Work

CPR-Centered Redox Interactions Between Cytochrome P450 Oxidoreductase and Cytochrome c Oxidase: Potential Pharmacological Implications

Year: 2026

Type: review

Abstract: The intracellular pool of nicotinamide adenine dinucleotide phosphate (NADPH) is a limited resource for which multiple enzyme systems compete. Among these systems, microsomal NADPH-cytochrome P450 oxidoreductase (CPR, POR) plays a central role in electron transfer to cytochrome P450 enzymes and can also reduce other redox-active electron acceptors in vitro. This review analyzes the molecular basis of competition between CPR-mediated cytochrome P450 reduction and cytochrome c reduction in vitro and discusses whether this can be extrapolated to an indirect interplay between CPR and cytochrome c oxidase (COX) in intact cells. In vitro, reduced cytochrome c (Fe2+) acts as a competitive inhibitor of NADPH-dependent cytochrome P450 reduction, apparently by binding to an overlapping site on CPR. However, CPR and COX are physically separated by subcellular compartmentalization, and cytosolic and mitochondrial NADPH pools are largely separate; therefore, CPR and COX should not be considered direct competitors for a common NADPH pool under physiological conditions. Potential pharmacological implications include modulation of drug metabolism, cellular energy homeostasis, and toxicity when both systems are challenged, but these remain hypothetical and require direct flux measurements in intact cells.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27209075

Author: Vladimir S. Ponamarev

Language: English

Topic: Pharmacogenetics and Drug Metabolism

Subfield: Pharmacology

Field: Pharmacology, Toxicology and Pharmaceutics

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499

Funders: Saint Petersburg State University, Russian Science Foundation