Kobayashi Takuma, Oishi Shiori, Matsui Misaki, Hara Kodai, Hashimoto Hiroshi, Watanabe Kenji, Yoshioka Yasukiyo, Miyoshi Noriyuki
Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, 4228526, Japan.
School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, 4228526, Japan.
PNAS Nexus. 2024 Jul 4;3(7):pgae265. doi: 10.1093/pnasnexus/pgae265. eCollection 2024 Jul.
Tyrosine phenol-lyase (TPL), which is expressed in intestinal bacteria, catalyzes the formation of phenol from the substrate L-Tyr. Bacterial metabolite phenol and the sulfate conjugate (phenyl sulfate) are known as a type of uremic toxins, some of which exert cytotoxicity. Therefore, pathologically elevated phenol and phenyl sulfate levels are strongly implicated in the etiology and outcome of uremia. In this study, we explored the inhibitory effects of dietary polyphenols on TPL-catalyzed phenol production using a TPL activity assay. Quercetin, one of the most popular polyphenols, exhibited the strongest inhibitory activity ( = 19.9 µM). Quercetin competitively inhibited TPL, and its activity was stronger than that of a known TPL inhibitor (Tyr analog; 2-aza-Tyr, = 42.0 µM). Additionally, quercetin significantly inhibited phenol production in TPL-expressing bacterial cultures ( and ) and Tyr-rich (5%) diet-fed C57BL/6J mouse feces. Our findings suggest that quercetin is the most promising polyphenol for reducing phenol levels. Because quercetin has a low gastrointestinal absorption rate, TPL inhibition in the intestinal tract by quercetin may be an effective strategy for treating uremia.
酪氨酸苯酚裂解酶（TPL）在肠道细菌中表达，催化底物L-酪氨酸生成苯酚。细菌代谢产物苯酚及其硫酸酯共轭物（硫酸苯酯）是一种尿毒症毒素，其中一些具有细胞毒性。因此，病理状态下苯酚和硫酸苯酯水平的升高与尿毒症的病因和预后密切相关。在本研究中，我们使用TPL活性测定法探究了膳食多酚对TPL催化苯酚生成的抑制作用。槲皮素是最常见的多酚之一，表现出最强的抑制活性（IC50 = 19.9 μM）。槲皮素竞争性抑制TPL，其活性强于已知的TPL抑制剂（酪氨酸类似物；2-氮杂酪氨酸，IC50 = 42.0 μM）。此外，槲皮素显著抑制表达TPL的细菌培养物（以及）和富含酪氨酸（5%）饮食喂养的C57BL/6J小鼠粪便中的苯酚生成。我们的研究结果表明，槲皮素是降低苯酚水平最有前景的多酚。由于槲皮素的胃肠道吸收率较低，槲皮素对肠道中TPL的抑制可能是治疗尿毒症的有效策略。
