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 p...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.展开更多
ATP-binding cassette transporter C2(ABCC2)is known to be a receptor for Bacillus thuringiensis(Bt)toxins in several lepidopteran insects.Mutations in the ABCC2 gene have been genetically linked to field-evolved resist...ATP-binding cassette transporter C2(ABCC2)is known to be a receptor for Bacillus thuringiensis(Bt)toxins in several lepidopteran insects.Mutations in the ABCC2 gene have been genetically linked to field-evolved resistance to the Cry1 F toxin from Bt in Spodoptera frugiperda.Here we generated a SfABCC2 knockout strain of S.frugiperda using the CRISPR/Cas9 system to provide further functional evidence of the role of this gene in susceptibility and resistance to Cry1 F.Results from bioassays showed that the SfABCC2 knockout S.frugiperda strain displayed 118-fold resistance to Cry1 F compared with the parental DH19 strain,but no resistance to Vip3 A toxin from Bt.These results provide the first reverse genetic evidence for SfABCC2 as a functional receptor for Cry1 F.展开更多
Gilbert syndrome （GS, MIM #143500） is characterized by fluctuating mild, unconjugated hyperbilirubinemia 〈85 μmol/L and is caused by mutations in the bilirubin uridine diphosphate （UDP）-glucuronosyltransferase g...Gilbert syndrome （GS, MIM #143500） is characterized by fluctuating mild, unconjugated hyperbilirubinemia 〈85 μmol/L and is caused by mutations in the bilirubin uridine diphosphate （UDP）-glucuronosyltransferase gene （ UGT1A 1 ）,Dubin-Johnson syndrome （DJS, M I M #237500） is characterized by fluctuating mild, predominantly conjugated hyperbilirubinemia and is caused by mutations in the ATP-binding cassette subfamily C member 2 gene （ABCC2）.展开更多
The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic pre...The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.展开更多
Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress.Dubin-Johnson syndrome is a rare,autosomal recessive,inherited disorder characteriz...Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress.Dubin-Johnson syndrome is a rare,autosomal recessive,inherited disorder characterized by biphasic,predominantly conjugatedhyperbilirubinemia with no progression to end-stage liver disease.The molecular basis in Dubin-Johnson syndrome is absence or deficiency of human canalicular multispecific organic anion transporter MRP2/cMOAT caused by homozygous or compound heterozygous mutation(s) in ABCC2 located on chromosome 10q24.Clinical onset of the syndrome is most often seen in the late teens or early adulthood.In this report,we describe a case of previously unrecognized Dubin-Johnson syndrome caused by two novel pathogenic mutations (c.2360_2366delCCCTGTC and c.3258+1G>A),coinciding with cholestatic liver disease in an 82-year-old male patient.The patient,suffering from advanced atherosclerosis with serious involvement of coronary arteries,developed colorectal cancer with nodal metastases.The subsequent findings do not support the protective role of Dubin-Johnson type hyperbilirubinemia.展开更多
Background:Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer(NSCLC);it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this tr...Background:Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer(NSCLC);it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment.Four important transporter genes are expressed in the kidney,including organic cation transporter 2(OCT2),multidrug and toxin extrusion 1(MATEl),ATP-binding cassette subfamily B member 1 {ABCB1),and ATP-binding cassette subfamily C member 2(ABCC2),and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs.This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinumbased chemotherapy response and toxicity in NSCLC patients.Methods:A total of 403 Chinese NSCLC patients were recruited for this study.All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy.The tumor response and toxicity were evaluated after two cycles of treatment,and the patients' genomic DNA was extracted.Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response.Results:OCT2 rs316019 was associated with hepatotoxicity(P = 0.026) and hematological toxicity(P = 0.039),and MATEl rs2289669 was associated with hematological toxicity induced by platinum(P = 0.016).In addition,ABCC2rs717620 was significantly associated with the platinum-based chemotherapy response(P = 0.031).ABCB1 polymorphisms were associated with neither response nor toxicity.Conclusion:OCT2 rs316019,MATEl rs2289669,and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients.Trial registration Chinese Clinical Trial Registry展开更多
