Abstract
With NADPH as the electron donor, rat liver NADPH cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4) catalyzes the single-electron reduction of several quinone antibiotics to a semiquinone or free radical state. The benzanthraquinones adriamycin, daunorubicin, carminomycin, 7-O-methylnogalarol, and aclacinomycin A and the N-heterocyclic quinones streptonigrin and mitomycin C are activated to free radical intermediates which can transfer their single electron to molecular oxygen to form superoxide. The overall Km range for this electron transfer is 0.4 to 42.1 X 10(-4) M. We postulate that the formation of the "site-specific free radical/ intermediate is central to the cytotoxic action of these antibiotics.
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Selected References
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- BLOIS M. S., Jr, MALING J. E. The coenzyme Q10 and vitamin K1 semiquinone free radicals. Biochem Biophys Res Commun. 1960 Aug;3:132–135. doi: 10.1016/0006-291x(60)90207-2. [DOI] [PubMed] [Google Scholar]
- Bachur N. R., Cradock J. C. Daunomycin metabolism in rat tissue slices. J Pharmacol Exp Ther. 1970 Nov;175(2):331–337. [PubMed] [Google Scholar]
- Bachur N. R. Daunorubicinol, a major metabolite of daunorubicin: isolation from human urine and enzymatic reactions. J Pharmacol Exp Ther. 1971 Jun;177(3):573–578. [PubMed] [Google Scholar]
- Bachur N. R., Gordon S. L., Gee M. V. A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res. 1978 Jun;38(6):1745–1750. [PubMed] [Google Scholar]
- Bachur N. R., Gordon S. L., Gee M. V. Anthracycline antibiotic augmentation of microsomal electron transport and free radical formation. Mol Pharmacol. 1977 Sep;13(5):901–910. [PubMed] [Google Scholar]
- Bachur N. R., Hildebrand R. C., Jaenke R. S. Adriamycin and daunorubicin disposition in the rabbit. J Pharmacol Exp Ther. 1974 Nov;191(2):331–340. [PubMed] [Google Scholar]
- Bachur N. R., Moore A. L., Bernstein J. G., Liu A. Tissue distribution and disposition of daunomycin (NCS-82151) in mice: fluorometric and isotopic methods. Cancer Chemother Rep. 1970 Apr;54(2):89–94. [PubMed] [Google Scholar]
- Cone R., Hasan S. K., Lown J. W., Morgan A. R. The mechanism of the degradation of DNA by streptonigrin. Can J Biochem. 1976 Mar;54(3):219–223. doi: 10.1139/o76-034. [DOI] [PubMed] [Google Scholar]
- Goodman J., Hochstein P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem Biophys Res Commun. 1977 Jul 25;77(2):797–803. doi: 10.1016/s0006-291x(77)80048-x. [DOI] [PubMed] [Google Scholar]
- Goodman M. F., Bessman M. J., Bachur N. R. Adriamycin and daunorubicin inhibition of mutant T4 DNA polymerases. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1193–1196. doi: 10.1073/pnas.71.4.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gregory E. M., Fridovich I. Oxygen toxicity and the superoxide dismutase. J Bacteriol. 1973 Jun;114(3):1193–1197. doi: 10.1128/jb.114.3.1193-1197.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Handa K., Sato S. Generation of free radicals of quinone group-containing anti-cancer chemicals in NADPH-microsome system as evidenced by initiation of sulfite oxidation. Gan. 1975 Feb;66(1):43–47. [PubMed] [Google Scholar]
