result in low glucuronidation rates of several drugs. METHODS: Enzyme activities and genetic polymorphisms were assessed in 39 human liver samples, and polymorphisms were also assessed in blood of 253 healthy controls. RESULTS: Associations were found between UGT enzyme activities of bilirubin (B) and 4-nitrophenol (NP; r=0.47, P=0.0024), B and 4-methylumbelliferone (MUB; r=0.54, P=0.0003), and NP and MUB (r=0.89, P<0.0001). In addition to the association between B-UGT enzyme activity and UGT1A1*28 (r=0.45, P=0.0034) as reported earlier, an association between B-UGT and UGT1A6*2 (r=0.43, P=0.007) was found. In 253 Dutch Caucasian controls, co-occurrence of UGT1A1*28 and UGT1A6*2 was found (r=0.9, P<0.0001). CONCLUSIONS: Most patients with Gilbert's syndrome, in addition to their reduced B-UGT enzyme activity, may have abnormalities in the glucuronidation of aspirin or coumarin- and dopamine-derivatives, due to this combination of UGT1A1*28 and UGT1A6*2 genotypes.     

Influenza A H1N1 in HIV-infected adults

Objectives

HIV‐infected adults are considered to be at higher risk for influenza A H1N1 complications but data supporting this belief are lacking. We aimed to compare epidemiological data, clinical characteristics, and outcomes of influenza A H1N1 infection between HIV‐infected and ‐uninfected adults.

Methods

From 26 April to 6 December 2009, each adult presenting with acute respiratory illness at the emergency department of our institution was considered for an influenza A H1N1 diagnosis by specific multiplex real‐time polymerase chain reaction. For every HIV‐infected adult diagnosed, three consecutive adults not known to be HIV‐infected diagnosed in the same calendar week were randomly chosen as controls.

Results

Among 2106 adults tested, 623 (30%) had influenza A H1N1 infection confirmed. Fifty‐six (9%) were HIV‐positive and were compared with 168 HIV‐negative controls. Relative to HIV‐negative controls, HIV‐positive patients were older, more frequently male, and more frequently smokers (P≤0.02). In the HIV‐positive group, prior or current AIDS‐defining events were reported for 30% of patients, 9% and 30% had CD4 counts of <200 and 200–500 cells/μL, respectively, and 95% had HIV‐1 RNA <50 copies/mL. Pneumonia (9%vs. 25%, respectively, in the HIV‐positive and HIV‐negative groups; P=0.01) and respiratory failure (9%vs. 21%, respectively; P=0.04) were less common in the HIV‐positive group. Oseltamivir (95%vs. 71% in the HIV‐positive and HIV‐negative groups, respectively; P=0.003) was administered more often in HIV‐positive patients. Three patients (all HIV‐negative) died. In the HIV‐positive group, CD4 cell count and plasma HIV‐1 RNA did not differ before and 4–6 weeks after influenza A H1N1 diagnosis (P>0.05).

Conclusions

HIV infection did not increase the severity of influenza A H1N1 infection, and influenza A H1N1 infection did not have a major effect on HIV infection.     

甲型H1N1流感研究进展

2009年6月11日世界卫生组织（WHO）宣布将甲型H1N1流感大流行警告级别提高为最高级6级,这意味着甲型H1N1流感已在全球大流行。甲型H1N1流感是一种新发疾病,其特点仍待进一步观察总结。本文就近期关于甲型H1N1流感的研究进展做一总结。     

UDP-glucuronosyltransferase1A1 directly binds to albumin.

UDP-glucuronosyltransferase1A1 (UGT1A1) catalyses glucuronidation of bilirubin (the final break down product of heme which is produced mainly in the spleen and liver) and is located on the lumen of the endoplasmic reticulum (ER). To identify partner UGTs that form hetero-oligomers with UGT1A1, or other proteins that bind directly to UGT1A1, yeast two-hybrid screening was performed using UGT1A1 as bait. From these studies, cDNA clones specific for human serum albumin (HSA) were unexpectedly isolated. The direct interaction between UGT1A1 and albumin was confirmed in vitro by a pull-down assay. FITC-albumin uptake into HepG2 and Huh7 cells was observed only when bilirubin are present in the culture medium. Furthermore, the endocytosis inhibitor phenylarsine oxide (PAO) prevented albumin uptake into the cells, suggesting that the albumin/bilirubin complex is internalized through receptor-mediated endocytosis. From these studies, it would appear that production of large amounts of toxic bilirubin might use different uptake pathways for entry into hepatocytes.     

