CPR-Centered Redox Interactions Between Cytochrome P450 Oxidoreductase and Cytochrome c Oxidase: Potential Pharmacological Implications
- 1Department of the Pharmacology and Toxicology, Federal State Budgetary Educational Institution of Higher Education “Saint-Petersburg State University of Veterinary Medicine”, 196084 Saint Petersburg, Russia
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.
Related
- Inhibition of cytochrome P450 activities by juglone in human and rat liver microsomes: kinetic characterization and implications for natural product–drug interaction assessment
- Diminazene as a Potential Pharmacological Candidate Against Tebuconazole-Induced Cardiotoxicity
- Vagal maneuvers and pharmacological cardioversion in stable PSVT: A systematic review with implications for emergency nursing practice
- Compartment-specific roles of gasdermin D and E in photoreceptor degeneration: evidence and pharmacological implications
- Tryptophan metabolism circadian regulation: clinical and pharmacological implications
BibTeX
@article{ponamarev2026cprcentered,
title = {{CPR-Centered Redox Interactions Between Cytochrome P450 Oxidoreductase and Cytochrome c Oxidase: Potential Pharmacological Implications}},
author = {Vladimir S. Ponamarev},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209075},
url = {https://www.mdpi.com/1422-0067/27/20/9075},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CPR-Centered Redox Interactions Between Cytochrome P450 Oxidoreductase and Cytochrome c Oxidase: Potential Pharmacological Implications
AU - Vladimir S. Ponamarev
PY - 2026
DA - 2026/10/13
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209075
UR - https://www.mdpi.com/1422-0067/27/20/9075
AB - 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.
SN - 1422-0067
ER -