Effects of Cangfudaotan Tang on Expression of Organic Anion Transporting Polypeptide (oatp2b1) in Liver and Kidney Tissues of Rats with Phlegm Dampness Type Polycystic Ovary Syndrome (PCOS)

Objective: To explore the effect of Cangfudaotan Tang on phlegm dampness type of PCOS and the role of oatp2b1 in transportation and transformation of phlegm dampness. Methods: 36 SD female rats were randomly divided into three groups: blank control group, model group and Cangfudaotan Tang group, 12 cases in each one. After PCOS rat models were made, rats of Cangfudaotan Tang group were treated with Cangfudaotan Tang (1.42 g/kg/d) by intragastric administration for 14 days;blank control and model group were given with isodose saline. The expression of oatp2b1 mRNA/Protein in liver and kidney tissues was measured and the level of testosterone (T), follicle stimulating hormone(FSH), estradiol (E2), luteinizing hormone(LH), Serum total cholesterol (TG), Triacylglycerols (TC), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were detected at the same time. Results: Compared with blank control group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL, LH, FSH, T in model group were significantly increased (P < 0. 05), while the level of HDL was significantly decreased (P < 0. 05);compared with model group, the expression of oatp2b1 mRNA and the level of TC, TG, LDL in Cangfudaotan Tang group were significantly lowered (P < 0.05);the level of HDL was significantly higher;the oatp2b1 protein in kidney and liver tissues had different degrees of expression, while there was no statistical significance among the three groups. Conclusions: Oatp2b1 might be one of the material bases participating in transportation and transformation of phlegmy dampness. The mechanism of Cangfudaotan Tang treating phlegm dampness type of PCOS may be achieved by regulating the expression of oatp2b1.

Influence of organic anion transporting potypeptide(SLCO1B1 and SLCO1B3)genetic polymorphisms on mycophenolic acid in Chinese kidney transplantation patients

Objective To analyze the relationship between genetic polymorphisms of organic anion transporting polypeptide ( SLCO1B1 and SLCO1B3) and mycophenolic acid ( MPA) pharmacokinetics in Chinese kidney transplant recipients. Methods Gene mutations ( SLCO1B3 T334G,SLCO1B1 A338G) were detected in 68 recipi-

Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

SLCO1B1基因521 T>C多态性与他汀类药物对中国人群降脂疗效关系的系统评价

目的：探讨SLCO1B1基因521 T〉C多态性与他汀类药物对中国人群降脂疗效的关系。方法：计算机检索Pub Med、Web of Science、Embase、Cochrance Library、CNKI、Wan Fang Data、VIP。检索时间均从建库至2014年6月12日。采用非随机试验性研究的质量评价表进行质量评价。统计分析通过Rev Man 5.2和Stata 12.0软件实现。结果：共纳入5个研究,812名研究对象。SLCO1B1基因521 T〉C多态性与他汀降低中国人群血脂疗效相关性无统计学意义：显性遗传模型TC＋CC vs.TT（MD=-0.38,95%CI=-1.91~1.14,P=0.62）、隐性遗传模型CC vs.TT＋TC（MD=0.09,95%CI=-1.77~1.96,P=0.92）、加性遗传模型CC vs.TT（MD=-0.03,95%CI=-2.34~2.28,P=0.98）和TC vs.TT（MD=0.00,95%CI=-1.95~1.95,P=1.00）。结论：基于本文结果,尚不能认为SLCO1B1基因521 T〉C多态性与他汀对中国人群降脂疗效有关联。期待今后针对中国人群开展更大样本、高质量的研究。

Gadoxetic acid-enhanced magnetic resonance imaging in the assessment of hepatic sinusoidal obstruction syndrome in a mouse model

