Mode of action for mitomycin C inactivating factors of Pseudomonas convexa 4-87.

Abstract

Mutagenicity of the anti-cancer agent mitomycin C was suppressed by incubation with the desmutagenic factor of Pseudomonas convexa 4-87 and NAD(P)H. The main reaction products were isolated and identified as \,2-cis-and l,2-?ra«s-2,7-diamino-l-hydroxymitosene and 2,7diaminomitosene. A reaction schemethrough reduction of the benzoquinone moiety, elimination of the methoxy group, opening of the aziridine ring, and formation of mitosene-type derivatives was proposed. The desmutagenic factor of P. convexa 4-87 was shown to be a quinone-reducing enzyme requiring NAD(P)H, but its physiological role in the cell remains unclear. Since its discovery by Wakaki et al. in 1958,1* mitomycin C (MMC)has been extensively studied for its unique structure and strong antitumor activity. It is used clinically as an antitumor agent in spite of its rather high toxicity. Pioneering work by Iyer and Szybalski,2) and by Schwartz et al.3) clearly demonstrated that MMC was activated by biological reductive systems. Various metabolic pathways have been postulated.4~6) Recently, Tomasz and Lipman7) succeeded in identifying some metabolites of MMC generated by incubation of MMC with rat liver microsomes and NADPH under anaerobic conditions. All the metabolites thus obtained were 2,7-diaminomitosene type derivatives, in which the C-l position was substituted. Hashimoto et al.8) obtained MMC modified DNA adducts from rat liver intraperitoneally injected with MMC, and the C-l position of its mitosene moiety was modified. Recently,