Variable Expression of Mrp2 (Abcc2) in Human Placenta: Influence of Gestational Age and Cellular Differentiation

Schwabedissen, Henriette E. Meyer zu; Jedlitschky, Gabriele; Gratz, Matthias; Haenisch, Sierk; Linnemann, Knud; Fusch, Christoph; Cascorbi, Ingolf; Kroemer, Heyo K.

doi:10.1124/dmd.104.003335

Cited by 141 publications

(90 citation statements)

References 55 publications

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“…Previous studies showed that multiple mechanisms underlie the regulation of MRP2/Mrp2 expression. For example, the MRP2 level in human placenta was affected by gestational age with an increased MRP2 protein level at later stages of pregnancy (Meyer zu Schwabedissen et al, 2005). In rat, Mrp2 protein started to be detected in livers of 16-and 20-day-old fetuses and tend to increase (Zinchuk et al, 2002).…”

Section: Difference In Hepatic Mrp2/mrp2 Protein Across Speciesmentioning

confidence: 98%

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Li¹,

Zhang²,

Hua³

et al. 2008

Drug Metab Dispos

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ABSTRACT:We previously reported that hepatobiliary transporter multidrug resistance-associated protein (MRP2/Mrp2) is considered to be the major cause of the interspecies differences detected by efflux of fluorescent substrates in isolated hepatocytes. In the present study, the interspecies differences of MRP2/Mrp2 were first evaluated by quantitative real-time polymerase chain reaction and Western blotting. The mRNA levels were able to distinguish the difference among species with a rank order comparable with the corresponding activities observed, whereas the extents of the differences remained unknown. The cross-reactions of MRP2/Mrp2 protein of different species with anti-human MRP2 polyclonal antibody were found by Western blotting. However, because of the unknown binding affinity of antibody to MRP2/Mrp2 protein across species and lack of purified MRP2/Mrp2 proteins for calibration, the immunoblotting assay was excluded from the absolute quantification of MRP2/Mrp2 protein for multiple species. By using our newly developed liquid chromatography-tandem mass spectrometry quantification method, we were able to measure the absolute amount of MRP2/Mrp2 in liver tissues and isolated hepatocytes across species. Freshly isolated hepatocytes conserved MRP2/ Mrp2 protein levels that are comparable with those in the liver tissues. The amount of Mrp2 in rat liver was approximately 10-fold higher than that in other species. Moreover, a significant loss of Mrp2 protein in the membrane fraction of rat cryopreserved hepatocytes was observed. Thus, the absolute differences of MRP2/ Mrp2 levels in various species were determined, for the first time, by direct quantification. The results could potentially fill the translational gaps of in vitro/in vivo or preclinical species to human extrapolation of hepatobiliary elimination mediated by MRP2/ Mrp2.Xenobiotics and their metabolites are generally eliminated and detoxified by phase I and phase II enzymatic metabolism, by phase III transporter-mediated drug efflux to bile, or by both mechanisms. The excretion of drugs by hepatocytes into bile is one of the primary elimination routes for xenobiotics and the conjugate metabolites (Arias et al., 1993). In each stage of drug discovery, accurate prediction of human pharmacokinetics for a potential drug candidate is of great value (Mahmood, 1999). Even though the interspecies scaling methods based on physiologically allometric procedures have been successfully applied, particularly into extrapolation of hepatic enzymatic metabolism and urinary excretion (Dedrick et al., 1970;Iwatsubo et al., 1997;Ito et al., 1998), the in vitro or in vivo model for biliary excretion predication is far from being mature (Mahmood and Sahajwalla, 2002). The remarkable interspecies differences in biliary excretion of xenobiotics and drugs/metabolites (Ishizuka et al., 1999;Shilling et al., 2006) may cause significant overestimation of biliary excretion in humans simply by an exponential allometric extrapolation approach (Lave et al., 1999;Pahlman et al., ...

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Section: Difference In Hepatic Mrp2/mrp2 Protein Across Speciesmentioning

confidence: 98%

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Li¹,

Zhang²,

Hua³

et al. 2008

Drug Metab Dispos

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“…ABCC2/MRP2 is the second member identified in the MRP family, which shares considerable similarities in substrate specificity and structure characteristics with ABCC1/MRP1, the founder member of this family. ABCC2 is predominantly expressed in excretory organs and physiological barriers and exclusively localized to the apical membrane domain of hepatocytes , absorptive enterocytes (Mottino et al, 2000), kidney proximal tubule epithelial cells (Schaub et al, 1999;Schaub et al, 1997), brain capillary endothelial cells (Potschka et al, 2003), lung epithelial cells and placenta syncytiotrophoblasts (Meyer zu Schwabedissen et al, 2005;St-Pierre et al, 2000). In liver, kidney and intestine, ABCC2 is thought to mediate secretion and elimination of numerous organic anions, including endogenous compounds such as bilirubin and exogenous compounds such as drugs and toxic chemicals (Payen et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…In liver, kidney and intestine, ABCC2 is thought to mediate secretion and elimination of numerous organic anions, including endogenous compounds such as bilirubin and exogenous compounds such as drugs and toxic chemicals (Payen et al, 2002). In the blood-brain barrier, lung epithelia and blood-placenta barrier, ABCC2 functions to limit the penetration and accumulation of drugs and toxicants Meyer zu Schwabedissen et al, 2005;Potschka et al, 2003). Mutations in human ABCC2 result in defects in excretion of conjugated bilirubin and other cholephiles known as the Dubin-Johnson syndrome (Kartenbeck et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals

Long

Zhong

et al. 2011

Comparative Biochemistry and Physiology Part C: Toxicology &

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“…ABCB1 is highly expressed in human placenta during early gestation, [17][18][19] while ABCG2 is expressed more in mid gestation. 20 During late gestation, ABCC1 21 and ABCC2 22 show the highest placental expression. Therefore, we can speculate that ABCB1 is vital in protecting the early fetus from xenobiotics insult, 23,24 such as maternal pharmacotherapy and even fetal waste products, while ABCC1, ABCC2, and ABCG2 can provide better protection to the mature fetus.…”

Section: Discussionmentioning

confidence: 99%

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

et al. 2013

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ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case-control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (Po0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR) ¼ 2.04; 95% confidence interval (CI) ¼ 1.42-2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case-control analysis comparing NSOC probands with controls (OR ¼ 1.58; 95% CI ¼ 1.12-2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI ¼ 1.38-2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface.

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Variable Expression of Mrp2 (Abcc2) in Human Placenta: Influence of Gestational Age and Cellular Differentiation

Cited by 141 publications

References 55 publications

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

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