BACKGROUND Neoadjuvant chemotherapy can cause hepatic sinusoidal obstruction syndrome(SOS)in patients with colorectal cancer liver metastases and increases posto-perative morbidity and mortality.AIM To evaluate T1 mapping based on gadoxetic acid-enhanced magnetic resonance imaging(MRI)for diagnosis of hepatic SOS induced by monocrotaline.METHODS Twenty-four mice were divided into control(n=10)and experimental(n=14)groups.The experimental groups were injected with monocrotaline 2 or 6 days before MRI.MRI parameters were:T1 relaxation time before enhancement;T1 relaxation time 20 minutes after enhancement(T_(1post));a reduction in T1 relaxation time(△T_(1)%);and first enhancement slope percentage of the liver parenchyma(ESP).Albumin and bilirubin score was determined.Histological results served as a reference.Liver parenchyma samples from the control and experimental groups were analyzed by western blotting,and organic anion transporter polypeptide 1(OATP1)was measured.RESULTS T_(1post),△T_(1)%,and ESP of the liver parenchyma were significantly different between two groups(all P<0.001)and significantly correlated with the total histological score of hepatic SOS(r=-0.70,0.68 and 0.79;P<0.001).△T_(1)%and ESP were positively correlated with OATP1 levels(r=0.82,0.85;P<0.001),whereas T_(1post) had a negative correlation with OATP1 levels(r=-0.83;P<0.001).INTRODUCTION Hepatic sinusoidal obstruction syndrome(SOS)is also known as hepatic veno-occlusive disease of the liver[1].The main pathological feature of hepatic SOS is damage to liver terminal vessels,and the clinical symptoms of it include ascites and abdominal pain[2].It was first proposed in 1979 as an early complication of hematopoietic stem cell transplantation[3].The prevalence ranges from 5%to 60%,and hepatic SOS is a potentially severe complication and can even lead to death in severe cases[4].Recently,systemic neoadjuvant chemotherapy became widely regarded as one of the causes hepatic SOS in the patients with advanced metastatic colorectal cancer[5,6],especially those were treated with oxaliplatin[7,8].Oxaliplatin-based preoperative chemotherapy is used for patients with colorectal liver metastases as the standard regimen[8,9],because it could improve tumor resection outcome by shrinking the metastatic sites and reducing recurrence rate[10].Nevertheless,chemotherapy-induced hepatic SOS has been associated with a higher risk of postresection morbidity[11],such as intraoperative bleeding,intraoperative transfusions,and postoperative liver failure[12].Therefore,it is important to detect and diagnose of hepatic SOS timely.Currently,the gold standard is still based on liver biopsy[13],but it is an invasive procedure and has several limitations and complications,such as hemorrhage[14].A noninvasive diagnostic modality is needed for the assessment of hepatic SOS.Some noninvasive tools have been used for diagnosis of hepatic SOS.Researchers have utilized a preoperative platelet count and aspartate aminotransferase to platelet ratio index[15].In addition,some imaging methods such as shear wave ultrasonography,computed tomography,and gadoxetic acid-enhanced magnetic resonance imaging(MRI)have been promoted as useful methods for evaluation of hepatic SOS[16-18].Recent studies with monocrotaline(MCT)-treated rats were conducted to investigate diagnosis and prediction of severity of SOS.For example,intravoxel incoherent motion diffusion-weighted imaging,non-Gaussian diffusion models,and T1 rho quantification[19,20].The MCT-induced hepatic SOS animal model was reproducible,with a detailed pathological scoring criteria[21].Gadoxetic acid is a hepatocyte-specific contrast substance,which can provide parenchymal contrast in the hepato-biliary phase.It is reported that gadoxetic acid is absorbed into the liver parenchyma via organic anion transporter polypeptide 1(OATP1)on the hepatocyte membranes[22-24].Recently,several authors have described the feasibility of gadoxetic acid-enhanced MRI for the diagnosis of oxaliplatin-induced hepatic SOS[25].They mainly diagnosed hepatic SOS based on the signal intensity of the hepatobiliary specific phase.However,there were several limitations due to the inconsistency between signal intensity of the liver parenchyma and the concentration of contrast agent for evaluation of the degree of hepatic SOS[26].Therefore,we measured T1 relaxation time on parametric mapping because it is linearly related to the concentration of the contrast agent and is not affected by other factors[27].Yang et al[28]demonstrated T1 mapping on gadoxetic acid-enhanced MRI for the assessment of oxaliplatin-induced liver injury in a C57BL/6 mouse model.However,the main pathological changes in their model were hepatocyte degeneration and fibrosis.Therefore,we aimed to explore the effectiveness of T1 mapping based on gadoxetic acid-enhanced MRI for the diagnosis of hepatic SOS in a C57BL/6 mouse model,as well as a possible relation between OATP1 Levels and MRI parameters.

