Regeneration experiments of the platinated enzyme fumarase, using sodium diethyldithiocarbamate, thiourea, and sodium thiosulfate.
The enzyme fumarase is inhibited by [cis-Pt(NH3)2(H2O)2] (NO3)2. The Pt compound most likely binds at a S-methionine site. Sodium diethyldithiocarbamate (Naddtc) appears to be a powerful regenerator of enzymatic activity. Thiourea is less active, while sodium thiosulfate (STS) is almost inactive in restoring the activity of the enzyme. The regeneration phenomena are based on the dissociation of the Pt-S bonds of the methionine type, and formation of species like [Pt(ddtc)2]. In the model adduct [Pt(dien)GS-Me]2+ Naddtc, thiourea and STS easily break the Pt-S bond of the methionine type. It is concluded that the model system for Naddtc and thiourea does resemble fumarase quite well. S-donor ligands, which may be used as rescue agents in Pt antitumor therapy, are known to suppress nephrotoxicity caused by [cis-PtCl2(NH3)2]. A parallel is drawn between the enzyme reactivation, modeled by fumarase, and the [cis-PtCl2(NH3)2] nephrotoxicity suppression by rescue agents. It is proposed that a Pt-methionine type binding is broken by the rescue agents Naddtc and thiourea, but that the rescue agent STS only inhibits the nephrotoxicity by inactivating unbound Pt species in the cell.
Boelrijk
A
A
Department of Chemistry, Gorlaeus Laboratories, Leiden University, The Netherlands.
Boogaard
P J
PJ
Lempers
E L
EL
Reedijk
J
J
D000818:Animals; D001665:Binding Sites; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology*; D005649:Fumarate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008962:Models, Theoretical; D009206:Myocardium / Q000201:enzymology; D013552:Swine; D013885:Thiosulfates / Q000494:pharmacology*; D013890:Thiourea / Q000494:pharmacology*
D008024:Ligands; D013885:Thiosulfates; D004050:Ditiocarb; D005649:Fumarate Hydratase; D013890:Thiourea; C017717:sodium thiosulfate; D002945:Cisplatin