Localization, substrate specificity, and drug resistance conferred by conjugate export pumps of the MRP family

Keppler, Dietrich; Kamisako, Toshinori; Leier, Inka; Cui, Yunhai; Nies, Anne T.; Tsujii, Hiroyuki; König, Jörg

doi:10.1016/s0065-2571(99)00022-9

Cited by 70 publications

(45 citation statements)

References 37 publications

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“…treatment, choosing the appropriate chemotherapy is crucial. An important obstacle to successful treatment of solid tumours is the resistance to cytotoxic drugs (Wright et al, 1998;Germann, 2000;Keppler et al, 2000). In this context, the drug resistance examination is a potential valuable tool (Csoka et al, 1994(Csoka et al, , 1995.…”

Section: Discussionmentioning

confidence: 99%

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study

et al. 2004

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Patients with peritoneal or local metastases from colorectal cancer have a poor prognosis. However, aggressive treatments by debulking surgery and infusional intraperitoneal (i.p.) chemotherapy have been tried and appear to benefit selected patients. We assayed the effects of debulking surgery and i.p. chemotherapy with respect to survival and compared the results with matched control patients treated by intravenous (i.v.) chemotherapy. In all, 18 patients with peritoneal and/or local metastases from colorectal adenocarcinoma underwent debulking surgery followed by 5-fluorouracil (5-FU) 550 mg m À2 day À1 i.p. and leucovorin (LV) 60 mg m À2 day À1 i.v. The chemotherapy was started the day after surgery and was given daily for 6 days and repeated monthly for totally eight courses. The control patients, matched for age, gender, performance status and metastatic site, were randomly selected from controlled clinical chemotherapy trials and treated with i.v. 5-FU þ LV or i.v. methotrexate þ 5-FU þ LV. There was no treatment-related mortality. The median survival among i.p. patients was 32 months compared to 14 months in the control group. In all, 11 patients who underwent macroscopically radical surgery had a longer survival than those who were not radically operated (P ¼ 0.02). These results indicate that patients with peritoneal metastases and/or locally advanced cancers but without distant metastases may benefit from cytoreductive surgery combined with i.p. chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study

et al. 2004

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“…Insofar, MRP1-MRP6 are the best-characterized members of the ABCC subfamily. Conjugates of lipophilic compounds with glutathione, glucuronate or sulfate are the preferred physiological substrates of MRP1 and MRP3 [78][79][80][81][82][83]. MRP6 is described to transport glutathione conjugates as well as the endothelin receptor antagonist BQ123 [78][79][80][81][82].…”

Section: Abc Transportersmentioning

confidence: 99%

“…Conjugates of lipophilic compounds with glutathione, glucuronate or sulfate are the preferred physiological substrates of MRP1 and MRP3 [78][79][80][81][82][83]. MRP6 is described to transport glutathione conjugates as well as the endothelin receptor antagonist BQ123 [78][79][80][81][82]. Substrates for MRP4 and MRP5 include cyclic AMP, cyclic GMP and nucleotide analogues [78][79][80][81][82].…”

Section: Abc Transportersmentioning

confidence: 99%

“…Reduced glutathione (GSH) has been recognized as a co-substrate for MRP1, for MRP2 and most recently for MRP4 [78][79][80][81][82]. In addition to being important export pumps for physiological substances, MRP subfamily members are involved in the active efflux of toxic organic anions [78][79][80][81][82]. MRP transporters have been shown to confer resistance to harmful drugs, possibly by the above-mentioned ATP-dependent export of such molecules [54][55][56][57].…”

Section: Abc Transportersmentioning

confidence: 99%

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ABC transporters, neural stem cells and neurogenesis – a different perspective

2006

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“…Members from the multidrug resistance protein (MRP) family play a prominent role in the cellular export of glucuronides (Keppler et al, , 2000König et al, 1999). Based on transport inhibition studies, at least three different transporters with distinct glucuronide substrate affinities were identified in rat liver microsomes (Csala et al, 2004), and the differential expression of MRPs could thus confer a specific glucuronide transport modality to a cell.…”

Section: Discussionmentioning

confidence: 99%

A physiological role for glucuronidated thyroid hormones: Preferential uptake by H9c2(2-1) myotubes

Heide

Joosten

Dragt

et al. 2007

Molecular and Cellular Endocrinology

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Conjugation reactions are important pathways in the peripheral metabolism of thyroid hormones. Rat cardiac fibroblasts produce and secrete glucuronidated thyroxine (T4G) and 3,3 ,5-triiodothyronine (T3G). We here show that, compared to fibroblasts from other anatomical locations, the capacity of cardiofibroblasts to secrete T4G and T3G is highest. H9c2(2-1) myotubes, a model system for cardiomyocytes, take up T4G and T3G at a rate that is 10-15 times higher than that for the unconjugated thyroid hormones. T3 and T4, and their glucuronides, stimulate H9c2(2-1) myoblast-to-myotube differentiation. A substantial ␤-glucuronidase activity was measured in H9c2(2-1) myotubes, and this confers a deconjugating capacity to these cells, via which native thyroid hormones can be regenerated from glucuronidated precursors. This indicates that the stimulatory effects on myoblast differentiation are exerted by the native hormones. We suggest that glucuronidation represents a mechanism to uncouple local thyroid hormone action in the heart from that in other peripheral tissues and in the systemic circulation. This could represent a mechanism for the local fine-tuning of cardiac thyroid hormone action.

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Localization, substrate specificity, and drug resistance conferred by conjugate export pumps of the MRP family

Cited by 70 publications

References 37 publications

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study

Improved survival in patients with peritoneal metastases from colorectal cancer: a preliminary study

ABC transporters, neural stem cells and neurogenesis – a different perspective

A physiological role for glucuronidated thyroid hormones: Preferential uptake by H9c2(2-1) myotubes

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