BACKGROUND Hereditary spherocytosis(HS)is a hereditary disease of hemolytic anemia that occurs due to the erythrocyte membrane defects.Dubin–Johnson syndrome(DJS),which commonly results in jaundice,is a benign heredi...BACKGROUND Hereditary spherocytosis(HS)is a hereditary disease of hemolytic anemia that occurs due to the erythrocyte membrane defects.Dubin–Johnson syndrome(DJS),which commonly results in jaundice,is a benign hereditary disorder of bilirubin clearance that occurs only rarely.The co-occurrence of HS and DJS is extremely rare.We recently diagnosed and treated a case of co-occurring HS and DJS.CASE SUMMARY A 21-year-old female patient presented to our department because of severe jaundice,severe splenomegaly,and mild anemia since birth.We eventually confirmed the diagnosis of co-occurring DJS and HS by next generation sequencing(NGS).The treatment of ursodeoxycholic acid in combination with phenobarbital successfully increased hemoglobin and reduced total bilirubin and direct bilirubin.CONCLUSION The routine application of NGS can efficiently render a definite diagnosis when inherited disorders are suspected.展开更多
BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiop...BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiopathic jaundice as the main clinical manifestation.Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS;however,the causative ABCC2 point mutation in Chinese patients remains unknown.Research on ABCC2 mutations in Chinese DJS patients is extremely rare,and the diagnosis of DJS remains limited.The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS.Here,we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient.This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses.ABCC2 mutations were identified by next-generation sequencing(NGS).The patient showed intermittent jaundice and conjugated hyperbilirubinemia.Histopathological examinations were consistent with the typical phenotype of DJS.Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant,namely c.2443C>T(p.Arg815*),which has not been reported previously in the domestic or foreign literature.CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS,especially in patients with atypical presentations.Currently,NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.展开更多
Aim:This study investigated the ATP binding cassette(ABC)transporter(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)expression in high grade serous ovarian cancer(HGSOC)tissues,cell lines and primary cells to determine their poten...Aim:This study investigated the ATP binding cassette(ABC)transporter(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)expression in high grade serous ovarian cancer(HGSOC)tissues,cell lines and primary cells to determine their potential relationship with acquired chemotherapy resistance and patient outcome.Methods:ABC transporter mRNA and protein expression(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)was assessed in publicly available datasets and in a tissue microarray(TMA)cohort of HGSOC at diagnosis,respectively.ABC transporter mRNA expression was also assessed in chemosensitive ovarian cancer cell lines(OVCAR-5 and CaOV3)versus matching cell lines with acquired carboplatin resistance and in primary HGSOC cells from patients with chemosensitive disease at diagnosis(n=10)as well as patients with acquired chemotherapy resistance at relapse(n=6).The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and-resistant cell lines were also investigated.Results:High ABCA1 mRNA and protein expression was found to be significantly associated with poor patient outcome.ABCA1 mRNA and protein levels were significantly increased in ovarian cancer cell lines(OVCAR-5 CBPR and CaOV3 CBPR)with acquired carboplatin resistance.ABCA1 mRNA was significantly increased in primary HGSOC cells obtained from patients with acquired chemotherapy resistance.Apabetalone treatment reduced ABCA1 protein expression and increased the sensitivity of both parental and carboplatin-resistant ovarian cancer cells to carboplatin.Conclusion: These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.展开更多
基金Supported by The Project(Ministry of Health,Czech Republic)for Development of Research Organization 00023001(IKEM,Prague,Czech Republic),Institutional support
文摘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.
