Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition
Introduction
As one of the important factors influencing inter-individual differences in the drug disposition, many analyses of single nucleotide polymorphisms (SNPs) of drug metabolizing enzymes have been performed. For many kinds of drugs, an excellent correlation has been demonstrated between genotype and phenotype, and consequently, it is now possible to predict the in vivo drug disposition in mutated subjects from in vitro data obtained using mutated enzymes [1], [2], [3], [4]. Moreover, there have also been studies of the mechanism of induction which may affect the inter-individual differences in the expression level of metabolizing enzymes [5], [6].
In addition to these enzymes, drug transporters are important in determining drug disposition [7], [8], [9], [10], [11], [12], [13], [14], [15]. Many transporters which play a major role in drug absorption, drug distribution to tissues, and drug excretion into the urine and bile have been cloned and, in addition, some information is now available on their mutations. For example, one of the SNPs for mutations in MDR1 P-glycoprotein (P-gp), an ATP-dependent active transporter responsible for the cellular extrusion of many kinds of hydrophobic cationic and neutral drugs, has been shown to affect its intestinal expression level, along with the absorption of substrate drugs [16], [17]. Moreover, Ala893Ser mutation in MDR1 gene results in the reduced oral bioavailability of fexofenadine [17]. As far as the transporters responsible for the hepatic uptake of many kinds of anionic drugs such as pravastatin are concerned [18], [19], [20], [21], SNP analysis of organic anion transporting polypeptide (OATP)-2 (SLC21A6) has been reported [22]. In vitro experiments with cultured cells expressing the wild type (wt) and mutated OATP2s revealed that some of the SNP mutations are linked with the decreased transport activity and/or abnormalities in targeting to the cell surface [22]. In this article, we will focus on the possible inter-individual differences in drug disposition which may be caused by mutations in multidrug resistance associated protein 2 (MRP2/ABCC2), an ATP-dependent active transporter responsible for the biliary excretion of many kinds of organic anions. Previously published reviews on the function of MRP2 are also available [7], [23], [24], [25], [26].
Section snippets
Biliary excretion
MRP2, originally referred to as canalicular multispecific organic anion transporter (cMOAT), is located on the bile canalicular membrane. Its function has been studied extensively by comparing the transport across the bile canalicular membrane between normal and MRP2-deficient mutant rats (such as Groningen Yellow (GY), transport deficient (TR−) and Eisai hyperbilirubinemic rats (EHBRs)) [7], [23], [24], [25], [26]. These mutant animals have been used as a model to study the pathogenesis of
Mutation of MRP2 in DJS
Based on the similarity with MRP1, it may be assumed that MRP2 has 17 membrane-spanning domains with two nucleotide binding domains (NBDs) [32], [33] (Fig. 1). Human and rat MRP2 consists of 1545 and 1541 amino acid residues, respectively, with a molecular mass of ∼190 kDa of glycosylated protein [25], [26]. The mechanism for the impaired expression of MRP2 in TR− and EHBR [34], [35], [37] was investigated by determining its cDNA sequence. It was demonstrated that the mutation resulted in the
Amino acid residues and/or sequences affecting MRP2 function
Several lines of investigation have been followed to investigate the amino acid residues in MRP2 which are important in substrate recognition and/or transport. Since most MRP2 substrates possess a negative charge, it is possible that charged amino acids, particularly cationic amino acids, in the membrane-spanning domains may play an important role in the recognition/transport of substrates. We have focused on the charged amino acids in the transmembrane domains conserved in organic anion
SNPs in MRP2
SNP analysis of MRP2 has also been performed in 48 healthy Japanese subjects [118]. As shown in Fig. 3, six kinds of SNPs have been identified. Among them, C-24T (promoter), G1249A (exon 10) and C3972 (exon 28) are frequently observed (Fig. 3) [118]. Their allele frequency is 18.8, 12.5 and 21.9%, respectively (Fig. 3) [118]. G1249A is associated with amino acid alterations from Val to Ile at 417, whereas C3972T is the ‘silent’ mutation at 1324 (Ile1324Ile) (Fig. 3) [118]. In addition to these
Inter-individual differences in MRP2 expression
In order to discuss the inter-individual differences in MRP2 function, the difference in the expression level of MRP2 on the bile canalicular membrane should be taken into consideration [120]. Under cholestatic conditions, it has been suggested that MRP2 is internalized from the cell surface in rats and humans [121], [122], [123], [124], [125], [126]. Moreover, severe glutathione depletion results in the internalization of MRP2 [127]. Although the activation of protein kinase C results in the
Kinetic considerations
The impact of reduced MRP2 function in the liver on the disposition of its substrates should be discussed in relation to the rate-determining process for biliary excretion. The steady-state blood concentration of orally administered drugs which are predominantly eliminated by biliary excretion without metabolic conversion (e.g. pravastatin) is given by Eq (1).Where τ, fB and CLint represent the interval for drug administration, blood unbound fraction and intrinsic clearance
Conclusion
In this article, we have summarized the factors which may affect inter-individual differences in the disposition of drugs whose elimination is mediated by MRP2. Although the SNPs of MRP2 have been reported, the functional analysis of mutated proteins has not been performed yet. Moreover, in correlating the altered function of MRP2 determined in vitro with the in vivo disposition of substrate drugs, we met with a number of difficulties. Firstly, since most of MRP2 substrates are also transported
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports and Science of Japan and from the Ministry of Health, Labor and Welfare of Japan.
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