ABCMdb

PMID: 20082599

Jemnitz K, Heredi-Szabo K, Janossy J, Ioja E, Vereczkey L, Krajcsi P
ABCC2/Abcc2: a multispecific transporter with dominant excretory functions.
Drug Metab Rev. 2010 Aug;42(3):402-36., [PubMed]

Sentences

No. Mutations Sentence Comment

86 ABCC2 p.Ile1173Phe The I1173F mutation showed a similar defect in trafficking (Keitel et al., 2003). Login to comment 87 ABCC2 p.Arg768Trp ABCC2 p.Gln1382Arg Interestingly, two missense mutations, R768W and Q1382R, of the nucleotide-binding domains (NBDs) behaved differently. Login to comment 88 ABCC2 p.Gln1382Arg Pulse-chase analysis revealed that the precursor forms of the wild type and Q1382R ABCC2 fully matured, as they were resistant to endoglycosidase H (Endo H). Login to comment 89 ABCC2 p.Arg768Trp However, the precursor form of the R768W remained sensitive to Endo H and was degraded within 120 minutes (Hashimoto et al., 2002). Login to comment 97 ABCC2 p.Arg1230Ala ABCC2 p.Ser789Phe ABCC2 p.Ala1450Thr ABCC2 p.Ile1173Phe ABCC2 p.Trp1254Tyr ABCC2 p.Trp1254Tyr ABCC2 p.Trp1254Tyr ABCC2 p.Trp1254Ala ABCC2 p.Trp1254Ala ABCC2 p.Trp1254Ala ABCC2 p.His1042Ala ABCC2 p.Lys329Ala ABCC2 p.Arg1257Ala ABCC2 p.Trp1254Phe ABCC2 p.Trp1254Phe ABCC2 p.Trp1254Phe ABCC2 p.Trp1254Cys ABCC2 p.Trp1254Cys ABCC2 p.Trp1254Cys ABCC2 p.Arg1100Ala ABCC2 p.Lys316Ala ABCC2 p.Arg1210Ala ABCC2 p.Lys324Ala ABCC2 p.Arg412Gly ABCC2 p.His439Ala ABCC2 p.Pro1158Ala ABCC2 p.Arg1023Ala ABCC5 p.Arg1096Leu ABCC2 p.Lys483Ala Mutant Predicted location Substrate Activity changes Reference Human MRP2 Δ1-188 TMD0 LTC4 ↓ Fernandez et al., 2002 K316A JC, TM6 GMF ↔ Ryu et al., 2000 K324A TM6 GMF ↓ Ryu et al., 2000 K329A TM6 GMF ↔ Ryu et al., 2000 R412G DJ IC MTX ↓ Hulot et al., 2005 W417I IC, TM7-TM8 E2-17βG ↓ Hirouchi et al., 2004 LTC4 ↓ DNP-SG ↓ H439A TM8 GMF ↔ Ryu et al., 2000 K483A IC, JM, TM9 GMF ↓ Ryu et al., 2000 K590A JC, TM11 GMF ↔ Ryu et al., 2000 S789F NBD1 E2-17βG ↓ Hirouchi et al., 2004 LTC4 ↓ DNP-SG ↓↓ R1023A EC, JM, TM13 GMF ↔ Ryu et al., 2000 H1042A TM13 GMF ↔ Ryu et al., 2000 R1100A JC, TM14 GMF ↔ Ryu et al., 2000 P1158A IC, JM, TM15 LTC4 ↓↓ Letourneau et al., 2007 E2-17βG ↔ MTX ↔ Table 1. continued on next page Mutant Predicted location Substrate Activity changes Reference I1173F DJ IC, TM15-16 LTC4 No act Keitel et al., 2003 E2-17βG No act R1210A EC, JC, TM16 GMF ↓↓ Ryu et al., 2000 R1230A TM16 GMF ↔ R1257A JC, TM17 GMF ↓↓ W1254A JC, TM17 E2-17βG ↓↓ Ito et al., 2001a W1254C ↓↓ W1254F ↔ W1254Y ↔ W1254A JC, TM17 LTC4 ↓↓ Ito et al., 2001b W1254C ↓↓↓ W1254F ↓↓ W1254Y ↓↓ W1254A JC, TM17 MTX ↓↓ Ito et al., 2001a W1254C ↓↓ W1254F ↓↓ W1254Y ↓↓↓ A1450T NBD2 E2-17βG ↓↓ Hirouchi et al., 2004 LTC4 ↓↓ DNP-SG ↓↓ Rat Mrp2 K308M IC, JM, TM6 TLC-S ↔ Ito et al., 2001b DNP-G ↑ LTC4 ↓ E3040G ↔ K320M TM6 TLC-S ↑ DNP-G ↑ LTC4 ↓ E3040G ↑ K325M TM6 TLC-S ↓* DNP-G ↓↓↓* LTC4 ↓↓↓* E3040G ↓ D329N TM6 TLC-S ↔ DNP-G ↓ LTC4 ↓↓↓* E3040G ↓ R586L TM11 TLC-S ↓ DNP-G ↓↓* LTC4 ↓↓* E3040G ↔ R1019M IC, JM, TM13 TLC-S ↔ DNP-G ↑* LTC4 ↔ E3040G ↔ R1096L TM14 TLC-S ↑ DNP-G ↑ LTC4 ↔ E3040G ↔ EC, extracellular; IC, intracellular; JC, near the cytosol in the membrane; JM, juxtamembrane; TLC-S, tauro-litocholate-sulfate; GMF, glutathione- methyl-fluorescein; ↑, activity over control>1.2; ↔, 1.2>activity over control>0.8; ↓, 0.8>activity over control>0.5; ↓↓, 0.5>activity over control>0.1; ↓↓↓, 0.1>activity over control. Login to comment 102 ABCC2 p.Ile1173Phe ABCC2 p.Arg412Gly Similarly, deletion of amino acids 1-188 (Fernandez et al., 2002), the R412G change (Hulot et al., 2005), and an I1173F replacement (Keitel et al., 2003) in two Dubin-Johnson variants impaired leukotriene-C4 (LTC4) transport. Login to comment 105 ABCC2 p.Trp1254Phe The W1254F mutation did not affect estradiol-17β-glucuronide (E2-17βG) transport, but