基金supported by the Key Project for Breeding Genetic Modified Organisms of China(2016ZX08012004003)。
文摘ATP-binding cassette transporter C2(ABCC2)is known to be a receptor for Bacillus thuringiensis(Bt)toxins in several lepidopteran insects.Mutations in the ABCC2 gene have been genetically linked to field-evolved resistance to the Cry1 F toxin from Bt in Spodoptera frugiperda.Here we generated a SfABCC2 knockout strain of S.frugiperda using the CRISPR/Cas9 system to provide further functional evidence of the role of this gene in susceptibility and resistance to Cry1 F.Results from bioassays showed that the SfABCC2 knockout S.frugiperda strain displayed 118-fold resistance to Cry1 F compared with the parental DH19 strain,but no resistance to Vip3 A toxin from Bt.These results provide the first reverse genetic evidence for SfABCC2 as a functional receptor for Cry1 F.
文摘Gilbert syndrome （GS, MIM #143500） is characterized by fluctuating mild, unconjugated hyperbilirubinemia 〈85 μmol/L and is caused by mutations in the bilirubin uridine diphosphate （UDP）-glucuronosyltransferase gene （ UGT1A 1 ）,Dubin-Johnson syndrome （DJS, M I M #237500） is characterized by fluctuating mild, predominantly conjugated hyperbilirubinemia and is caused by mutations in the ATP-binding cassette subfamily C member 2 gene （ABCC2）.
文摘The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.
基金Supported by The Project(Ministry of Health,Czech Republic)for Development of Research Organization00023001(IKEM,Prague,Czech Republic)-Institutional supportthe grant SVV-2012-264502
文摘Hyperbilirubinemia has been presumed to prevent the process of atherogenesis and cancerogenesis mainly by decreasing oxidative stress.Dubin-Johnson syndrome is a rare,autosomal recessive,inherited disorder characterized by biphasic,predominantly conjugatedhyperbilirubinemia with no progression to end-stage liver disease.The molecular basis in Dubin-Johnson syndrome is absence or deficiency of human canalicular multispecific organic anion transporter MRP2/cMOAT caused by homozygous or compound heterozygous mutation(s) in ABCC2 located on chromosome 10q24.Clinical onset of the syndrome is most often seen in the late teens or early adulthood.In this report,we describe a case of previously unrecognized Dubin-Johnson syndrome caused by two novel pathogenic mutations (c.2360_2366delCCCTGTC and c.3258+1G>A),coinciding with cholestatic liver disease in an 82-year-old male patient.The patient,suffering from advanced atherosclerosis with serious involvement of coronary arteries,developed colorectal cancer with nodal metastases.The subsequent findings do not support the protective role of Dubin-Johnson type hyperbilirubinemia.
基金supported by the National High-tech R&D Program of China(863 Program)(2012AA02A517)National Natural Science Foundation of China(81173129,81202595,81373490,81273595)
文摘Background:Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer(NSCLC);it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment.Four important transporter genes are expressed in the kidney,including organic cation transporter 2(OCT2),multidrug and toxin extrusion 1(MATEl),ATP-binding cassette subfamily B member 1 {ABCB1),and ATP-binding cassette subfamily C member 2(ABCC2),and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs.This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinumbased chemotherapy response and toxicity in NSCLC patients.Methods:A total of 403 Chinese NSCLC patients were recruited for this study.All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy.The tumor response and toxicity were evaluated after two cycles of treatment,and the patients' genomic DNA was extracted.Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response.Results:OCT2 rs316019 was associated with hepatotoxicity(P = 0.026) and hematological toxicity(P = 0.039),and MATEl rs2289669 was associated with hematological toxicity induced by platinum(P = 0.016).In addition,ABCC2rs717620 was significantly associated with the platinum-based chemotherapy response(P = 0.031).ABCB1 polymorphisms were associated with neither response nor toxicity.Conclusion:OCT2 rs316019,MATEl rs2289669,and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients.Trial registration Chinese Clinical Trial Registry
基金Supported by the National Science and Technology Important and Special Project of China,No.2017ZX09304024
文摘BACKGROUND Hereditary spherocytosis(HS)is a hereditary disease of hemolytic anemia that occurs due to the erythrocyte membrane defects.Dubin–Johnson syndrome(DJS),which commonly results in jaundice,is a benign hereditary disorder of bilirubin clearance that occurs only rarely.The co-occurrence of HS and DJS is extremely rare.We recently diagnosed and treated a case of co-occurring HS and DJS.CASE SUMMARY A 21-year-old female patient presented to our department because of severe jaundice,severe splenomegaly,and mild anemia since birth.We eventually confirmed the diagnosis of co-occurring DJS and HS by next generation sequencing(NGS).The treatment of ursodeoxycholic acid in combination with phenobarbital successfully increased hemoglobin and reduced total bilirubin and direct bilirubin.CONCLUSION The routine application of NGS can efficiently render a definite diagnosis when inherited disorders are suspected.