丹皮酚对HepG2细胞药物转运体BCRP及SLCO1B1表达及功能的影响

目的：分析丹皮酚对肝细胞株HepG2细胞药物转运体乳腺癌耐药蛋白（ breast cancer－resistance protein，BCRP）及有机阴离子转运多肽1B1（organic anion－transporting polypeptide 1Bl，SLCO1B1）表达及部分转运功能的影响。方法采用CCK8法检测丹皮酚对HepG2细胞存活率的影响，以确定适当的用药浓度；qPCR法测定丹皮酚对HepG2细胞BCRP及SLCO1B1 mRNA表达水平的影响；流式细胞术测定丹皮酚对BCRP及SLCO1B1转运特异性底物脱镁叶绿酸盐和二氯荧光素功能的影响。结果丹皮酚在2～8μg／mL浓度范围内对HepG2细胞存活率影响较小，丹皮酚浓度高于16μg／mL时，HepG2细胞存活率明显降低（P＜0．05）。与对照组相比，丹皮酚组BCRP及SLCO1B1药物转运体的mRNA水平均明显上调，对特异性底物的转运效率明显增加（P＜0．05）。结论丹皮酚能够诱导肝细胞药物转运体BCRP及SLCO1B1基因表达，从而促进其底物的跨膜转运。提示当丹皮酚与BCRP及SLCO1B1转运体所转运的药物联合应用时，可能存在药物相互作用风险。

人源有机阴离子转运多肽1B1和多药耐药相关蛋白2双转MDCKⅡ细胞株的构建及其功能验证

目的构建人源有机阴离子转运多肽1B1(human organic anion transporting polypeptide 1B1,hOATP1B1)和多药耐药相关蛋白2(multidrug resistance-associated protein2,hMRP2)双转MDCKⅡ细胞株,验证其功能,并应用其考察创新药物2,3-双加氧化酶(indoleamine 2,3-dioxygenase,IDO)抑制剂1-甲基色氨酸(1-methyl-tryptophan,1-MT)的转运特性。方法采用基因工程手段获得hOATP1B1和hMRP2表达真核载体pVITRO2-SLCO1B1-ABCC2,转染MDCKⅡ细胞,通过遗传霉素G418筛选得到稳定表达的细胞株;通过Realtime PCR、Western blot、免疫荧光共聚焦显微镜确认目的蛋白特异性;利用该双转模型考察普伐他汀(不同pH环境和不同底物浓度)和1-MT的转运。结果经电泳分析、双酶切、DNA测序鉴定表明重组质粒构建成功;通过Real-time PCR、Western blot、免疫荧光共聚焦显微镜证明经遗传霉素筛选的MDCK-OATP1B1/MRP2细胞构建成功;pH=6.5时,普伐他汀在所构建双转细胞模型上转运最佳;在0~500μmol/L的浓度范围内,普伐他汀在该模型上的转运呈现浓度依赖性。1-MT在该细胞模型上无明显转运。结论成功构建人源MDCKOATP1B1/MRP2双转细胞株,发现1-MT既不是OATP1B1蛋白也不是MRP2蛋白的底物,该细胞株可用于OATP1B1/MRP2介导的外源性物质(如药物)和内源性物质(如胆红素)的转运研究。

Characterization of organic anion transporting polypeptide 1b2 knockout rats generated by CRISPR/Cas9:a novel model for drug transport and hyperbilirubinemia disease

Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encoded by the Slcolb2 gene,is homologous to human OATP1 B1/3.Although OATP1 B1/3 is very important,few animal models can be used to study its properties.In this report,we successfully constructed the Slco1 b2 knockout(KO)rat model via using the CRISPR/Cas9 technology for the first time.The novel rat model showed the absence of OATP1 B2 protein expression,with no offtarget effects as well as compensatory regulation of other transporters.Further pharmacokinetic study of pitavastatin,a typical substrate of OATP1 B2,confirmed the OATP1 B2 function was absent.Since bilirubin and bile acids are the substrates of OATP1 B2,the contents of total bilirubin,direct bilirubin,indirect bilirubin,and total bile acids in serum are significantly higher in Slco1 b2 KO rats than the data of wild-type rats.These results are consistent with the symptoms caused by the absence of OATP1 B1/3 in Rotor syndrome.Therefore,this rat model is not only a powerful tool for the study of OATP1 B2-mediated drug transportation,but also a good disease model to study hyperbilirubinemia-related diseases.

