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多氯联苯(PCB)和二恶英中的羟基衍化物能够结合到转甲状腺素(TTR)而与甲状腺素竞争。在妊娠期头三个月和六个月,如果孕母患甲状腺功能低下,常可使后来胎脑发育有不可逆的损害。多氯联苯和二恶英由孕母血循环传至胎儿会影响转甲状腺素,进而妨碍甲状腺凝素传给胎儿。因此,造成胎儿的甲低和认知发育迟缓。1965年在日本,1975年在台湾在提炼米油的过程中的冷冻剂中出多氯联苯,食用污染油毒性一肝炎,孕妇生下的孩子智离偏低。美国报告吃了米希根湖里的鱼,生下孩子认知功能低,荷兰、斯洛伐克、比利时也有报告。 相似文献
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锰对大鼠肝混合功能氧化酶的影响 总被引:4,自引:0,他引:4
锰对大鼠肝混合功能氧化酶的影响韦小敏,胡万达,纪淑琴,姜岳明许多重金属对机体的损害作用早期常表现在生化代谢方面的改变,尤其是一些与金属元素相关酶的活性改变。很多实验表明,铅、汞、镉等金属过量摄入均可抑制实验动物肝混合功能氧化酶(MFO)的活性,锰在急... 相似文献
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细胞色素P450氧化酶的基因多态性是导致药物代谢个体差异的重要原因。已经发现的数百万个基因突变中,仅有少数影响蛋白功能,极少部分具有临床意义。本文综述了功能相关的细胞色素P450氧化酶的基因多态性的研究进展,以期为个体化药物治疗提供参考。 相似文献
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细胞色素P450(CYP450)是肝微粒体混合功能氧化酶中最重要的一族,据献报道它可被许多化合物诱导或抑制,但有关中草药对CYP450影响作用的研究尚不多见报导。本课题的目的是要筛选几种有潜力的、临床上经常应用的、毒副作用小的中药,采用体内实验和体外实验两种手段来评价中药对细胞色素P450的影响。 相似文献
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Han Chang Louis W Chang Ya-Hsin Cheng Wen-Tin Tsai Ming-Xian Tsai Pinpin Lin 《Toxicological sciences》2006,89(1):205-213
Both benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are potent ligands of aryl hydrocarbon receptors (AhR). Although animal studies indicate that both compounds induce pathological changes in the peripheral lung, the specific cell type involved remains unclear. Clara cells, expressing Clara cell specific protein (CCSP) and abundant in cytochrome P450, are nonciliated bronchiolar epithelial cells in the peripheral lung. Here we explore the hypothesis that CCSP-positive Clara cells are highly responsive to AhR ligands and are the primary cell type involved in BaP- and TCDD-induced toxicities. The responsiveness to AhR ligands was evaluated by measuring the respective mRNA and protein levels of cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) using real-time RT-PCR and immunocytochemistry assays. Two in vitro models were used: primary cultures of human small airway epithelial (SAE) cells and rat lung slice cultures. In the presence of calcium, human SAE cells differentiated into CCSP-positive cells. BaP- and TCDD-induced mRNA and protein levels of CYP1A1 and CYP1B1 levels were significantly elevated in CCSP-positive cell cultures. Similarly, AhR mRNA and protein levels were increased in CCSP-positive cell cultures, as determined by real-time RT-PCR and Western blot analysis. When rat lung slice cultures were treated with BaP or TCDD for 24 h, CYP1A1 and CYP1B1 proteins were strongly induced in Clara cells. These results indicate that, in the peripheral lung of both rats and humans, CCSP-positive cells (Clara cells) may be more sensitive to AhR ligands than other cell types. 相似文献
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人体存在多种类型的药物转运体,对于药物的吸收、分布和排泄起重要作用。参与药物跨膜转运的转运体功能受影响,将可能导致诸多临床药物的疗效、毒副作用甚至药物相互作用的发生。在各种影响因素中,遗传多态性所起的作用最为重要,可导致基因表达和蛋白功能发生改变。目前,阐明转运体基因的多态性以及基因型与表型之间的相互关系已成为应用遗传信息指导临床个体化用药的必要步骤。本文就肝脏有机阴离子转运多肽1B1(OATP1B1[OATP-C],编码基因SLCO1B1)基因多态性对药代动力学和药效动力学的影响及其临床意义等方面的进展作一综述。 相似文献
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M. Miksits A. Maier-Salamon S. Aust T. Thalhammer G. Reznicek O. Kunert 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(12):1101-1119
Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3′-phosphoadenosine-5′-phosphosulfate, three metabolites (M1–3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4′-O-sulfate, and trans-resveratrol-3-O-4′-O-disulfate, respectively. The kinetics of M1 formation in human liver cytosol exhibited an pattern of substrate inhibition with a Ki of 21.3?±?8.73?µM and a Vmax/Km of 1.63?±?0.41?µL?min?1mg?1 protein. Formation of M2 and M3 showed sigmoidal kinetics with about 56-fold higher Vmax/Km values for M3 than for M2 (2.23?±?0.14 and 0.04?±?0.01?µL?min?1?mg?1). Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. In conclusion, the results elucidate the enzymatic pathways of resveratrol in human liver, which must be considered in humans following oral uptake of dietary resveratrol. 相似文献
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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。 相似文献
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Effect of TCDD exposure on CYP1A1 and CYP1B1 expression in explant cultures of human endometrium. 总被引:8,自引:0,他引:8
D P Bofinger L Feng L H Chi J Love F D Stephen T R Sutter K G Osteen T G Costich R E Batt S T Koury J R Olson 《Toxicological sciences》2001,62(2):299-314
Endometriosis is a debilitating disease estimated to affect 10% of reproductive-age women and characterized by the growth of endometrial tissue outside of the uterus. The present study characterizes a human endometrial explant culture model for studying the direct effects of TCDD exposure by assessing the expression of CYP1A1 and CYP1B1 mRNA (Northern blotting), protein (Western blotting), and activity (7-ethoxyresorufin-O-deethylase; EROD) in explants cultured with and without TCDD. Explants were obtained at laparoscopy or laparotomy from women undergoing surgery for tubal ligation, endometriosis, or pelvic pain unrelated to endometriosis. The explants were cultured with 10 nM estradiol (E(2)) or 1 nM E(2) plus 500 nM progesterone (P(4)) with or without TCDD (first 24 h). The expression of CYP1A1 and CYP1B1 mRNA was greatest with 10 nM TCDD and increased up to 72 h after initial exposure. EROD activity increased up to 120 h. Explants from a secretory phase biopsy became reorganized in culture and formed a new epithelial membrane, while maintaining basic endometrial morphology and viability for up to 120 h. At 24 h, TCDD significantly increased CYP1A1 and CYP1B1 mRNA, and at 72 h, TCDD significantly increased EROD activity and CYP1B1 protein compared to explants cultured without TCDD for similar times. CYP1B1 protein also exhibited substantial constitutive expression that was similar in uncultured biopsies, where CYP1B1 protein was immunolocalized in the cytoplasm of epithelial glands, with only occasional patches of protein in the surface epithelial membrane. In explants cultured with and without TCDD exposure, CYP1B1 protein was localized in the cytoplasm of the new surface epithelial membrane and glands closest to the surface. CYP1A1 protein was not detected in uncultured biopsies or explants. Both younger age (age 30 and under) and proliferative phase were associated with higher TCDD-induced EROD activity in specimens treated with E(2):P(4). No significant endometriosis-related differences were observed for any of the biomarkers, but the detection of disease-specific change was limited by small sample size and variability in tissue-cycle phase. The human endometrial explant culture model will be useful for future studies of the effects of dioxin-like compounds on human endometrium in relationship to cycle phase and hormonal exposure. 相似文献
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陈海松 《中国医药工业杂志》2002,33(11):569-572
内皮素-1(ET-1)是一种内源性的具有强缩血管活性的肽类物质,参与多种心血管疾病的病理生理过程。ET-1经与ET-1受体结合而发挥作用,多种不同结构类型的ET-1受体拮抗剂对某些心血管疾病均有良好的疗效。本文综述了近年来在ET-1及其受体拮抗剂等方面的研究进展。 相似文献