School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
Phytomedicine. 2023 Jan;108:154521. doi: 10.1016/j.phymed.2022.154521. Epub 2022 Oct 22.
Berberrubine (BRB), one of the major metabolites of berberine (BBR), exerts an anti-hyperuricemic effect even superior to BBR. Liver is an important location for drug transformation. Nevertheless, there are few studies on the bioactivities and metabolites of BRB.
We investigated whether oxyberberrubine (OBR), a liver metabolite of BRB, exerted urate-lowering and reno-protective effects in hyperuricemic mice.
Liver microsomes were used to incubate BRB for studying its biotransformation. We isolated and identified its new metabolite OBR, and investigated its anti-hyperuricemic and reno-protective effects. In this work, the hyperuricemic mice model was established by receiving potassium oxonate (PO) and hypoxanthine (HX) for 7 consecutive days. 1 h after modeling, different dosages of OBR (5, 10 and 20 mg/kg), BRB (20 mg/kg) or febuxostat (Fex, 5 mg/kg) were given mice by gavage.
Results showed that OBR possessed potent anti-hyperuricemic and reno-protective effects in hyperuricemic mice. Serum uric acid (UA) level was lowered, and the activities of xanthine oxidase (XOD) as well as adenosine deaminase (ADA) in the liver were suppressed after treatment with OBR. Hepatic expressions of XOD were remarkably decreased at mRNA and protein levels by OBR treatment. In addition, OBR prominently alleviated renal injury, embodied in markedly reduced serum creatinine and blood urea nitrogen (BUN) levels, decreased inflammatory mediators (TNF-α, IL-1β, IL-6 and IL-18) levels, mRNA expression of CYP27B1 and repairment of renal tissues damage. Besides, OBR down-regulated renal expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 at mRNA and protein levels.
In short, our study indicated that OBR possessed superior anti-hyperuricemic and reno-protective effects, at least in part, through the inhibition of XOD, URAT1, GLUT9 and NLRP3 inflammasome signaling pathway in the kidney.
小檗红碱（BRB）是小檗碱（BBR）的主要代谢物之一，其降尿酸作用甚至优于 BBR。肝脏是药物转化的重要场所。然而，关于 BRB 的生物活性和代谢物的研究较少。
研究 BRB 的肝代谢物氧小檗红碱（OBR）在高尿酸血症小鼠中是否具有降尿酸和肾保护作用。
使用肝微粒体孵育 BRB 研究其生物转化。我们分离并鉴定了其新的代谢物 OBR，并研究了其抗高尿酸血症和肾保护作用。在这项工作中，通过连续 7 天接受氧嗪酸钾（PO）和次黄嘌呤（HX）建立高尿酸血症小鼠模型。建模后 1 小时，给予不同剂量的 OBR（5、10 和 20mg/kg）、BRB（20mg/kg）或非布司他（Fex，5mg/kg）灌胃。
结果表明，OBR 对高尿酸血症小鼠具有较强的降尿酸和肾保护作用。血清尿酸（UA）水平降低，肝脏黄嘌呤氧化酶（XOD）和腺苷脱氨酶（ADA）活性受到抑制。OBR 处理后，肝 XOD 的 mRNA 和蛋白表达明显降低。此外，OBR 明显减轻肾脏损伤，表现为血清肌酐和血尿素氮（BUN）水平显著降低，炎症介质（TNF-α、IL-1β、IL-6 和 IL-18）水平降低，CYP27B1 的 mRNA 表达和肾脏组织损伤修复。此外，OBR 下调了肾脏尿酸转运蛋白 1（URAT1）、葡萄糖转运蛋白 9（GLUT9）、NOD 样受体 3（NLRP3）、凋亡相关斑点样蛋白含 CARD（ASC）和半胱氨酸天冬氨酸蛋白酶-1 的 mRNA 和蛋白表达。
总之，我们的研究表明，OBR 通过抑制肾脏中的 XOD、URAT1、GLUT9 和 NLRP3 炎症小体信号通路，具有优越的降尿酸和肾保护作用。