醋柴胡多糖对拉米夫定体外抗乙型肝炎病毒的增效作用研究

目的:考察醋柴胡多糖对拉米夫定抗乙型肝炎病毒(HBV)的增效作用,并初步探讨其作用机制。方法:将不同浓度的醋柴胡多糖、拉米夫定及二者联合作用于人肝癌细胞HepG2.2.15,同时设立对照组,孵育48 h,酶联免疫吸附试验试剂盒检测细胞上清液中乙型肝炎表面抗原(HBsAg)、乙型肝炎e抗原(HBeAg)分泌量,荧光探针定量聚合酶链式反应(PCR)检测细胞HBV脱氧核糖核酸(DNA)表达量,金(正均)氏公式定量分析醋柴胡多糖的增效作用。采用高效液相色谱法测定细胞内拉米夫定含量;Western blot法测定有机阳离子转运蛋白(OCT)1、OCT2、P糖蛋白(P-gp)和多药耐药蛋白2(MRP2)的表达量。结果:与拉米夫定单用组相比,醋柴胡多糖增加拉米夫定对HBsAg分泌的抑制作用,表现为相加作用、对HBeAg作用表现为协同增强,Q值达6.55、对HBV-DNA抑制作用表现为相加。醋柴胡多糖低剂量组、醋柴胡多糖低中剂量组、醋柴胡多糖低高剂量组可显著促进拉米夫定的摄取;醋柴胡多糖高剂量联用组可显著降低P-gp的表达;醋柴胡多糖单用及联用组均可显著提高OCT1的表达。结论:醋柴胡多糖可通过增加拉米夫定的摄取发挥协同抗HBV作用,其作用机制可能P-gp、OCT1有关。

Construction and characterization of a humanized SLCO1B1 rat model with its application in evaluating the uptake of different statins

Organic anion-transporting polypeptides IB1(OATPIB1)plays a crucial role in the transport of statins.However,there are too few animal models related to OATPIB1,especially humanized animal models.In this study,the human SLCOIB1 cDNA was inserted into the second exon of the rat Slcolb2 gene using CRISPR/Cas9 technology.Pharmacokinetic characteristics of statins were conducted in wild-type(WT),humanized OATPIB1(hOATPIB1),and OATPIB2 knockout(OATPIB2 KO)rats,respec-tively.The results showed that human OATPIB1 was successfully expressed in rat liver and exhibited transport function.Furthermore,the pharmacokinetic results revealed that OATPIB1 exhibited varying uptake levels of pivastatin,rosuvastatin,and fluvastatin,leading to different levels of exposure within the body.These results were consistent with those obtained from in vitro experiments using overexpressed cell lines.In conclusion,we established a novel humanized SLCOIBI transgenic rat model to assess the role of human OATPIB1 in the uptake of different statins.The different uptake mediated by OATPIB1 may be an important reason for the different efficacy of statins.The hOATPIB1 rat is a promising model for improving the prediction of human drug transport.

Oatp1和Oct1在大鼠下颌骨来源成骨细胞中的表达

目的:通过检测大鼠下颌骨成骨细胞中Oatp1和Oct1蛋白的表达,观察其在成骨细胞中的分布,探讨Oatp1和Oct1在成骨细胞跨膜转运中的作用及意义。方法:分离培养大鼠下颌骨成骨细胞并鉴定,应用免疫细胞化学及Western-Blot的方法检测大鼠下颌骨来源成骨细胞中Oatp1和Oct1蛋白的表达。结果:组织块法可成功培养大鼠下颌骨成骨细胞,Oatp1和Oct1在成骨细胞中有广泛表达,且主要分布在胞膜和胞质中。结论:大鼠下颌骨来源的成骨细胞可广泛表达Oatp1和Oct1,为研究药物在成骨细胞中的跨膜转运提供了基础。

大鼠下颌骨来源的成骨细胞对普伐他汀的摄取

目的:应用SD大鼠下颌骨来源的成骨细胞,观察成骨细胞对普伐他汀的摄取,研究其可能的跨膜转运机制。方法:将成年大鼠成骨细胞与溶于PBS的药物共同孵育后,弃去细胞外液,收集细胞悬液,用高效液相色谱法测定细胞内药物量,用考马斯亮蓝法测定细胞蛋白总量,以细胞内药物含量与细胞蛋白的比值作为药物转运量的观察指标。同时考察时间和药物浓度对成骨细胞摄取普伐他汀的影响,以及普伐他汀对成骨细胞OATP1(Organic anion transporting polypeptide1)转运蛋白表达的影响。结果:(1)高效相色谱法可以准确测定普伐他汀的量。(2)成骨细胞可将普伐他汀转运至细胞内。(3)成骨细胞对普伐他汀的摄取随着药物浓度及给药时间的增加呈现饱和趋势。(4)普伐他汀可上调成骨细胞OATP1的表达。结论:成骨细胞有转运普伐他汀的能力,且可能以OATP1转运载体为介导的主动转运。