A simple microchromatographic column for determination of hemoglobins A1a + b and A1c

A simple microchromatographic homemade column was devised for the measurement of glycosylated minor hemoglobin fractions. The mean and one standard deviation of hemoglobins A1a + b, A1c and A1a + b + c determined by the homemade column in 150 nondiabetic controls and 56 juvenile onset insulin-dependent diabetics were 2.6 +/- 0.5%, 6.0 +/- 1.0%, 8.6 +/- 1.1%, 3.3 +/- 0.9%, 13.7 +/- 2.2% and 16.9 +/- 2.8% respectively. A twofold increase in hemoglobins A1c and A1a + b + c levels was observed in the diabetics as compared to the non-diabetic controls suggesting that the homemade column is valid for the measurement of all three glycosylated hemoglobin fractions and assessment of blood glucose control in diabetic patients. The homemade column procedure yields accurate and reproducible results, is simple to perform, inexpensive, relatively rapid and may be used in the routine clinical laboratory. Hemoglobin A1a + b + c levels measured by a commercial column in 35 non-diabetic controls and in 56 diabetics showed good correlation (R = 0.91) with hemoglobin A1a + b + c levels determined by the homemade column. The commercial column is valid for the measurement of the combined glycosylated hemoglobin A1a + b + c fraction and may be used in the routine clinical laboratory to assess diabetic control.     

A Simple Microchromatographic Column for Determination of Hemoglobins A1a+b and A1c

A simple microchromatographic homemade column was devised for the measurement of glycosylated minor hemoglobin fractions. the mean and one standard deviation of hemoglobins A_1a+b,A_1c and A_1a+b+c determined by the homemade column in 150 non-diabetic controls and 56 juvenile onset insulin-dependent diabetics were 2.6 + 0.5%, 6.0 + 1.0%, 8.6 + 1.1%, 3.3 + 0.9%, 13.7 + 2.2% and 16.9 + 2.8% respectively. A twofold increase in hemoglobins A_1c and A_1a+b+c levels was observed in the diabetics as compared to the non-diabetic controls suggesting that the homemade column is valid for the measurement of all three glycosylated hemoglobin fractions and assessment of blood glucose control in diabetic patients. the homemade column procedure yields accurate and reproducible results, is simple to perform, inexpensive, relatively rapid and may be used in the routine clinical laboratory. Hemoglobin A_1a+b+c levels measured by a commercial column in 35 non-diabetic controls and in 56 diabetics showed good correlation (R=0.91) with hemoglobin A_1a+b+c levels determined by the homemade column. the commercial column is valid for the measurement of the combined glycosylated hemoglobin A_1a+b+c fraction and may be used in the routine clinical laboratory to assess diabetic control.     

某中学甲型H1N1流感暴发疫情调查

目的 描述洪雅县某中学甲型H1N1流感暴发疫情的流行病学特征,为学校甲型H1N1流感暴发防控提供参考.方法 应用现场流行病学方法开展调查,用RT - PCR检测病例标本,用Epidata录入数据,用Excel、Epiinfo软件进行结果分析.结果 该校共发现流感病例151例,罹患率6.31％,学生病例149例,首发病例为高一学生,高一年级罹患率最高(11.19％),住校生罹患率9.1％,走读生为2.83％.病原学检测,采集25例病例的咽拭子标本,甲型H1N1流感病毒阳性率20％.结论 此次疫情是为甲型H1N1流感暴发疫情,住校学生罹患率较高,住宿条件较差和学生接触密切是此次疫情的危险因素.