Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have sh...Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.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
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
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
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
文摘Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.
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.
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 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