New insights in bilirubin metabolism and their clinical implications

Bilirubin,a major end product of heme breakdown,is an important constituent of bile,responsible for its characteristic colour.Over recent decades,our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates,mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes.Several inherited disorders characterised by impaired bilirubin conjugation(Crigler-Najjar syndrome typeⅠand typeⅡ,Gilbert syndrome)or transport(Dubin-Johnson and Rotor syndrome)result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type.Moreover,disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders.In this review,we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome.The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood,from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3.OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs,such as the intestine and kidney,and for a number of endogenous compounds,xenobiotics and drugs.Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins,sartans,methotrexate or rifampicin.The liverblood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.

Total Saponins from Dioscorea Septemloba Thunb Reduce Serum Uric Acid Levels in Rats with Hyperuricemia through OATP1A1 Up-regulation

The aim of this study is to evaluate the efficacy of total saponins of Dioscorea（TSD）, an extract of the Chinese herbal Bi Xie, on hyperuricemia and to elucidate the underlying mechanisms. The rat hyperuricemia model was established by administration of adenine. Thirty-two rats were randomly allocated into 4 groups： model group, low/high-dose TSD-treated groups, and allopurinol-treated group. Meanwhile, 8 rats were used as normal controls. Serum uric acid（UA）, blood urea nitrogen（BUN）, serum creatinine（Scr）, and organic anion transporting polypeptide 1A1（OATP1A1） levels were measured. Comparison between the model group and treatment（allopurinol and TSD） groups showed the serum UA levels were significantly decreased in treatment groups. TSD had similar effects to allopurinol. It was found that the OATP1A1 protein expression levels in treatment groups were higher than in model group and normal controls. And different from the allopurinol-treated groups, TSD-treated group had elevated OATP1A1 expression levels in the stomach, liver, small intestine and large intestine tissues. It was suggested that TSD may facilitate the excretion of UA and lower UA levels by up-regulating OATP1A1 expression.

Evaluating the regulation of transporter proteins and P-glycoprotein in rats with cholestasis and its implication for digoxin clearance

BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.

抗结核药物性肝损伤危险因素及其与SLCO1B1/ABCB1基因多态性的关联性

目的分析不同抗结核治疗方案致药物性肝损伤(DILI)情况及其与肝脏药物转运体1B1(SLCO1B1)/多药耐药性蛋白1(ABCB1)基因多态性的关联性。方法回顾性分析2018年10月-2020年4月医院收治的621例接受抗结核治疗的肺结核患者临床资料,按是否发生DILI分为DILI组78例、非DILI组543例,测定两组抗结核治疗前后肝功能[丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、谷氨酰转肽酶(GGT)、碱性磷酸酶(ALP)、总胆红素(TBIL)]变化,分析两组的临床资料并筛选DILI的危险因素,以聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测SLCO1B1基因rs4149014位点及ABCB1基因rs2231142位点多态性,分析SLCO1B1/ABCB1基因多态性与DILI的相关性。结果78例出现DILI,发生率为12.56%(78/621),复治肺结核、耐多药肺结核患者DILI发生率高于初治肺结核患者,耐多药肺结核患者DILI发生率高于复治肺结核患者(P<0.05);78例DILI组抗结核治疗后ALT、AST、GGT、ALP、TBIL峰值均高于抗结核治疗前及非DILI组(P<0.01),非DILI组治疗前后ALT、AST、GGT、ALP、TBIL差异无统计学意义;年龄、肝病史、饮酒史、抗结核治疗时机为发生DILI的独立危险因素(P<0.05);DILI组SLCO1B1基因rs4149014位点的基因型TT、GT、等位基因T频率高于非DILI组,DILI组ABCB1基因rs2231142位点的基因型AC、等位基因A频率高于非DILI组(P<0.05);Logistic回归分析显示,SLCO1B1基因rs4149014位点的基因型GT、等位基因T及ABCB1基因rs2231142位点的基因型AC与肺结核患者DILI具有相关性(P<0.05)。结论抗结核药物治疗肺结核导致的DILI发生率高,SLCO1B1/ABCB1基因多态性也与DILI有密切关系,可能是DILI的易感基因。

Effect of polypeptide 2B1 on condition of dampness pattern in rats in terms of Traditional Chinese Medicine

