TY - JOUR
T1 - Metabolic activation of mitomycin C by liver microsomes and nuclei
AU - Kennedy, Katherine A.
AU - Sligar, Stephen G.
AU - Polomski, Lydia
AU - Sartorelli, Alan C.
N1 - Funding Information:
* Supported in part by U.S. Public Health Service Grants CA-02817, CA-16359 and GM-24976. t Recipient of U.S. Public Health Service Postdoctoral Fellowship CA-06177 from the National Cancer Institute. Present address: Department of Pharmacology, George Washington University, 2300 Eye Street NW, Washington, DC 20037, U.S.A. $ Recipient of Research Career Development Award AM-00778 from the National Institutes of Health. 5 To whom requests for reprints should be addressed.
PY - 1982/6/1
Y1 - 1982/6/1
N2 - Bioreductive alkylating agents require reductive activation prior to exerting their cytotoxic actions. This property results in preferential toxicity to hypoxic cells. Previous data have demonstrated that mitomycin C is activated by hypoxic tumor cells and is selectively cytotoxic to these oxygen-deficient cells. The biotransformation of mitomycin C was studied in liver microsomes and nuclei and in a reconstituted, partially purified cytochrome P-450 drug-metabolizing system to provide information on these reductive processes. Both the metabolism of mitomycin C, measured by disappearance of the quinone portion of the substrate, and the formation of an alkylating metabolite(s), determined by employing 4-(p-nitrobenzyl)pyridine as a trapping agent, required anaerobic conditions and an NADPH-generating system, and were inhibited by O2 and CO in both microsomes and nuclei. A reconstituted enzyme system consisting of NADPH, NADPH-cytochrome P-450 reductase, phospholipid and cytochrome P-450 converted mitomycin C to a reactive metabolite(s) under hypoxic conditions. Omission of N2 or any component of the system decreased the metabolic activation of mitomycin C. These findings support the concept that the cytochrome P-450 system is capable of activating mitomycin C under hypoxic conditions to the alkylating metabolite(s) that is responsible for antineoplastic activity.
AB - Bioreductive alkylating agents require reductive activation prior to exerting their cytotoxic actions. This property results in preferential toxicity to hypoxic cells. Previous data have demonstrated that mitomycin C is activated by hypoxic tumor cells and is selectively cytotoxic to these oxygen-deficient cells. The biotransformation of mitomycin C was studied in liver microsomes and nuclei and in a reconstituted, partially purified cytochrome P-450 drug-metabolizing system to provide information on these reductive processes. Both the metabolism of mitomycin C, measured by disappearance of the quinone portion of the substrate, and the formation of an alkylating metabolite(s), determined by employing 4-(p-nitrobenzyl)pyridine as a trapping agent, required anaerobic conditions and an NADPH-generating system, and were inhibited by O2 and CO in both microsomes and nuclei. A reconstituted enzyme system consisting of NADPH, NADPH-cytochrome P-450 reductase, phospholipid and cytochrome P-450 converted mitomycin C to a reactive metabolite(s) under hypoxic conditions. Omission of N2 or any component of the system decreased the metabolic activation of mitomycin C. These findings support the concept that the cytochrome P-450 system is capable of activating mitomycin C under hypoxic conditions to the alkylating metabolite(s) that is responsible for antineoplastic activity.
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U2 - 10.1016/0006-2952(82)90414-2
DO - 10.1016/0006-2952(82)90414-2
M3 - Article
C2 - 6810899
AN - SCOPUS:0019992640
VL - 31
SP - 2011
EP - 2016
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 11
ER -