Reductive metabolism and alkylating activity of mitomycin C induced by rat liver microsomes

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Abstract
Mitomycin C, an antitumor antibiotic, is rapidly metabolized in the presence of rat liver microsomes. NADPH and anaerobic conditions are required for the process. The products isolated after reexposure to air are 2,7-diaminomitosene derivatives. Specifically, in the presence of Pi, 1,2-cis- and trans-2,7-diaminomitosene 1-phosphates, 1,2-cis- and -trans-2,7-diamino-1-hydroxymitosenes and 2,7-diaminomitosene are formed. The last substance is a new mitomycin C derivative and proof for its structure is presented. Mytomycin C has previously postulated to be an alkylating agent requiring reduction for activity [Iyer, V. N., and Szybalski, W. (1964)]. The 1-phosphates above represent the first chemically characterized bioreductive alkylation products of the drug. 5''-Uridylic acid is alkylated analogously under these conditions, to give cis- and trans-2,7-diaminomitosene 1-(5''-uridylate), while the phosphodiester UpU and uridine itself are inert. Hydrogen gas/PtO2 gives the same results are microsomes/NADPH. The formation of the observed compounds indicates that enzymatic (or chemical) reduction of the quinone system of mitomycin C induces ring opening of the aziridine function, generating a reactive center at the C1 position as previously postulated by others (ibid.). The 2nd alkylating center, also postulated, is not evident, however, under the conditions tested, indicating that the aziridine is the primary bioreductive alkylation function of mitomycin C. Identification of the products and mechanism of the microsomal anaerobic metabolism of mitomycin C are significant in view of the reported toxicity of the drug to anaerobic cancer cells.