Mitochondrial and Pharmacokinetic Insights into 3,5,7,2’,6’-Pentahydroxyflavanone: Respiratory Modulation, Calcium Handling, and Membrane Stability
DOI:
https://doi.org/10.48048/tis.2025.10984Keywords:
3,5,7,2′,6′-Pentahydroxyflavanone; Mitochondrial respiration; Oxidative phosphorylation; Calcium accumulation; Membrane stabilization; Dehydrogenase activity; ADMET profiling; Cytochrome P450; Flavonoid; Cytoprotection; Pharmacokinetics; In vitro; In vivoAbstract
This study investigates the mitochondrial effects and pharmacokinetic profile of 3,5,7,2’,6’-pentahydroxyflavanone (PHF), a naturally occurring flavonoid. In vitro results showed that PHF at 40 and 60 µg/mg protein reduced glutamate-supported state 3 respiration by 6% - 10% and slightly increased state 4 respiration, leading to a decrease in respiratory control ratio (RCR) and ADP/O ratio. For succinate as substrate, PHF at the same doses reduced V3, V4, and VDNP respiration rates by 15% - 33% and increased the ADP/O ratio up to 1.44-fold, indicating enhanced coupling efficiency. Enzymatic assays revealed that PHF selectively suppressed succinate dehydrogenase and oxidase activities by up to 25% without affecting NADH-linked enzyme systems. Notably, PHF reduced mitochondrial calcium uptake by 10.7% - 47.8% in a dose-dependent manner (100 - 500 mg/kg, i.p.) and attenuated the activity of membrane-bound oxidases under phospholipase A2 stress, suggesting membrane-stabilizing effects. ADMETlab predictions indicated favorable drug-like properties (MW 286.05, logP 2.25, TPSA 111.13), high plasma protein binding (PPB 95.2%), and acceptable oral bioavailability (F50%: +++). PHF was predicted to inhibit CYP1A2, CYP2D6, and CYP3A4 enzymes but not act as their substrate. Toxicity alerts were minimal, though genotoxicity (0.956) and eye irritation (0.996) probabilities were elevated. Taken together, PHF demonstrates mitochondria-targeted bioactivity and a moderate ADMET profile, positioning it as a potential lead compound for cytoprotective drug development.
HIGHLIGHTS
- 3,5,7,2’,6’-Pentahydroxyflavanone (PHF) selectively modulates mitochondrial respiration depending on the substrate used.
- PHF decreases glutamate-supported oxidative phosphorylation and enhances coupling efficiency during succinate oxidation.
- The compound significantly reduces mitochondrial Ca2+ accumulation in a dose-dependent manner (up to 47.8%).
- PHF stabilizes mitochondrial membrane enzymes under thermal and phospholipase A2-induced stress.
- ADMET profiling confirms PHF has favorable drug-likeness, low cardiotoxicity, and high predicted oral bioavailability.
- PHF exhibits selective interaction with CYP450 enzymes and low toxicity alerts, supporting its drug development potential.
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