Effects of the new nitrosourea derivative, fotemustine, on the glutathione reductase activity in rat tissues in vivo and in isolated rat hepatocytes.
Fotemustine, a new clinically active nitrosourea, is demonstrated herein to be a poor inhibitor of glutathione reductase activity from rat liver, lung and kidney cytosols. In order to show that an intracellular step of activation does not lead to a toxic intermediary metabolite, rat hepatocytes were incubated with fotemustine. Their glutathione-related pathways were checked and shown not to be altered, while under similar experimental conditions BCNU was shown to be dramatically harmful. Furthermore, association of fotemustine with a H2O2 production leading drug, diquat, was shown to be inefficient--while BCNU is efficient--in potentiating the diquat toxicity. Considering the role of glutathione level in the detoxification of mutagens and carcinogens, the advantage of fotemustine over BCNU in therapeutic use seems substantiated.
Boutin
J A
JA
Division de Pathologies Cancéreuses et Immunes, Institut de Recherches Servier, Suresnes, France.
Norbeck
K
K
Moldeus
P
P
Genton
A
A
Paraire
M
M
Bizzari
J P
JP
Lavielle
G
G
Cudennec
C A
CA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002469:Cell Separation; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology; D008297:Male; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D005980:Glutathione Reductase; C054368:fotemustine