Among NAD(P)H-dependent disulfide-reducing flavoenzymes, mammalian lipoamide dehydrogenase (LipDH, EC 1.8.1.4) possesses the highest quinone reductase activity. The mixed single- and two-electron reduction of quinones is performed via the FAD cofactor, with the participation of both 4e^–- and 2 e^–-reduced forms of LipDH. We found that Lip-DH reduced the anticancer aziridinyl-substituted quinones AZQ, DZQ, MeDZQ, RH1, and BZQ, whose reactivity (k_cat/K_m) increased with an increase in their single-electron reduction potential (E¹₇). At [NAD⁺]/[NADH] = 4.7 which corresponds to the LipDH turnover under the physiological conditions, i.e. its cycling between the oxidized and 2e–-reduced forms, the k_cat/K_m values for quinones were decreased by 8–20 times. We also found that the physiological substrate of LipDH, lipoamide, accelerated the reduction of aziridinyl-benzoquinones because of their parallel reduction by the reduction product, dihydrolipoamide (Lip(SH)₂). These reactions may be partly responsible for the cytotoxicity of aziridinylsubstituted benzoquinones, which arise both from their 1 e^–-reduction (oxidative stress) and from their 2e^–-reduction (formation of DNA-alkylating aziridinyl-hydroquinones).

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