Hyperforin (Phloroglucinol)

Hyperforin is a polyprenylated acylphloroglucinol derivative (molecular formula C35H52O4, MW 536.8 g/mol) and is not a nutritional source of macronutrients, vitamins, or minerals. It is the principal bioactive phloroglucinol compound found in Hypericum perforatum (St. John's Wort), typically concentrated in the reproductive structures (flowers and buds). Key biochemical and bioavailability details: • Concentration in dried St. John's Wort flowering tops: approximately 2–5% w/w in standardized pharmaceutical-grade extracts (e.g., WS 5570 extract standardized to 5% hyperforin); raw herb contains roughly 0.2–4.5% depending on harvest time and chemotype. • Co-occurring bioactive compounds in the native plant matrix include hypericin (0.1–0.3%), pseudohypericin, adhyperforin (structurally related acylphloroglucinol, present at ~0.2–1.9%), flavonoids (rutin, hyperoside, quercetin glycosides totaling 2–4%), and biflavones (amentoflavone, biapigenin). • Hyperforin is highly lipophilic (logP ~7–9) and chemically unstable; it is readily oxidized and degraded by light and oxygen, forming furohyperforin and other oxidation products, which significantly reduces effective concentration in poorly stabilized preparations. • Oral bioavailability is moderate but variable; peak plasma concentrations (Cmax) of approximately 150–300 ng/mL are reached 3–5 hours after a single 300 mg dose of extract containing ~5% hyperforin (≈15 mg hyperforin per dose). Steady-state plasma levels of ~100 ng/mL are achieved with standard t.i.d. dosing (900 mg extract/day providing ~45 mg hyperforin/day). • Elimination half-life is approximately 9–12 hours. Hyperforin is extensively metabolized hepatically, primarily via CYP3A4, and is itself a potent inducer of CYP3A4, CYP2C9, CYP2C19, and P-glycoprotein through activation of the pregnane X receptor (PXR/SXR). • Primary mechanism of action involves activation of TRPC6 (transient receptor potential canonical 6) cation channels, leading to non-selective inhibition of neurotransmitter reuptake (serotonin, norepinephrine, dopamine, GABA, and L-glutamate) with IC50 values in the range of 0.05–0.6 µM. • No significant caloric, protein, fiber, or mineral contribution; hyperforin is consumed exclusively as a phytopharmaceutical bioactive, not as a food or nutritional supplement in the macronutrient sense. • Stability-enhanced formulations (e.g., hyperforin dicyclohexylammonium salt or CO2 supercritical extracts in lipid matrices) improve shelf-life and may enhance oral bioavailability by protecting against oxidative degradation.