The mechanism of interaction between cisplatin and selenite.
Cisplatin is a widely used antitumor drug, highly effective in the treatment of several tumors. Cisplatin exerts its antitumor activity through an interaction with DNA, which results in the formation of bidentate adducts. An important side-effects of cisplatin is nephrotoxicity. Selenite can reduce the nephrotoxicity of cisplatin without reducing the antitumor activity of the drug. We have studied the mechanism of selenite protection against cisplatin-induced nephrotoxicity. The protection correlates with higher levels of selenium in the kidney (about eight times) and with higher levels of glutathione in the kidney, both compared to tumors. Selenite is metabolized into selenols, specifically into methylselenol and glutathionylselenol; this bioactivation of selenite into selenols is a glutathione-dependent process. HPLC with on-line radioactivity detection of 195mPt showed that methylselenol is capable of forming a complex with cisplatin in vitro. 1H-NMR gave evidence that the complex contains one or more Pt-Se-CH3 bonds. Attempts to obtain further structural information by Desorption Chemical Ionization and Fast Atom Bombardment mass-spectrometry failed. It is proposed that the formation of a cisplatin-selenol complex also takes place in vivo, especially in the kidney, thereby preventing cisplatin exerting its nephrotoxic activity.
Baldew
G S
GS
Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
Mol
J G
JG
de Kanter
F J
FJ
van Baar
B
B
de Goeij
J J
JJ
Vermeulen
N P
NP
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004347:Drug Interactions; D005260:Female; D006863:Hydrogen-Ion Concentration; D008658:Inactivation, Metabolic; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D020887:Selenious Acid; D012643:Selenium / Q000493:pharmacokinetics* / Q000633:toxicity; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D020887:Selenious Acid; D012643:Selenium; D002945:Cisplatin