3,5-Dihydroxybenzoic Acid as a Potent Inhibitor of Tyrosine Phenol-Lyase Decreases Fecal Phenol Levels in Mice

Phenol is produced by beta-elimination of l-tyrosine (Tyr) catalyzed by tyrosine phenol-lyase (TPL) during intestinal bacterial metabolism. Phenol and its conjugate, phenyl sulfate (PhS), are protein-bound uremic toxins (PBUTs). Elevated levels of phenol and PhS are strongly implicated in the etiology and outcomes of uremia. Because hemodialysis is insufficient in removing phenol and PhS, novel methods are necessary for inhibiting phenol production during bacterial metabolism. We explored TPL inhibitors and found that dietary polyphenols, particularly gallic acid (GA), strongly inhibited TPL-catalyzed phenol production. A GA derivative, 3,5-dihydroxybenzoic acid (3,5DHBA), competitively inhibited TPL and significantly decreased phenol levels in TPL-expressing bacteria (Morganella morganii and Citrobacter koseri) and Tyr-rich-diet-fed C57BL/6J mouse feces. Our findings suggested that 3,5DHBA was the most promising polyphenol in decreasing phenol levels. Therefore, dietary intake of 3,5DHBA or its phenolic precursors may be useful in minimizing PBUT levels by targeting intestinal bacteria.