One- and two-electron reductase enzymes

One- and two-electron reductase enzymes are a diverse group of oxidoreductases that facilitate the transfer of electrons to various endogenous and exogenous substrates, playing a critical role in cellular redox balance and xenobiotic metabolism (Kappus, H. (1986). "Overview of enzyme systems involved in bio-reduction of drugs and in formation of reactive oxygen species". Archives of Toxicology). One-electron reductases, such as NADPH-cytochrome P450 reductase (POR), transfer a single electron to substrates like quinones or nitro compounds, frequently generating reactive radical intermediates (Belinsky, M., & Jaiswal, A. K. (1993). "NAD(P)H:quinone oxidoreductase 1 (DT-diaphorase) expression in normal and tumor tissues". Cancer Metastasis Reviews). These radicals can undergo redox cycling in the presence of oxygen to produce superoxide radicals, leading to oxidative stress. In contrast, two-electron reductases, most notably NAD(P)H:quinone oxidoreductase 1 (NQO1), catalyze the simultaneous transfer of two electrons (Ross, D., et al. (2000). "NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms". Chemico-Biological Interactions). This two-electron process generally bypasses the formation of reactive radicals and serves as a key detoxification pathway for the cell. These enzymes are strategically targeted in oncology for the activation of bioreductive prodrugs, such as Mitomycin C and Tirapazamine, which are designed to be converted into cytotoxic agents specifically within the hypoxic environment of solid tumors (Wilson, W. R., & Hay, M. P. (2011). "Targeting hypoxia in cancer therapy". Nature Reviews Cancer). The therapeutic utility of these enzymes depends on their differential expression in tumor versus normal tissues and the oxygen-dependent stability of the resulting drug intermediates. However, the potential for systemic toxicity remains a challenge, particularly if these enzymes activate drugs in well-oxygenated healthy tissues or if the resulting oxidative stress exceeds the cell's antioxidant capacity (Workman, P. (1994). "Enzyme-directed bioreductive drug development". Oncology Research).

Other names

Bioreductive enzymesQuinone reductasesOxidoreductasesDT-diaphoraseNADPH-cytochrome P450 reductasePORNQO1

Bioreductive activation of prodrugs into cytotoxic species and induction of oxidative stress via redox cycling (Wilson & Hay, 2011; Kappus, 1986).