Metabolism of spirohydantoin mustard in the mouse. Isolation of an alkylating, mutagenic metabolite.
The metabolism of spirohydantoin mustard (SHM), a central nervous system-directed nitrogen mustard with reported anticancer activity, was studied using both the Salmonella/mammalian microsome mutagenicity assay and radiolabeled drug. SHM had little or no mutagenic activity by itself but was metabolized to a mutagen(s) in the presence of mouse postmitochondrial liver fraction (9000 g supernatant, S9). Metabolism was NADPH-dependent and was enhanced with phenobarbital-induced S9. Both SHM and mutagen(s) were extractable in chloroform. Studies using [14C]SHM, uniformly labeled on the bis(2-chloroethyl)amino group, and thin-layer chromatography (TLC) of chloroform extracts of liver S9 incubation mixtures indicated the formation of a single major metabolite fraction that contained a direct-acting mutagen. Chloroform extracts of both blood and brain from BDF1 mice injected i.p. with SHM (60 mg/kg) were found to be mutagenic in the absence of S9. Also, TLC of chloroform extracts of brain taken 15 min after i.p. injection of [14C]SHM suggested the presence of SHM and the mutagenic metabolite. These results suggest that the mutagenic metabolite may have a significant role in the mechanism of action of SHM.
D000477:Alkylating Agents / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D005260:Female; D006827:Hydantoins / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D009153:Mutagens / Q000378:metabolism*; D009588:Nitrogen Mustard Compounds / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000235:genetics
D000477:Alkylating Agents; D006827:Hydantoins; D009153:Mutagens; D009588:Nitrogen Mustard Compounds; C015511:spiromustine; D010634:Phenobarbital