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      Association of ABCB1 (C3435T) and ABCC1 (G2012T) Polymorphisms with Clinical Response to Atorvastatin in Iranian Patients with Primary Hyperlipidemia

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          Abstract

          Background:

          Atorvastatin is prescribed for the primary and the secondary prevention of coronary artery diseases. A wide variation in inter-individual statin response suggests that genetic differences may contribute to this variation. This study investigated the association of ABCB1 (C3435T) and ABCC1 (G2012T) polymorphisms with clinical response to atorvastatin in Iranian primary hyperlipidemic patients.

          Methods:

          Individuals (n=179) with primary hypercholesterolemia were enrolled, and peripheral blood samples were collected. Genotyping of two polymorphisms were performed by amplification refractory mutation system PCR.

          Results:

          Following four weeks of treatment, a significant reduction of LDL-C was observed in variant groups (CT+TT) of ABCB1 ( P=0.018) and wild-type group (GG) of ABCC1 genes ( P=0.029). Logistic regression analysis revealed a significant difference between male and female responses to 10 mg/day atorvastatin ( P=0.004, odds ratio=0.2, CI 95%=0.06-0.6).

          Conclusion:

          Our finding indicated that these polymorphisms may be attributed to LDL-C serum levels in the primary hypercholesterolemia patients receiving atorvastatin.

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          Most cited references22

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          Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense.

          Elaine Leslie, Roger G Deeley, Susan P C Cole (2005)
          In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.
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            The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox).

            Csilla Ozvegy-Laczka, Gergely Szakacs, András Váradi … (2008)
            ATP binding cassette (ABC) drug transporters play an important role in cancer drug resistance, protection against xenobiotics, and in general in the passage of drugs through cellular and tissue barriers. This review explores how human ABC transporters modulate the pharmacological effects of various drugs, and how this predictable ADME-TOX modulation can be used during the process of drug discovery and development. We provide a description of the relevant human ABC drug transporters and review the models and assay systems that can be applied for the analysis of their expected drug interactions. The use of the in vitro, in vivo, in silico models, their combination, and the emerging clinical information are evaluated with respect to their potential application in early drug screening.
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              Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance.

              Catia Marzolini, Erik J Paus, Thierry Buclin … (2004)
              Drug transporters are increasingly recognized to be important to drug disposition and response. P-glycoprotein, the encoded product of the human MDR1 (ABCB1) gene, is of particular clinical relevance in that this transporter has broad substrate specificity, including a variety of structurally divergent drugs in clinical use today. Moreover, expression of this efflux transporter in certain tissue compartments such as the gastrointestinal tract and brain capillary endothelial cells limits oral absorption and central nervous system entry of many drugs. Recently, a number of single-nucleotide polymorphisms (SNPs) in MDR1 have been identified. An increasing number of studies have also implicated certain commonly occurring SNPs in MDR1 in problems including altered drug levels and host susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and CD4 cell recovery during human immunodeficiency virus therapy. However, in many such cases, the reported effects of MDR1 SNPs have been inconsistent and, in some cases, conflicting. In this review SNPs in MDR1 in relation to population frequencies, drug levels, and phenotypes are outlined. In addition, issues relating to MDR1 haplotypes, environmental factors, and study design, as potential confounding factors of the observed MDR1 polymorphism effect in vivo, are also discussed.
              Article 0 comments Cited 102 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Iran Biomed J
                Journal ID (iso-abbrev): Iran. Biomed. J
                Title: Iranian Biomedical Journal
                Publisher: Pasteur Institute (Iran )
                ISSN (Print): 1028-852X
                ISSN (Electronic): 2008-823X
                Publication date (Print): March 2017
                Volume: 21
                Issue: 2
                Pages: 120-125
                Affiliations
                [1 ]Department of Pharmacotherapy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
                [2 ]Department of Cardiology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
                [3 ]Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
                Author notes
                Corresponding Author: Soha Namazi Department of Pharmacotherapy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Tel.: (+98-711) 2424128; E-mali: namazisoha@ 123456yahoo.com , snamazi@ 123456sums.ac.ir
                Article
                Publisher ID: IBJ-21-120
                DOI: 10.18869/acadpub.ibj.21.2.120
                PMC ID: 5274711
                PubMed ID: 27238935
                SO-VID: 6af93e29-eccc-4ee8-b3ff-68f80ec9c41a
                Copyright © Copyright: © Iranian Biomedical Journal
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 05 December 2015
                Date revision received : 05 January 2016
                Date accepted : 19 January 2016
                Categories
                Subject: Short Communication

                Keywords: hypercholesterolemia,statin,gene polymorphisms
                Data availability:
                Keywords: hypercholesterolemia, statin, gene polymorphisms

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