GSTM1和GSTT1基因多态性与抗结核药物性肝损害的关系

目的 探讨汉族人群谷胱甘肽S转移酶M1(GSTMl)和T1(GSTT1)基因多态性与抗结核药物性肝损害(ATDLI)易感性的关系.方法 回顾性分析抗结核治疗后发生肝损害的结核病患者228例(病例组)及未发生肝损害的结核病患者300例(对照组),应用多重PCR技术检测其GSTM1和GSTT1基因多态性.结果 病例组与对照组GSTM1基因缺失型频率分别为58.3％和50.7％,差异无统计学意义(OR=1.363,95％CI=0.963～1.929); GSTT1基因缺失型频率分别为45.2％和49.3％,差异也无统计学意义.联合分析也未发现两种基因在抗结核药物性肝损害发生中具有协同作用.结论 汉族人群GSTM1和GSTT1基因多态性与抗结核药物性肝损害的发生无关.     

蒙古族与汉族人群GSTM3及CYP1A1基因多态性的研究

目的研究内蒙古地区蒙、汉族人群GSTM3和CYP1A1 Exon7基因多态性。方法采用聚合酶链式反应-限制性片断长度多态性（PCR-RFLP）和等位基因特异性扩增（ASA）技术分析内蒙古地区412例健康蒙古族人和436例健康汉族人的GSTM3及CYP1A1 Exon7基因多态性及基因型分布频率。结果内蒙古地区蒙、汉族人群GSTM3基因型之间的分布频率具有显著性差异（P〈0.05）,CYP1A1 Exon7基因型分布频率无显著性差异（P〉0.05）。结论 GSTM3基因型频率在内蒙古地区健康蒙、汉族人群中的分布具有显著差异,而CYP1A1 Exon7基因型分布频率无显著性差异。     

GSTT1、GSTM1基因多态性与大剂量甲氨蝶呤血药浓度及消化道黏膜损伤的关系研究

目的研究谷胱甘肽硫转移酶（Glutathione S-transferases,GSTs）家族中GSTT1、GSTM1基因多态性与急性淋巴细胞白血病患儿甲氨蝶呤（Methotrexate,MTX）血药浓度及消化道黏膜损伤的关系。方法筛选急性淋巴细胞白血病患儿98例,采用多重PCR技术分析GSTT1、GSTM1基因型,运用荧光偏振免疫分析法（FPIA）测定MTX血药浓度,同时观察患儿消化道黏膜损伤情况。结果大剂量甲氨蝶呤（3-5 g·m^-2）致消化道黏膜损伤的发生率为62.24%。相对于GSTT1基因非缺失型患儿,GSTT1基因缺失型患儿MTX 44 h血药浓度较高（P=0.003 9）。GSTM1基因型与甲氨蝶呤44 h血药浓度无明显相关。GSTT1、GSTM1两基因型均与甲氨蝶呤导致的消化道黏膜损伤无明显相关。结论 GSTT1、GSTM1基因多态性可能与MTX消化道黏膜损伤无关,尚不能作为预测HDMTX消化道黏膜损伤的遗传学标记。     

GSTT1基因、GSTM1基因多态性与乳腺癌关系的对照研究

目的：探讨女性乳腺癌人群中GSTT1基因、GSTM1基因多态性在乳腺癌发生发展中的作用。为筛选易感人群、早期诊断及有效地预防和治疗措施的建立提供参考依据。方法：采用聚合酶链反应（PCR）、限制性片段长度多态性（RFLP）及琼脂糖凝胶电泳法对105例正常人和100例乳腺癌患者GSTT1基因、GSTM1基因的多态性分布进行检测，Logistic回归等方法估计基因、基因与乳腺癌相关危险因素的交互作用对乳腺癌发病的危险度。结果：GSTT1、GSTM1基因和乳腺癌的危险性呈负相关，OR（95％CI）分别为0．322（0．175～0．593）和0．340（0．188～0．615）；GSTT1基因与GSTM1基因的交互作用和乳腺癌的发病有统计学关联，GSTM1基因和GSTT1基因同时缺失的人群OR（95％CI）为12．338（3．621～22．042）；GSIT1基因及GSTM1基因与多个乳腺癌相关危险因素存在交互作用。结论：GSIT1、GSTM1基因的缺失是乳腺癌发病的危险因素；特定的环境暴露背景下，基因在与环境危险因素的相互作用促进乳腺癌的发生。     

