Transport of glutathione prostaglandin A conjugates by the multidrug resistance protein 1

The human multidrug resistance protein MRP1 mediates transport of organic substrates conjugated to glutathione, glucuronide, or sulfate. The naturally occurring prostaglandins Al and Az can form two diastereomeric glutathione S-conjugates, and it has been speculated that these might be substrates for MRP1. Here we present evidence that polarized MDCKII cells expressing MRP1 cDNA transport PGA(1)-GS to the basolateral side of a cell monolayer, in accordance with the lateral localization of human MRP1 in these cells, Furthermore, we show that vesicles made from yeast cells expressing MRP1 cDNA and from mouse erythrocytes (known to contain mrp1) actively accumulate both diastereomers of PGA(2)-GS with a similar efficiency. Recently, we generated mice with a homozygous mutant mrp1 allele. Uptake of PGA(2)-GS in vesicles made from erythrocytes of these mice was 3.2 times lower than in wild-type vesicles, but was still significantly above background, This residual transport activity was partly inhibited by methotrexate and cAMP, whereas mrp1-mediated activity was unaffected by these compounds. We conclude that mouse erythrocytes contain at least two transport systems for PGA(2)-GS. One of these is mrp1; the other one has not been identified yet, but can be inhibited by methotrexate and cAMP. (C) 1997 Federation of European Biochemical Societies.