Affiliations: Membrane Research Group, Hungarian Academy of
Sciences, Budapest, Hungary | Institute of Enzymology, Hungarian Academy of
Sciences, Budapest, Hungary | Institute of Haematology, National Medical Center,
Budapest, Hungary
Abstract: Many endogenous or xenobiotic lipophilic substances are eliminated
from the cells by the sequence of oxidation, conjugation to an anionic group
(glutathione, glucuronate or sulfate) and transport across the plasma membrane
into the extracellular space. The latter step is mediated by integral membrane
glycoproteins belonging to the superfamily of ATP-Binding Cassette (ABC)
transporters. A subfamily, referred as ABCC, includes the famous/infamous
cystic fibrosis transmembrane regulator (CFTR), the sulfonylurea receptors (SUR
1 and 2), and the multidrug resistance-associated proteins (MRPs). The name of
the MRPs refers to their potential role in clinical multidrug resistance, a
phenomenon that hinders the effective chemotherapy of tumors. The MRPs that
have been functionally characterized so far share the property of ATP-dependent
export pumps for conjugates with glutathione (GSH), glucuronate or sulfate.
MRP1 and MRP2 are also mediating the cotransport of unconjugated amphiphilic
compounds together with free GSH. MRP3 preferentially transports glucuronides
but not glutathione S-conjugates or free GSH. MRP1 and MRP2 also contribute to
the control of the intracellular glutathione disulfide (GSSG) level. Although
these proteins are low affinity GSSG transporters, they can play essential role
in response to oxidative stress when the activity of GSSG reductase becomes
rate limiting. The human MRP4, MRP5 and MRP6 have only partially been
characterized. However, it has been revealed that MRP4 can function as an
efflux pump for cyclic nucleotides and nucleoside analogues, used as anti-HIV
drugs. MRP5 also transports GSH conjugates, nucleoside analogues, and possibly
heavy metal complexes. Transport of glutathione S-conjugates mediated by MRP6,
the mutation of which causes pseudoxantoma elasticum, has recently been shown.
In summary, numerous members of the multidrug resistance-associated protein
family serve as export pumps that prevent the accumulation of anionic
conjugates and GSSG in the cytoplasm, and play, therefore, an essential role in
detoxification and defense against oxidative stress.
Journal: BioFactors, vol. 17, no. 1-4, pp. 103-114, 2003