GSTT1基因、GSTM1基因多态性与乳腺癌关系的对照研究

目的：探讨女性乳腺癌人群中GSTT1基因、GSTM1基因多态性在乳腺癌发生发展中的作用。为筛选易感人群、早期诊断及有效地预防和治疗措施的建立提供参考依据。方法：采用聚合酶链反应（PCR）、限制性片段长度多态性（RFLP）及琼脂糖凝胶电泳法对105例正常人和100例乳腺癌患者GSTT1基因、GSTM1基因的多态性分布进行检测，Logistic回归等方法估计基因、基因与乳腺癌相关危险因素的交互作用对乳腺癌发病的危险度。结果：GSTT1、GSTM1基因和乳腺癌的危险性呈负相关，OR（95％CI）分别为0．322（0．175～0．593）和0．340（0．188～0．615）；GSTT1基因与GSTM1基因的交互作用和乳腺癌的发病有统计学关联，GSTM1基因和GSTT1基因同时缺失的人群OR（95％CI）为12．338（3．621～22．042）；GSIT1基因及GSTM1基因与多个乳腺癌相关危险因素存在交互作用。结论：GSIT1、GSTM1基因的缺失是乳腺癌发病的危险因素；特定的环境暴露背景下，基因在与环境危险因素的相互作用促进乳腺癌的发生。     

中国健康汉族和维吾尔族人谷胱甘肽硫转移酶的基因多态性

目的 比较中国健康汉族人和维吾尔族人GSTM1、GSTT1和GSTP1基因多态性分布。方法 用多重PCR分析GSTM1和GSTT1基因多态性，PCR—RFLP检测GSTP15号外显子105位密码子基因多态性。结果 汉族人与维吾尔族人的GSTM1纯合缺失频率接近。分别为56.1％和53.2％。而汉族人的GSTT1纯合缺失频率（50．0％）较维吾尔族人（26．6％）高。汉族人GSTP1 105I／I、I／V和V／V基因型频率分别为60．7％，35．2％和4．1％；维吾尔族人分别为51．3％，40．2％and 8．4％。结论 维吾尔族人与汉族人，除GSTM1外，GSTT1与GSTP1突变基因型频率存在明显种族差异。     

抗结核药物性肝损害与CYP2E1和GSTM1基因多态性的相关性研究

目的:分析抗结核药物性肝损害(ADIH)与细胞色素P450酶(CYP)2E1和谷胱甘肽-S-转移酶(GST)M1基因多态性的相关性,并探讨其易感因素。方法:选择我院2011年10月-2015年6月收治的我国南方汉族肺结核住院患者91例,根据治疗过程中是否出现ADIH将其分为ADIH组(34例)和无ADIH组(57例);抽取患者外周静脉血,分别采用聚合酶链式反应(PCR)和多重PCR法检测其CYP2E1和GSTM1基因多态性,采用Logistic回归分析考察ADIH的易感因素。结果:所有患者CYP2E1基因型均为c2/c2型(100%);GSTM1基因型分布符合Hardy-Weinberg平衡(P>0.05)。ADIH组GSTM1(+/-)基因型患者有9例(26.5%),GSTM1(-/-)基因型患者有25例(73.5%),差异有统计学意义(P<0.05);无ADIH组GSTM1(+/-)基因型患者有17例(29.8%),GSTM1(-/-)基因型患者有40例(70.2%),差异有统计学意义(P<0.05);但GSTM1(+/-)和(-/-)基因型在两组患者中的分布差异均无统计学意义(P>0.05)。Logistic回归分析结果显示,患者性别、年龄、体质量指数和GSTM1基因型与ADIH均无相关性(P>0.05)。结论:患者性别、年龄、体质量指数和GSTM1基因型可能与ADIH无关。由于仅检出1种CYP2E1基因型,尚无法判断其多态性与ADIH的相关性。     

