The apical conjugate efflux pump ABCC2 (MRP2)

Abstract

ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

Modulation of trabectedin (ET-743) hepatobiliary disposition by multidrug resistance-associated proteins (Mrps) may prevent hepatotoxicity

“…Patients with Dubin-Johnson syndrome lack MRP2 and hence suffer from hereditary conjugated hyperbilirubinemia (Paulusma et al, 1997). In the absence of Mrp2/ MRP2, rats and humans exhibit increased expression of basolateral Mrp3/MRP3 as a compensatory mechanism that enables the excretion of Mrp2/MRP2 substrates into the systemic circulation, thus avoiding excessive accumulation of organic anions in the hepatocyte (Kiuchi et al, 1998;Hirohashi et al, 1999;Johnson et al, 2006;Nies and Keppler, 2007).…”

ABC transporters: circadian rhythms and sex-related differences

“…Doku mikroölçüm çalışmalarında, MRP2'nin akciğer, meme ve gastrik karsinomlardaki ekspresyonu da gösterilmiştir. MRP2'nin bir çok antikanser ilaca karşı direnç oluşturduğu göz önüne alındığında, insan tümör hücrelerindeki ekspresyonu klinik açıdan önem taşıyabilir (36).…”

Pharmacogenetics of drug transporters in the enterohepatic circulation

“…The exact role of MATE1 for biliary drug elimination needs to be worked out in more details, but it may be involved in handling of antiarrhythmics, antibacterials and antimalarials [63]. MRP2 represents the main biliary export pump for phase II drug conjugates [70] and ABCG2 has been shown to be involved in the biliary elimination of some anticancer drugs [54]. Finally, the canalicular bile salt export pump BSEP is a crucial "bottle neck" for biliary secretion of conjugated bile salts [18,71].…”

“…As nonfunctional MRP2 leads to the Dubin-Johnson syndrome, a long list of mutations with very low frequencies has been published [70]. 11 polymorphisms display ethnicity variations in frequency rates [48,70] Studies focusing on the effect of ABCC2 polymorphisms on pharmacokinetics of drugs are rare, but they have been associated with alterations of methotrexate and irinotecan disposition [8,48].…”

“…11 polymorphisms display ethnicity variations in frequency rates [48,70] Studies focusing on the effect of ABCC2 polymorphisms on pharmacokinetics of drugs are rare, but they have been associated with alterations of methotrexate and irinotecan disposition [8,48]. For example, in a pharmacokinetic study of high-dose methotrexate treatment of pediatric acute lymphoblastic anemia, the c.-24T allele of ABCC2 was associated with significantly elevated AUC 36-48 in females [123].…”