Substrates and Inhibitors of Human Multidrug Resistance Associated Proteins and the Implications in Drug Development

Abstract

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

Structurally Distinct Ligands Rescue Biogenesis Defects of the KATP Channel Complex via a Converging Mechanism

“…SUR1 belongs to the ABC transporter family, which comprises a large number of proteins involved in movement of structurally diverse endogenous and xenobiotic compounds across biological membranes (59). Unlike other members in the family, however, SUR has uniquely evolved to regulate the activity of an ion channel without being a transporter or ion channel itself (60).…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…All the intestinal transporters for organic anions are also expressed in human hepatocytes more or less, although ASBT, OATP1A2 and MRP1 appear not to be present in these cells, and little seems to be known about the expression of hepatic MCTs. [50][51][52] However, several additional transporters are expressed in the liver. The majority of these are mainly transporters for organic anions, i.e.…”

“…Apart from the listed compounds in Table 2, the MRP transporters are known for carrying many anionic phase II metabolites such as glutathione and glucuronate conjugates. [52] BCRP is probably the most well characterized transporter with regard to its in-vitro drug affinity after several in-vivo and clinical reports have pointed out the importance of this transporter in the pharmacokinetics of various drugs. [175,176] OATP2B1 also quickly gained great attention when the family of OATP transporters was realized to influence drug pharmacokinetics.…”

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

“…One of the most common processes is the insertion of hydroxyl groups by P450 oxidases [4,5]. These hydroxyls are then targeted by conjugative enzymes of Phase II metabolism, in particular sulfotransferases [6,7] and uridine diphosphate-glucuronosyltransferases [8,9], to produce water-soluble, inactivated metabolites which can be re-exported via Organic Anion/Cation Transporters (OATPs) [10] and ATP-Binding Cassette (ABC)/Multi Drug Resistance (MDR) efflux transporters [11][12][13] and eliminated.…”