NADPH as a Bifurcation Point: Pharmacological Antagonism Between Cytochrome P450 Oxidoreductase and Cytochrome-C Oxidase

The intracellular pool of reduced nicotinamide adenine dinucleotide phosphate (NADPH) is a limited resource for which multiple enzyme systems compete. At the center of this competition are two fundamentally different oxidoreductases: microsomal NADPH‑cytochrome P450 oxidoreductase (CPR, POR) and mitochondrial cytochrome‑c oxidase (COX, complex IV). In this review, we examine the molecular mechanisms of pharmacological antagonism between these enzymes, mediated by the common NADPH pool and competition for cytochrome c. It has been shown that reduced cytochrome c (Fe²⁺) acts as a competitive inhibitor of NADPH‑dependent reduction of cytochrome P450, binding to the same site on CPR as cytochrome P450. This creates a bifurcation point at which the direction of electron flow – into the mitochondrial respiratory chain or into the microsomal xenobiotic‑metabolizing system – is determined by the concentration ratio of competing acceptors and NADPH availability. Pharmacological consequences of this antagonism include modulation of drug metabolism, alterations in cellular energy homeostasis, and potential toxicity under simultaneous load on both systems. Understanding this antagonism opens new perspectives for predicting drug interactions and developing pharmacological correction strategies.