Effects of glutathione and ethylxanthate on mitomycin C activation by isolated rat hepatic or EMT6 mouse mammary tumor nuclei.
Mitomycin C (MC) activation to a reactive species was studied in nuclei isolated from rat liver and EMT6 tumor cells. Both preparations were similar in the rate of 4-(p-nitrobenzyl)pyridine (NBP) alkylation by MC and the levels of NADPH-cytochrome P-450 reductase. MC activation by both hepatic and EMT6 cell nuclei was inhibited by the presence of O2 and by heat inactivation. NADPH was preferred over NADH as the source of reducing equivalents by both types of isolated nuclei. MC activation to alkylating metabolites was not affected when EDTA or diethylenetriaminepentaacetic acid, two Fe2+ chelating agents, was present in the incubation system with either preparation of isolated nuclei. Glutathione (1 and 5 mM) and N-acetylcysteine (1 and 10 mM) both inhibited MC alkylation of NBP in nuclear preparations from rat liver and EMT6 tumor cells by 50-60%. Ethylxanthate (1 mM) effectively inhibited the MC alkylation of NBP by hepatic nuclei but was unable to inhibit MC alkylation of NBP by tumor cell nuclei. At 100 mM, ethylxanthate produced a slight stimulation in the rate of MC alkylation of NBP. These data are consistent with the hypothesis that MC activation in EMT6 tumor cells proceeds via a one electron reduction pathway which is inhibitable by glutathione but not inhibitable by ethylxanthate. Hepatic nuclei are apparently able to activate MC by either a one- or two-electron pathway.
K A
KA
Kennedy
E G
EG
Mimnaugh
M A
MA
Trush
B K
BK
Sinha
D000818:Animals; D001711:Biotransformation; D002467:Cell Nucleus / Q000378:metabolism*; D001728:Dicumarol / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology*; D006358:Hot Temperature; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D016685:Mitomycin; D008937:Mitomycins / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D004369:Pentetic Acid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013871:Thiones / Q000494:pharmacology*
D008937:Mitomycins; D013871:Thiones; D009243:NAD; D016685:Mitomycin; D004369:Pentetic Acid; D001728:Dicumarol; D004492:Edetic Acid; C004918:ethylxanthate; D005978:Glutathione; D010100:Oxygen