Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects.
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.
Verschraagen
Miranda
M
Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands.
Boven
Epie
E
Torun
Emine
E
Hausheer
Frederick H
FH
Bast
Aalt
A
van der Vijgh
Wim J F
WJ
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D002945:Cisplatin / Q000009:adverse effects*; D003545:Cysteine / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004563:Electrochemistry; D004798:Enzymes / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015080:Mesna / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D020011:Protective Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004798:Enzymes; D020011:Protective Agents; C027032:2,2'-dithiodiethanesulfonic acid; D005978:Glutathione; D003545:Cysteine; D015080:Mesna; D002945:Cisplatin