Disodium 2,2'-dithio-bis-ethane sulfonate (
BNP7787) is under investigation as a potential new chemoprotector against
cisplatin-induced nephrotoxicity. The selective protection of
BNP7787 appears to arise from the preferential uptake of the
drug in the kidneys, where
BNP7787 would undergo intracellular conversion into
mesna (2-mercapto
ethane sulfonate), which in turn can prevent
cisplatin induced toxicities. In the present study, we have investigated whether the reduction of
BNP7787 into the reactive compound
mesna is restricted to the kidney or whether it can also occur in other organs, cells and physiological compartments, including the cytosolic fraction of the renal cortex, plasma, red blood cells (RBCs), liver and small intestine from rats and several
tumors (OVCAR-3, MRI-H-207 and WARD). We also determined whether the endogenous
thiols glutathione (GSH) and
cysteine and the
enzyme systems
glutaredoxin and
thioredoxin, which are all present in the kidney, can be involved in the
BNP7787 reduction. UV detection and micro-HPLC with dual electrochemical detection were used to analyze the various incubation mixtures. Our observations are that, in contrast to plasma, a very large reductive conversion of
BNP7787 to
mesna was measured in RBC lysate. Intact RBCs, however, did not take up
BNP7787. Although
BNP7787 could be reduced in cytosol of liver and several
tumors, this reduction will not be relevant in vivo, since these tissues do not take up large amounts of
BNP7787. Kidney cortex cytosol was, similar to the small intestine cytosol, able to substantially reduce
BNP7787 to
mesna. The ability to reduce
BNP7787 in the presence of the endogenous
thiols GSH and
cysteine, the
glutaredoxin system as well as the
thioredoxin system, could at least in part explain the high
BNP7787 reductive activity of the kidney cortex cytosol. In conclusion, the high reduction of
BNP7787 into
mesna in the kidney as well as our earlier observation that the distribution of
BNP7787 and
mesna was mainly restricted to rat kidney are strong arguments in favor of selective protection of the kidney by
BNP7787.