Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
New Use Agriculture & Natural Plant Products Program, Department of Plant Biology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901, USA.
Int J Mol Sci. 2021 Jul 12;22(14):7460. doi: 10.3390/ijms22147460.
Dihydromyricetin is a natural bioactive flavonoid with unique GABA receptor activity with a putative mechanism of action to reduce the intoxication effects of ethanol. Although dihydromyricetin's poor oral bioavailability limits clinical utility, the promise of this mechanism for the treatment of alcohol use disorder warrants further investigation into its specificity and druggable potential. These experiments investigated the bioavailability of dihydromyricetin in the brain and serum associated with acute anti-intoxicating effects in C57BL/6J mice. Dihydromyricetin (50 mg/kg IP) administered 0 or 15-min prior to ethanol (PO 5 g/kg) significantly reduced ethanol-induced loss of righting reflex. Total serum exposures (AUC024) of dihydromyricetin (PO 50 mg/kg) via oral (PO) administration were determined to be 2.5 µM × h (male) and 0.7 µM × h (female), while intraperitoneal (IP) administration led to 23.8-fold and 7.2- increases in AUC024 in male and female mice, respectively. Electrophysiology studies in α5β3γ2 GABA receptors expressed in Xenopus oocytes suggest dihydromyricetin (10 µM) potentiates GABAergic activity (+43.2%), and the metabolite 4-O-methyl-dihydromyricetin (10 µM) negatively modulates GABAergic activity (-12.6%). Our results indicate that administration route and sex significantly impact DHM bioavailability in mice, which is limited by poor absorption and rapid clearance. This correlates with the observed short duration of DHM's anti-intoxicating properties and highlights the need for further investigation into mechanism of DHM's potential anti-intoxicating properties.
二氢杨梅素是一种具有独特 GABA 受体活性的天然生物活性黄酮类化合物，其作用机制可能是降低乙醇的中毒作用。尽管二氢杨梅素的口服生物利用度较差限制了其临床应用，但鉴于其作用机制在治疗酒精使用障碍方面具有应用前景，因此有必要进一步研究其特异性和可成药性。这些实验研究了二氢杨梅素在 C57BL/6J 小鼠大脑和血清中的生物利用度及其与急性解毒作用的关系。在给予乙醇（PO 5 g/kg）前 0 或 15 分钟给予二氢杨梅素（IP 50 mg/kg），可显著减少乙醇诱导的翻正反射丧失。通过口服（PO）给予 50 mg/kg 二氢杨梅素的总血清暴露（AUC024）分别为雄性 2.5 µM × h 和雌性 0.7 µM × h，而腹腔内（IP）给予分别导致雄性和雌性小鼠 AUC024 增加 23.8 倍和 7.2-倍。在表达于非洲爪蟾卵母细胞的 α5β3γ2 GABA 受体中的电生理学研究表明，二氢杨梅素（10 µM）增强了 GABA 能活性（+43.2%），而代谢产物 4-O-甲基二氢杨梅素（10 µM）负性调节 GABA 能活性（-12.6%）。我们的结果表明，给药途径和性别显著影响小鼠中二氢杨梅素的生物利用度，这是由于吸收不良和快速清除所致。这与二氢杨梅素解毒作用持续时间短的观察结果相关，突出了需要进一步研究二氢杨梅素潜在解毒作用的机制。
