Formation, toxicity and inactivation of acrolein during biotransformation of cyclophosphamide as studied in freshly isolated cells from rat liver and kidney.
In the present study the formation and the effects of cyclophosphamide-derived acrolein were investigated using isolated cells from rat liver and kidney, with particular regard to the protective action of low molecular weight thiols against cellular toxicity. The results may be summarized as follows: Cyclophosphamide (CTX)-mediated toxicity to isolated cells is dependent on cytochrome P-450 activity; Loss of viability in cells incubated with cyclophosphamide is preceded by a depletion of cellular GSH; Stimulation of cellular GSH synthesis or the presence of low molecular weight thiols in the incubation medium protects against cyclophosphamide-induced toxicity; Acrolein is probably formed extracellularly as well as intracellularly and can be detoxified by thiol compounds, forming a thiochemiacetal or a thioether.
D000171:Acrolein / Q000378:metabolism* / Q000633:toxicity; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D000447:Aldehydes; D013438:Sulfhydryl Compounds; D000171:Acrolein; D003520:Cyclophosphamide; D005978:Glutathione; D010634:Phenobarbital; D008797:Metyrapone