almost completely erased LTC4 and methotrexate (MTX) transport by the protein (Ito et al., 2001a). Login to comment 107 ABCB1 p.Arg588Leu Moreover, several mutations in the rat Abcc2 were shown to affect substrate specificity (Ito et al., 2001b), with D329N and R588L being the most striking, as these mutations did not significantly modulate the transport of taurolitocholate-sulfate and E3040-glucuronide, whereas these changes inhibited the efflux of DNP-SG and LTC4. Login to comment 113 ABCC2 p.Arg1150His ABCC2 p.Arg1066* ABCC2 p.Ile1173Phe ABCC2 p.Arg393Trp ABCC2 p.Arg100* Among these mutations recently compiled by Nies and Keppler (2007), of the five amino acids affected that are located outside the nucleotide-binding domains, four are basic (R100X, R393W, R1066X, and R1150H) and one is neutral (I1173F). Login to comment 114 ABCC2 p.Arg1150His R1150H is normally processed, but nonfunctional (Mor-Cohen et al., 2001). Login to comment 115 ABCC2 p.Ile1173Phe I1173F is improperly processed and degraded, but has been shown in membrane assays as nonfunctional (Keitel et al., 2003). Login to comment 116 ABCC2 p.Arg1066* ABCC2 p.Arg393Trp ABCC2 p.Arg100* For the R100X, R393W, and R1066X, in vitro expression and analysis needs to be carried out to explore if functional activity is affected by the mutation. Login to comment 396 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu Finally, the effect Table 5. Pharmacokinetics of substrates affected by ABCC2/Abcc2. Compound Assay Data References Endogenous compounds E2-17-beta-Gluc In vitro (CMV) and in vivo (biliary excretion after i.v.) experiments Impaired in EHBR rats Morikawa et al., 2000 Hydroxy-nonenal-gluc Biliary clearance No detectable excretion in EHBR rats Ji et al., 2002 Drugs and drug metabolites Acetaminophen sulfate IPL Rate constant of biliary excretion was decreased by 90% in TR- rats, a further 50% decrease upon GF admin Zamek-Gliszczynski et al., 2005 Acetaminophen, sulfate, and glucuronide IPL A- sulf 20-30% in TRA- Gluc; A-GS negligible in TR- Xiong et al., 2000 Acetaminophen, glutathione, -mercapturate, and glucuronide Biliary excretion after i.v. administration Biliary conc of A-GSH negligible; A-Gluc; A-NAC significantly reduced in TR- Chen et al., 2003a Acetaminophene glucuronide Single-pass liver perfusion (wild type vs. TR- ) 500-fold lower excretion rate in TR- liversXiong et al., 2002 Azithromycin Bolus injection, biliary excretion 60% lower in EHBR rats (0.7 vs. 1.2% in SD) Sugie et al., 2004 Cefoperazone Biliary and urinary excretion Biliary excretion decreased by 90% in EHBR rats Kato et al., 2008 Cisplatin In vitro and i.p. in vivo xenograft experiments Lentiviral RNAi adm knocked down ABCC2 exp to cca 20%; cisp accumulation 3-4-fold incr; reduced IC50 4-5-fold; worked in vivo Xie et al., 2008 Diclofenac glucuronide Liver perfusion (wild type vs. TR- ) 30-fold lower excretion in TR- livers Seitz et al., 1998 [D-penicillamine2,5]enkephalin (DPDPE) Sandwich hepatocytes Biliary clearance decreased by 83% Hoffmaster et al., 2005 Doxorubicin IPL Biliary excretion decreased by 30% in TR- rats Gaugg et al., 2001 In vitro (K562/ADR) and in vivo (biliary clearance) Biliary excretion reduced in EHBR rats Asakura et al., 2004 Clinical Val1188Glu-Cys1515Tyr haplotype associated with acute anthracycline cardiotoxicity (ACT) Wojnowski et al., 2005 E3040 (6-hydroxy-5,7-dimethyl-2- methylamino-4-(3-pyridylmethyl) benzothiazole) and glucuronide IPL and VT In EHBR biliary clearance of E3040G was 1/30 of wild type Takenaka et al., 1995 Enalapril; enalaprilate IPL Biliary excretion reduced to almost zero in EHBR rat Liu et al., 2006 Ezetimibe and glucuronide Intestinal secretion upon rifampicin treatm. 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