TY - JOUR
T1 - Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects
AU - Verschraagen, Miranda
AU - Boven, Epie
AU - Torun, Emine
AU - Hausheer, Frederick H.
AU - Bast, Aalt
AU - Van Der Vijgh, Wim J F
PY - 2004/8/1
Y1 - 2004/8/1
N2 - 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.
AB - 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.
KW - BNP7787
KW - glutathione
KW - glutathione reductase
KW - GR
KW - GSH
KW - GSSG
KW - Mesna
KW - NADPH
KW - nicotinamide adenine dinucleotide phosphate
KW - oxidized glutathione
KW - PBS
KW - phosphate buffered saline
KW - RBC
KW - red blood cell
KW - thioredoxin reductase
KW - TrxR
KW - Vrije Universiteit medical center
KW - VUmc
UR - http://www.scopus.com/inward/record.url?scp=3042779809&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3042779809&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2004.04.005
DO - 10.1016/j.bcp.2004.04.005
M3 - Article
C2 - 15242815
AN - SCOPUS:3042779809
SN - 0006-2952
VL - 68
SP - 493
EP - 502
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 3
ER -