The relationships between cytochromes P450 and H2O2: Production, reaction, and inhibition

In this review we address the relationship between cytochromes P450 (P450) and H2O2. This association can affect biology in three distinct ways. First, P450s produce H2O2 as a byproduct either during catalysis or when no substrate is present. This reaction, known as uncoupling, releases reactive oxygen species that may have implications in disease. Second, H2O2 is used as an oxygen-donating co-substrate in peroxygenase and peroxidase reactions catalyzed by P450s. This activity has proven to be important mainly in reactions involving prokaryotic P450s, and investigators have harnessed this reaction with the aim of adaptation for industrial use. Third, H2O2-dependent inhibition of human P450s has been studied in our laboratory, demonstrating heme destruction and also the inactivating oxidation of the heme-thiolate ligand to a sulfenic acid (-SOH). This reversible oxidative modification of P450s may have implications in the prevention of uncoupling and may give new insights into the oxidative regulation of these enzymes. Research has elucidated many of the chemical mechanisms involved in the relationship between P450 and H2O2, but the application to biology is difficult to evaluate. Further studies are needed reveal both the harmful and protective natures of reactive oxygen species in an organismal context. Cytochromes P450 and H2O2 have a complex relationship that involves three aspects: (1) H2O2 production through an uncoupling mechanism. (2) Peroxidase/peroxygenase reactions that use H2O2 as an oxygen donating co-substrate. (3) H2O2-dependent inhibition of P450 through oxidation of the heme-thiolate ligand. [Display omitted] •P450s produce H2O2;known as uncoupling, th is releases reactive oxygen species that may have implications in disease.•H2O2 is an oxygen surrogate in some reactions catalyzed by P450 and has implications in industrial chemical synthesis.•Inhibition of human P450s by H2O2 occurs by oxidation of the heme-thiolate ligand, which may have physiological implications.