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. 2018 Feb:7:44-51.
doi: 10.1016/j.cotox.2017.10.003. Epub 2017 Oct 12.

ROLE OF CYTOCHROME P450S IN THE GENERATION AND METABOLISM OF REACTIVE OXYGEN SPECIES

Alex Veith  1   2 , Bhagavatula Moorthy  1   2
Affiliations

ROLE OF CYTOCHROME P450S IN THE GENERATION AND METABOLISM OF REACTIVE OXYGEN SPECIES

Alex Veith et al. Curr Opin Toxicol. 2018 Feb.

Abstract

The cytochrome P450 (CYP) enzymes are a diverse group of heme monooxygenases that, through the course of their reaction cycle, contribute to cellular reactive oxygen species (ROS). CYP enzymes play a crucial role in human physiology and are involved in drug and xenobiotic metabolism as well as biosynthesis of endogenous molecules and are expressed throughout the human body. However, during the course of the CYP catalytic cycle, ROS can be generated through uncoupling of the enzymatic cycle. ROS is known to modify endogenous molecules, included lipids, proteins, and nucleic acids, which can lead to cell damage and death and contribute to disease development. ROS has been implicated in a wide range of diseases and conditions, including cancer and ageing, but ROS also play a role in the normal physiological functions in the cell. Here, we discuss specific examples whereby ROS generated by CYPs contribute to or protect against various phenomena, such as hyperoxic lung injury, oxidative hepatic toxicity, formation of DNA adducts from lipid peroxidation products. We have also discussed the mechanistic roles of CYP enzymes belonging to various families, and their effect on cellular ROS production, in relation to normal cellular function as well as disease pathophysiology.

Keywords: Cytochrome P450; reaction uncoupling; reactive oxygen species.

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Figures

Figure 1
Figure 1. Mechanism by which CYPs contribute to ROS-mediated human diseases
As CYP enzymes metabolize their substrates, they can produce ROS which can increase cellular damage via increases in protein, nucleic acid, and lipid modifications. These products, including lipid peroxidation produces and DNA damage, are known to contribute to numerous human pathologies, including cancer.
Figure 2
Figure 2. Generalized CYP Reaction Mechanism
During the course of the CYP reaction mechanism, there are various steps that can generate ROS, shown in red. These ROS can then modify cellular components and contribute to disease. Reaction cycle adapted from refs [29] and [4].
See this image and copyright information in PMC

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