GSTM1、GSTT1基因多态与胃腺癌及幽门螺杆菌感染的关联

为探讨 GSTM1、GSTT1基因多态与胃腺癌 (GAC)临床特征及其与幽门螺杆菌 (Hp)感染的相关性 ,应用多重聚合酶链反应 (PCR)技术 ,检测了 GSTM1、GSTT1基因多态性、1 4C尿素呼气试验和外周血 ELISA法检测 Hp感染情况。结果显示 ,GSTM1空白基因型与 GAC易感性有关 ,肿瘤多处于早期 ;GSTT1空白基因型与肠型 GAC易感性有关 ,与肿瘤有临床分期无关     

GSTM1、GSTT1及GSTP1(rs1695)基因多态性与乳腺癌蒽环和（或）紫杉类药物化疗血液毒性关系的研究

【摘要】目的 研究乳腺癌外周血中谷胱甘肽转硫酶（GST）M1、GSTT1和GSTP1（rs1695）基因多态性与乳腺癌患者采用蒽环类和（或）紫杉类药物化疗发生血液毒性的关系。方法 应用多重PCR技术（M-PCR）和高分辨熔解曲线技术（HRM）检测3个基因在252例女性乳腺癌患者外周血中的基因多态性。结果 采用紫杉类、蒽环联合紫杉类药物化疗,携带GSTP1(rs1695)AG/GG的患者是发生Ⅲ~Ⅳ度中性粒细胞减低的危险因素(OR=6.111, 95%CI1.526~24.469, P＜0.05和OR=9.257, 95%CI2.903~29.522, P<0.01),而GSTM1(+)与GSTM1(-)、GSTT1(+)与GSTT1(-)患者Ⅲ~Ⅳ度血液毒性的发生率差异均无统计学意义;采用蒽环类药物化疗,GSTM1(+)和GSTM1(-)、GSTT1(+)和GSTT1(-)、GSTP1AA和GSTP1AG/GG患者Ⅲ~Ⅳ度血液毒性发生率差异均无统计学意义(P>0.05)。结论 GSTP1(rs1695)基因多态性可作为预测乳腺癌患者采用紫杉类药物化疗发生中性粒细胞毒性的标志。     

GSTP1、GSTM1基因多态性与顺铂导致骨髓抑制的相关性研究

目的考察顺铂致骨髓抑制与谷胱甘肽硫转移酶P1(GSTP1)和谷胱甘肽硫转移酶M1(GSTM1)基因多态性的关系。方法用病例对照研究的方法考察以顺铂为主要化疗方案的100例癌症初治肿瘤化疗患者基因多态性与骨髓移植的相关性,白细胞计数和血小板的数量为指标判断是否发生了骨髓抑制以及骨髓抑制程度。提取DNA扩增测序法判断GSTP1、GSTM1基因型。结果 GSTP1的3种基因型AA、AG、GG型均存在,并且在62例发生骨髓抑制的病例中,GSTP1 AG/GA型的患者的分布明显高于GSTP1 AA型患者。GSTM1包含缺失(-)和非缺失(+)2种基因型,100例病例中GSTM1(+)少于GSTM1(-)。Logistic分析结果表明GSTP1 AG/GG型是顺铂致骨髓抑制的独立危险因素,GSTM基因缺失虽不是顺铂致骨髓抑制的独立危险因素,但能促进GSTP1 AG/GG型的作用,导致顺铂致骨髓抑制进一步加重。结论顺铂导致的骨髓抑制程度与GSTP1基因多态性相关。     

Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors

The sphingolipid sphingosine-1-phosphate (S1P) acts on five subtypes of G-protein- coupled receptors, termed S1P(1) (formerly endothelial differentiation gene-1 [Edg-1]), S1P(2) (Edg-5), S1P(3) (Edg-3), S1P(4) (Edg-6) and S1P(5) (Edg-8), and possibly several other "orphan" receptors, such as GPR3, GPR6 and GPR12. These receptors are coupled to different intracellular second messenger systems, including adenylate cyclase, phospholipase C, phosphatidylinositol 3-kinase/protein kinase Akt, mitogen-activated protein kinases, as well as Rho- and Ras-dependent pathways. Consistently with this receptor multiplicity and pleiotropic signaling mechanisms, S1P influences numerous cell functions. S1P(1)1, S1P(2) and S1P(3) receptors are the major S1P receptor subtypes in the cardiovascular system, where they mediate the effects of S1P released from platelets, and possibly other tissues (such as brain). Thus S1P(1) and S1P(3) receptors enhance endothelial and vascular smooth muscle cell proliferation and migration, playing a key role in developmental and pathological angiogenesis. In contrast, S1P(2) receptors inhibit migration of these cell types, probably because of their unique stimulatory effect on a GTPase-activating protein inhibiting the activity of Rac. S1P receptors can also cause relaxation and constriction of blood vessels. The former effect is mediated by pertussis toxin-sensitive receptors (possibly S1P(1)) located on the endothelium and stimulating phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase (eNOS). The vasoconstricting effect of S1P is likely to be mediated by S1P(2) and/or S1P(3) receptors, via Rho-Rho-kinase, and is more potent in coronary and cerebral blood vessels. Finally, S1P also protects endothelial cells from apoptosis through activation of phosphatidylinositol 3-kinase/Akt/eNOS via S1P(1) and S1P(3) receptors. The variety of these effects, taken together with the existence of multiple receptor subtypes, provides an abundance of therapeutic targets that currently still await the development of selective agents.     

Sulfation of iodothyronines by human sulfotransferase 1C1 (SULT1C1)*

Sulfation is an important component of human thyroid hormone metabolism. The role of the human sulfotransferase 1C1 (SULT1C1) is not known. Because SULT1C1 is present in the adult thyroid, intra-thyroidal sulfation of thyroid hormones and their metabolites might occur. We tested this hypothesis by determining the ability of recombinant human SULT1C1 to catalyze iodothyronine sulfation. Apparent K(m) values for 3,3',5-triiodothyronine (T(3)), 3, 3'-diiodothyronine (3,3'-T(2)), 3',5',3-triiodothyronine (rT(3)), and 3,3',5,5'-tetraiodothyronine (T(4)) with SULT1C1 were 28.7, 10.3, 10.2, and 59.3 microM, respectively. Thermal stability and responses to inhibitors also were tested with T(3) as the substrate. Enzyme aliquots were measured simultaneously to determine SULT1C1 substrate preferences at optimal iodothyronine concentrations. SULT1C1 activity obtained with T(3) was used as 100%, and the activities with 3,3'-T(2), rT(3), T(4), and 3,5-diiodothyronine (3, 5-T(2)) were 614, 314, 25, and 4%, respectively. We report for the first time the characterization of human SULT1C1 with T(3) and the preferences of the enzyme for various iodothyronines. The presence of SULT1C1 in the adult thyroid gland raises the possibilities that the enzyme can contribute to intraglandular thyroid hormone processing and iodide reutilization.     

