Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species.

Background: Baicalein is the major bioactive flavonoid in some herb medicines and dietary plants; however, the detailed metabolism pathway of its major metabolite oroxylin A-7-O-β-D-glucuronide in human was not clear. It was important to illustrate the major metabolic enzymes that participate in its elimination for the clinic use of baicalein.

Objectives: We first revealed a two-step metabolism profile for baicalein and illustrated the combination of catechol-O-methyltransferase (COMT) and uridine diphosphate-glucuronosyltransferases (UGTs) in drug metabolism, further evaluated its bioactivity variation during drug metabolism.

Methods: The metabolism profiles were systematically characterized in different human biology preparations; after then, the anti-inflammatory activities of metabolites were evaluated in LPS-induced RAW264.7 cell.

Results: The first-step metabolite of baicalein was isolated and identified as oroxylin A; soluble-bound COMT (S-COMT) was the major enzyme responsible for its biotransformation. Specially, position 108 mutation of S-COMT significantly decreases the elimination. Meantime, oroxylin A was rapidly metabolized by UGTs, UGT1A1, -1A3, -1A6, -1A7, -1A8, -1A9, and -1A10 which were involved in the glucuronidation. Considerable species differences were observed with 1060-fold K (3.05 ± 1.86-3234 ± 475 μM) and 330-fold CL (5.93-1973 μL/min/mg) variations for baicalein metabolism. Finally, the middle metabolite oroxylin A exhibited a potent anti-inflammatory activity with the IC value of 28 μM.

Conclusion: The detailed kinetic parameters indicated that COMT provide convenience for the next glucuronidation; monkey would be a preferred animal model for the preclinical investigation of baicalein. Importantly, oroxylin A should be reconsidered in evaluating baicalein efficacy against inflammatory diseases.