Degradation of 2-(3-aminopropylamino)-ethanethiol (WR-1065) by Cu-dependent amine oxidases and influence on glutathione status of Chinese hamster ovary cells.
The radioprotective drug 2-(3-aminopropylamino)ethanethiol (WR-1065) can be degraded when incubated in cell culture medium in vitro. The degradation reaction consumes oxygen and results from the action of Cu-dependent amine oxidases present in the serum content of the medium. Analysis of the degradation products of WR-1065 demonstrates the formation of cysteamine, acrolein and H2O2. WR-2721, the inactive prodrug of WR-1065, is not a substrate for these enzymes. Extracellular degradation of WR-1065 by Cu-dependent amine oxidases leads to an intracellular depletion of glutathione (GSH) in Chinese hamster ovary (CHO) cells and to reduction of clonogenic cell survival. Addition of aminoguanidine, an inhibitor of Cu-dependent amine oxidases, protects CHO cells from the toxic effects of WR-1065 and under these conditions an increase of intracellular GSH levels occurs. These data demonstrate that WR-1065 can be degraded to toxic compounds by the presence of Cu-dependent amine oxidases which might have further implications for the clinical use of WR-2721.
Meier
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Forschungszentrum für Umwelt und Gesundheit (GSF), Institut für Klinische Hämatoloige and Klinikum Grosshadern, Ludwig-Maximilians-Universität München, Germany.
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D000171:Acrolein / Q000032:analysis; D004999:Amifostine / Q000378:metabolism; D006631:Amine Oxidase (Copper-Containing); D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D002470:Cell Survival; D003300:Copper / Q000378:metabolism*; D006224:Cricetinae; D003470:Culture Media / Q000737:chemistry; D003543:Cysteamine / Q000032:analysis; D005978:Glutathione / Q000032:analysis*; D006146:Guanidines / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000032:analysis; D008624:Mercaptoethylamines / Q000378:metabolism* / Q000633:toxicity; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000378:metabolism*; D013095:Spermidine / Q000494:pharmacology
D003470:Culture Media; D006146:Guanidines; D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D003543:Cysteamine; D000171:Acrolein; D003300:Copper; D006861:Hydrogen Peroxide; D006631:Amine Oxidase (Copper-Containing); D000587:Oxidoreductases Acting on CH-NH Group Donors; D005978:Glutathione; D004999:Amifostine; C004479:pimagedine; D013095:Spermidine