基金Supported by The Talents of Qiankehe platform of China,No.[2018]5779-40the Zhuke Contract,No.[2018]1-92and the Qiankehe Support,No.[2017]2874.
文摘BACKGROUND Dubin-Johnson syndrome(DJS)is a benign autosomal recessive liver disease involving mutations of the ABCC2 gene.It is characterized by chronic or intermittent conjugated hyperbilirubinemia,with chronic idiopathic jaundice as the main clinical manifestation.Genetic alterations of the ABCC2 gene are commonly used for diagnosing DJS;however,the causative ABCC2 point mutation in Chinese patients remains unknown.Research on ABCC2 mutations in Chinese DJS patients is extremely rare,and the diagnosis of DJS remains limited.The routine analysis of ABCC2 mutations is helpful for the diagnosis of DJS.Here,we report the clinical characteristics and ABCC2 genotype of an adult female DJS patient.This article is to expound the discovery of more potentially pathogenic ABCC2 variants will that contribute to DJS identification.CASE SUMMARY This study investigated a woman referred for DJS and involved clinical and genetic analyses.ABCC2 mutations were identified by next-generation sequencing(NGS).The patient showed intermittent jaundice and conjugated hyperbilirubinemia.Histopathological examinations were consistent with the typical phenotype of DJS.Genetic diagnostic analysis revealed an ABCC2 genotype exhibiting a pathogenic variant,namely c.2443C>T(p.Arg815*),which has not been reported previously in the domestic or foreign literature.CONCLUSION Pathogenic ABCC2 mutations play an important role in the diagnosis of DJS,especially in patients with atypical presentations.Currently,NGS is used in the routine analysis of DJS cases and such tests of further cases will better illuminate the relationship between various genotypes and phenotypes of DJS.
文摘Aim:This study investigated the ATP binding cassette(ABC)transporter(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)expression in high grade serous ovarian cancer(HGSOC)tissues,cell lines and primary cells to determine their potential relationship with acquired chemotherapy resistance and patient outcome.Methods:ABC transporter mRNA and protein expression(ABCA1,ABCB1,ABCB3,ABCC2 and ABCG2)was assessed in publicly available datasets and in a tissue microarray(TMA)cohort of HGSOC at diagnosis,respectively.ABC transporter mRNA expression was also assessed in chemosensitive ovarian cancer cell lines(OVCAR-5 and CaOV3)versus matching cell lines with acquired carboplatin resistance and in primary HGSOC cells from patients with chemosensitive disease at diagnosis(n=10)as well as patients with acquired chemotherapy resistance at relapse(n=6).The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and-resistant cell lines were also investigated.Results:High ABCA1 mRNA and protein expression was found to be significantly associated with poor patient outcome.ABCA1 mRNA and protein levels were significantly increased in ovarian cancer cell lines(OVCAR-5 CBPR and CaOV3 CBPR)with acquired carboplatin resistance.ABCA1 mRNA was significantly increased in primary HGSOC cells obtained from patients with acquired chemotherapy resistance.Apabetalone treatment reduced ABCA1 protein expression and increased the sensitivity of both parental and carboplatin-resistant ovarian cancer cells to carboplatin.Conclusion: These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.