OBJECTIVE： This study investigated how polypeptide 2B1 is involved in regulating and governing dampness in rat models with dampness pattern defined in terms of Traditional Chinese Medicine. METHODS： We randomly divided 48 SPF 10-week-old male Sprague-Dawley （SD） rats into a normal group, normal ＋ Aristolochic acid I （AA-I） for 5 min group, normal ＋ AA-I for 60 min group, dampness pattern group （DS-Group）, dampness pattern ＋ AA-I for 5 rain tern ＋ AA-I for 60 min group, and dampness pat- group. Groups were then treated accordingly. We took out the lung, stom- ach, liver, spleen, kidney, large intestine, and small intestine tissues to detect gene and protein expres- sion of organic anion transporter polypeptide 2B1 （OATP2B1）. RESULTS= Gene expression of OATP2B1 in spleen, kidney, and small intestine of rats with dampness pattern was lower than that in normal rats （P〈0.05）. The gene expressions of OATP2B1 in liver, stomach, large intestine, and small intestine were lower than that in control rats at different time points after being stimulated by AA-I （P〈0.05）. CONCLUSION There is coordination among multiple viscera in handling the condition of dampness, and the mechanism underlying the action may rely on regulating the expression of OATP2B1.

有机阴离子转运肽oatp2b1在痰湿证大鼠组织中表达及意义

目的:通过观察痰湿状态下大鼠有机阴离子转运肽oatp2b1基因和蛋白表达来探讨oatp2b1在痰湿转运中的作用。方法:24只大鼠随机分为2组,正常组、模型组各12只。模型组采用高脂饮食造模3个月,每只大鼠取脾、肝、肾组织各1块。采用实时荧光定量PCR、Western Blot方法及免疫组化法检测组织中oatp2b1的基因表达、蛋白表达情况。结果:模型组肝、肾组织中oatp2b1 mRNA表达量高于正常组(P<0.01,P<0.05);而模型组脾组织中oatp2b1 mRNA表达量低于正常组(P<0.01)。两组oatp2b1蛋白在脾、肝、肾组织有不同程度表达,但差异无统计学意义。模型组中脾脏的巨噬细胞、肝脏的枯否氏细胞及肾小管上皮细胞均有oatp2b1蛋白分布,较正常组表达增强。结论:痰湿伤脾,脾失运化状态下,肝、肾在痰湿转运中发挥重要作用,oatp2b1可能是机体参与痰湿运化的物质基础之一。

甲状腺激素转运体的研究进展

甲状腺激素在细胞和组织的生长、发育、代谢中发挥了重要的作用.长期以来一直认为亲脂性的甲状腺激素可以直接扩散到细胞内,但越来越多的证据显示甲状腺激素进出细胞是由细胞膜上的转运体介导的,这些甲状腺激素转运体的出现将有助于探讨甲状腺激素的组织特异性调节机制.

多个癫痫相关基因多态性与拉莫三嗪治疗儿童癫痫血药浓度的相关性

目的拉莫三嗪是儿童癫痫的一线治疗药物,其血药浓度与临床疗效个体差异较大,药效学和药动学通路多个相关基因突变可能是个体差异大的原因,本研究探讨代谢酶UGT1A4,转运体OCT1与ABCB1,受体SCN1A基因多态性与拉莫三嗪治疗儿童癫痫稳态血药浓度的相关性。方法于2018年1月—2019年6月纳入杭州市第一人民医院单用拉莫三嗪治疗的49例癫痫儿童,采集拉莫三嗪治疗达稳定剂量超过7 d以上患儿的稳态谷浓度血浆,使用高效液相色谱法测定拉莫三嗪血药浓度,直接测序法分析代谢酶UGT1A4(rs2011425)、转运体OCT1(rs628031)、ABCB1(rs1045642与rs1128503)和受体SCN1A(rs3812718)的基因分型。采用Kruskal-Wallis H检验或Mann-Whitney U检验探究不同基因分型与拉莫三嗪(LTG)血药浓度及标准化血药浓度相关性[即LTG血浆药物浓度除以每日每千克体重的服药剂量,CDR,(μg/mL)/(mg/kg)],P<0.05为具有显著相关性。结果转运体OCT1 rs628031与拉莫三嗪CDR具有显著相关性,其中AA+AG携带者CDR值显著高于GG携带者,分别是1.27(1.03,2.20)和0.69(0.57,1.02),P=0.002;但其他基因型与CDR值无显著相关性。结论OCT1 rs628031基因突变可能是拉莫三嗪血药浓度和临床疗效个体差异大的重要因素。