Possible (enzymatic) routes and biological sites for metabolic reduction of BNP7787, a new protector against cisplatin-induced side-effects

Biochemical Pharmacology
M VerschraagenW J F van der Vijgh

Abstract

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 meas...Continue Reading

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Citations

Aug 29, 2009·Cancer Chemotherapy and Pharmacology·Frederick H HausheerAulma R Parker
May 5, 2010·Cancer Chemotherapy and Pharmacology·F H HausheerH Kochat
Apr 21, 2011·Journal of Clinical Pharmacology·M J CutlerD J Freeman
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Nov 3, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Katsunobu HagiharaToshihiko Ikeda
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Sep 23, 2020·International Journal of Biological Macromolecules·Nikhilesh JoardarSanti P Sinha Babu
Jun 27, 2017·Trends in Pharmacological Sciences·Junmin ZhangJianguo Fang
Mar 13, 2009·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Dakshine ShanmugarajahFrederick H Hausheer

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