Mini Review
Pharmacogenomics of ABC transporters and its role in cancer chemotherapy

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Abstract

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, ABCP) are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual’s susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenomics of ABC transporters, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

Introduction

Cells exposed to toxic compounds can develop resistance by a number of mechanisms including decreased uptake, increased detoxification, alteration of target proteins, or increased excretion (Litman et al., 2001). Several of these pathways can lead to multidrug resistance (MDR) in which the cell is resistant to several commonly used drugs in addition to the initial compound to which it was exposed. This is a particular limitation to cancer chemotherapy, and cells with an MDR phenotype often display other properties, such as genome instability and loss of checkpoint control, that complicate further therapy (Dean, 2002). The ATP-binding cassette (ABC) genes play a role in MDR, and at least six genes are associated with anticancer drug transport (Table 1). These genes represent the largest family of transmembrane proteins that bind ATP and use the energy to drive the transport of various molecules across all cell membranes (Borst et al., 2000, Dean, 2002, Gottesman et al., 2002).

It is now well established that various ABC gene products also play a major role in host detoxification and protection against xenobiotic substances (Lin and Yamazaki, 2003). Indeed, genetic knock-outs of murine ABC transporter genes have shown altered blood–brain barrier function (Schinkel et al., 1997), intestinal drug absorption (Jonker et al., 2002, Sparreboom et al., 1997), fetal drug exposure (Smit et al., 1999), and drug-induced damage to testicular tubules (Wijnholds et al., 2000), choroid plexus epithelium and oropharyngeal mucosa (Rao et al., 1999). Further, recent re-sequencing of various ABC transporters has revealed a number of allelic variants that affect activity of the genes in vivo (Fromm, 2002). This genetic variation may potentially modulate phenotype in patients and therefore affect their predisposition to toxicity and response to drug treatment. This review focuses on the pharmacogenomics of ABC transporters and the implications of genetic variation of the proteins on anticancer drug response in humans.

Section snippets

Nomenclature and structural organization of the ABC proteins

Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding domains, also known as nucleotide-binding folds (NBFs). The NBFs contain characteristic motifs (viz. Walker A and B motifs), separated by approximately 90–120 amino acids, found in all ATP-binding proteins. ABC genes also contain an additional element, the signature (C) motif, located upstream of the Walker B site (Hyde et al., 1990). The functional protein typically contains two NBFs and two

ABC transporters and cancer therapy

Three ABC genes appear to account for nearly all of the MDR tumor cells in both human and rodent cells, which are selected with natural product cytotoxic drugs in vitro and show decreased drug accumulation: ABCB1,3 ABCC1, and ABCG2 encoding P-glycoprotein, MRP1 and BCRP

ABCB1 polymorphisms

To date, genetic variations of the human ABCB1 gene have been most extensively studied. Several recombinant variants have been generated either by in vivo drug selection or by site-directed mutagenesis techniques, which show altered substrate specificity or impaired function of a properly assembled protein (Ambudkar et al., 1999). Much less is known about naturally-occurring polymorphisms in the human population. Hoffmeyer et al. (2000) were the first to report a systematic screen of the ABCB1

Phenotype–genotype relationships

Variation in the pharmacokinetic behavior of an anticancer drug among different patients is the net result of complex interactions between genetic, physiological, and environmental factors. Thus, it is reasonable to assume that genetic variations in ABC transporter genes could alter drug disposition and might have clinical consequences. For instance, if the function or expression level of ABC transporters is altered due to genetic factors, intestinal secretion of the drug into the gut lumen may

Relevance of ABC genotypes in MDR in cancer

The development of an MDR phenotype within tumor cells is partially dependent on genetic alterations. The ability to detect them and assess their role in chemoresistance to anticancer agents is a topic of major clinical interest. Indeed, the widespread knowledge gained in the field of tumor biology encourages the adoption of strategies for treatment optimization based on the compatibility between the molecular profile of the disease and the drug to be administered (Danesi et al., 2001). Future

Conclusions and future perspectives

The ABC transporters have an established role in the pharmacokinetic behavior of many substrate drugs, including anticancer agents, and in the occurrence of multidrug resistance in malignant cells. Several polymorphic variants of ABC genes have been described recently, of which some, including those of the ABCB1 gene, may alter protein expression and function in humans. The effects of genetic variants in ABC transporter genes in relation to its phenotypical consequences are still debatable, as

Acknowledgements

We thank Dr. Michael M. Gottesman (National Cancer Institute, Bethesda, MD, USA) for his helpful comments on the manuscript.

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    1

    Present address: Saitama Medical School, Saitama 350-0495, Japan.

    2

    Present address: University of Illinois at Chicago, Chicago, IL 60612, USA.

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