- IYER V. N., SZYBALSKI W. MITOMYCINS AND PORFIROMYCIN: CHEMICAL MECHANISM OF ACTIVATION AND CROSS-LINKING OF DNA. Science. 1964 Jul 3;145(3627):55–58. doi: 10.1126/science.145.3627.55. [DOI] [PubMed] [Google Scholar]
- Iyanagi T., Yamazaki I. One-electron-transfer reactions in biochemical systems. 3. One-electron reduction of quinones by microsomal flavin enzymes. Biochim Biophys Acta. 1969 Apr 8;172(3):370–381. doi: 10.1016/0005-2728(69)90133-9. [DOI] [PubMed] [Google Scholar]
- Lown J. W., Sim S. K., Majumdar K. C., Chang R. Y. Strand scission of DNA by bound adriamycin and daunorubicin in the presence of reducing agents. Biochem Biophys Res Commun. 1977 Jun 6;76(3):705–710. doi: 10.1016/0006-291x(77)91557-1. [DOI] [PubMed] [Google Scholar]
- Meriwether W. D., Bachur N. R. Inhibition of DNA and RNA metabolism by daunorubicin and adriamycin in L1210 mouse leukemia. Cancer Res. 1972 Jun;32(6):1137–1142. [PubMed] [Google Scholar]
- Mizuno N. S. Effects of streptonigrin on nucleic acid metabolism of tissue culture cells. Biochim Biophys Acta. 1965 Nov 8;108(3):394–403. doi: 10.1016/0005-2787(65)90032-8. [DOI] [PubMed] [Google Scholar]
- Murakami H. Electron aspects of the mode of action of the mitomycin molecule. J Theor Biol. 1966 Feb;10(2):236–250. doi: 10.1016/0022-5193(66)90125-1. [DOI] [PubMed] [Google Scholar]
- Myers C. E., McGuire W. P., Liss R. H., Ifrim I., Grotzinger K., Young R. C. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977 Jul 8;197(4299):165–167. doi: 10.1126/science.877547. [DOI] [PubMed] [Google Scholar]
- NISHIBAYASHI H., OMURA T., SATO R. A flavoprotein oxidizing NADPH isolated from liver microsomes. Biochim Biophys Acta. 1963 Mar 12;67:520–522. doi: 10.1016/0006-3002(63)91861-4. [DOI] [PubMed] [Google Scholar]
- Omura T., Takesue S. A new method for simultaneous purification of cytochrome b5 and NADPH-cytochrome c reductase from rat liver microsomes. J Biochem. 1970 Feb;67(2):249–257. doi: 10.1093/oxfordjournals.jbchem.a129248. [DOI] [PubMed] [Google Scholar]
- Riggs C. E., Jr, Benjamin R. S., Serpick A. A., Bachur N. R. Bilary disposition of adriamycin. Clin Pharmacol Ther. 1977 Aug;22(2):234–241. doi: 10.1002/cpt1977222234. [DOI] [PubMed] [Google Scholar]
- SCHWARTZ H. S., SODERGREN J. E., PHILIPS F. S. MITOMYCIN C: CHEMICAL AND BIOLOGICAL STUDIES ON ALKYLATION. Science. 1963 Nov 29;142(3596):1181–1183. doi: 10.1126/science.142.3596.1181. [DOI] [PubMed] [Google Scholar]
- Schwartz H. S. DNA breaks in P288 tumor cells in mice after treatment with daunorubicin and adriamycin. Res Commun Chem Pathol Pharmacol. 1975 Jan;10(1):51–64. [PubMed] [Google Scholar]
- Tomasz M. H2O2 generation during the redox cycle of mitomycin C and dna-bound mitomycin C. Chem Biol Interact. 1976 Apr;13(1):89–97. doi: 10.1016/0009-2797(76)90016-8. [DOI] [PubMed] [Google Scholar]
- Ward D. C., Reich E., Goldberg I. H. Base specificity in the interaction of polynucleotides with antibiotic drugs. Science. 1965 Sep 10;149(3689):1259–1263. doi: 10.1126/science.149.3689.1259. [DOI] [PubMed] [Google Scholar]
- White H. L., White J. R. Interaction of streptonigrin with DNA in vitro. Biochim Biophys Acta. 1966 Sep;123(3):648–651. doi: 10.1016/0005-2787(66)90241-3. [DOI] [PubMed] [Google Scholar]
- White H. L., White J. R. Lethal action and metabolic effects of streptonigrin on Escherichia coli. Mol Pharmacol. 1968 Nov;4(6):549–565. [PubMed] [Google Scholar]