Antimykobakterielle 1-Phenyl-1-alkylaminoalkane

Antimycobacterial 1-Phenyl-1-alkylaminoalkanes Synthesis and testing for antimycobacterial properties (M. tuberculosis H 37 Ra, Middlebrook-7H9-broth) of 1-phenyl-1-alkylaminoalkanes, which differ from antimycobacterial N-alkylbenzylamines by an additional alkyl chain in α-position, is described. By variation of both alkyl chains and introduction of one or two Cl-substituents in the aromatic ring the activity increases up to an optimum within the homologous series. Overstepping optimal lipophilicity or ramification of the alkyl chains decrease activity. Compounds 19, 20, 33-35, 51-53, 61-63, 65-67, 70-73, 96 and 102 - 104 inhibit the growth of M. tuberculosis in concentrations of 2 to 4 μg/ml.     

Phenotype of the Cyp1a1/1a2/1b1-/- triple-knockout mouse

Crossing the Cyp1a1/1a2(-/-) double-knockout mouse with the Cyp1b1(-/-) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(-/-) triple-knockout mouse. In this triple-knockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(-/-) produced the same degree of marked immunosuppression as seen in the Cyp1a1(-/-) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(-/-) mice showed the same "rescued" response as that seen in the Cyp1a1/1b1(-/-) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up- and 62 genes down-regulated (P-value < or = 0.00086). Gene Ontology "classes of genes" most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect down-regulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and activities.     

间质作用因子1通过正调控窖蛋白1抑制FBJ-S1-H的迁移性

目的证明间质作用因子(stromal interaction molecule1,Stim1)在FBJ诱导的小鼠骨肉瘤细胞中的抑癌作用。方法在Stim1高表达的FBJ-S1-H细胞采用Stim1以siRNA干扰技术得到Stim1沉默的几株S1-H单克隆细胞株,通过细胞行为学方法和RT-PCR技术对其mRNA进行研究,通过明胶酶谱法对细胞基质金属酶活性进行研究。结果通过细胞行为学方法证明,Stim1的沉默提高了细胞的迁移性,通过对mRNA表达的研究发现,Stim1沉默引起了多种基因表达的变化,其中包括基质金属酶9(matrix mexalloprotelnase 9,MMP-9)的升高,窖蛋白(caveolinl,Cav1),甾醇调控因子Srebf1的降低等,提高单克隆细胞中的Cav1含量可以使细胞迁移性降低。结论实验结果证明在FBJ-S1-H细胞中,Stim1能够抑制细胞的移动性,沉默Stim1的表达能够提高细胞的迁移性。     

Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes

Our previous study has shown that propofol, a probe substrate for human UDP-glucuronosyltransferase (UGT) 1A9, activated the glucuronidation of 4-methylumbelliferone (4-MU) by recombinant UGT1A1 in a concentration-dependent manner. In the present study, we investigated the mechanism of activation, and whether the stimulatory effect occurs when another substrate is used with human liver microsomes. The glucuronidation of 4-MU followed Michaelis-Menten kinetics with a K(m) value of 101 microM in the absence of propofol. In the presence of 200 microM propofol, a concentration that causes heterotopic activation of 4-MU glucuronidation (4-MUG), the V(max) value increased to 1.5-fold, while the K(m) value decreased to 0.53-fold. In order to assess whether propofol activates UGT1A1 activity for a substrate other than 4-MU, the effect of propofol on oestradiol 3beta-glucuronidation by recombinant UGT1A1 and in human liver microsomes was evaluated. In contrast to 4-MUG activity, propofol inhibited UGT1A1-catalysed oestradiol 3beta-glucuronidation in recombinant UGT1A1 as well as in human liver microsomes with IC(50) values of 59 and 228 microM, respectively. In addition, a known UGT1A1 modulator, 17alpha-ethynyloestradiol, stimulated oestradiol 3beta-glucuronidation slightly at a concentration of 5 microM, while it inhibited 4-MUG in recombinant UGT1A1 at all concentrations tested (5-100 microM). These findings indicate that the modulation of UGT1A1 by propofol is substrate-dependent, and thus care should be taken when extrapolating the stimulatory effects of drugs for one glucuronidation substrate.