The Human Multidrug Resistance-Associated Protein (MRP) Gene Family: From Biological Function to Drug Molecular Design
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Abstract
The ATP-binding cassette transmembrane proteins play an important role in transport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions. MRP1 operates as an ATP-dependent primary active transporter for substrates conjugated with glucuronide, sulfate or glutathione. Leukotriene C4 is an important endogenous substrate for MRP1. Glutathione serves as a cofactor in MRP1-mediated drug transport as well.
Genes encoding both MRP1 and the catalytic subunit of γ-glutamylcysteine synthetase (γ-GCS) are coordinately regulated in cultured cancer cell lines as well as colorectal cancer tissues from colon cancer patients. The induction of MRP1 and γ-GCS expression by oxidative stress varies among different cell lines, and p53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione derivatives as photoreactive biochemical probes targeting the transporter protein. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-resistant cancer cells to anticancer prostaglandins in vitro, which was characterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.
Copyright © 2000 by Walter de Gruyter GmbH & Co. KG
Articles in the same Issue
- The Basis of the Medicine of Tomorrow "Validating and Using Pharmacogenomics" Joint IFCC-Roche Diagnostics Conference, Kyoto, Japan, 1619 April 2000
- Diagnostics and the Future of Medicine
- Operomics: Molecular Analysis of Tissues from DNA to RNA to Protein
- Idiosyncratic Reactions to Drugs: Can Medicine Response Profiles Provide a Dynamic Drug Surveillance System?
- Hunting for Disease Genes in Multi-Functional Diseases
- Familial Studies on the Genetics of Cardiovascular Diseases: the Stanislas Cohort
- Quantitative PCR
- Gene Amplification as Means for Determining Therapeutic Strategies in Human Cancers
- Apolipoprotein E Polymorphisms and Concentration in Chronic Diseases and Drug Responses
- Angiotensin I-Converting Enzyme Gene Polymorphism and Drug Response
- Drug-Metabolizing Enzymes, Polymorphisms and Interindividual Response to Environmental Toxicants
- Database Analysis and Gene Discovery in Pharmacogenetics
- How to Manage Individualized Drug Therapy: Application of Pharmacogenetic Knowledge of Drug Metabolism and Transport
- P-Glycoprotein and Bioavailability-Implication of Polymorphism
- Cancer Therapy and Polymorphisms of Cytochromes P450
- Polymorphisms in UDP Glucuronosyltransferase Genes: Functional Consequences and Clinical Relevance
- The Human Multidrug Resistance-Associated Protein (MRP) Gene Family: From Biological Function to Drug Molecular Design
- Ethnic Differences in Drug Metabolism
- Hypervariable Region 1 of Hepatitis C Virus Genome and Response to Interferon Therapy
- A Functional Genomic Study of the Effects of Antipsychotic Agent Chlorpromazine in PC12 Cells
- Influence of Glutathione S-Transferase M1 and T1 Genotypes on Larynx Cancer Risk among Korean Smokers
- CYP2D6 Genotyping in Patients on Psychoactive Drug Therapy
- Genotyping of CYP2D6 in Parkinsons's Disease
- Rapid Analysis of CGG Repeat Length in the FMR1 Gene
- Multiplex In-cell Reverse Transcription-Polymerase Chain Reaction for the Simultaneous Detection of p210 and p190 BCR-ABL mRNAs in Chronic Myeloid Leukemia and Philadelphia-Positive Acute Lymphoblastic Leukemia Cell Lines
Articles in the same Issue
- The Basis of the Medicine of Tomorrow "Validating and Using Pharmacogenomics" Joint IFCC-Roche Diagnostics Conference, Kyoto, Japan, 1619 April 2000
- Diagnostics and the Future of Medicine
- Operomics: Molecular Analysis of Tissues from DNA to RNA to Protein
- Idiosyncratic Reactions to Drugs: Can Medicine Response Profiles Provide a Dynamic Drug Surveillance System?
- Hunting for Disease Genes in Multi-Functional Diseases
- Familial Studies on the Genetics of Cardiovascular Diseases: the Stanislas Cohort
- Quantitative PCR
- Gene Amplification as Means for Determining Therapeutic Strategies in Human Cancers
- Apolipoprotein E Polymorphisms and Concentration in Chronic Diseases and Drug Responses
- Angiotensin I-Converting Enzyme Gene Polymorphism and Drug Response
- Drug-Metabolizing Enzymes, Polymorphisms and Interindividual Response to Environmental Toxicants
- Database Analysis and Gene Discovery in Pharmacogenetics
- How to Manage Individualized Drug Therapy: Application of Pharmacogenetic Knowledge of Drug Metabolism and Transport
- P-Glycoprotein and Bioavailability-Implication of Polymorphism
- Cancer Therapy and Polymorphisms of Cytochromes P450
- Polymorphisms in UDP Glucuronosyltransferase Genes: Functional Consequences and Clinical Relevance
- The Human Multidrug Resistance-Associated Protein (MRP) Gene Family: From Biological Function to Drug Molecular Design
- Ethnic Differences in Drug Metabolism
- Hypervariable Region 1 of Hepatitis C Virus Genome and Response to Interferon Therapy
- A Functional Genomic Study of the Effects of Antipsychotic Agent Chlorpromazine in PC12 Cells
- Influence of Glutathione S-Transferase M1 and T1 Genotypes on Larynx Cancer Risk among Korean Smokers
- CYP2D6 Genotyping in Patients on Psychoactive Drug Therapy
- Genotyping of CYP2D6 in Parkinsons's Disease
- Rapid Analysis of CGG Repeat Length in the FMR1 Gene
- Multiplex In-cell Reverse Transcription-Polymerase Chain Reaction for the Simultaneous Detection of p210 and p190 BCR-ABL mRNAs in Chronic Myeloid Leukemia and Philadelphia-Positive Acute Lymphoblastic Leukemia Cell Lines
