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Background: ALDH1A1 is a key enzyme mediating the metabolic activation of Isosorbide 5-Mononitrate (IS?5?MN). IS-5-MN is frequently co-administered with traditional Chinese medicines (TCMs) in clinical practice. This study aimed to establish an ALDH1A1 activity evaluation system and identify relevant TCM inhibitors for rational co-medication.
Methods: As theophylline acetaldehyde (TA) as a potential ALDH substrate probe, we confirmed the dominant role of ALDH1A1 in TA oxidative metabolism via metabolic phenotyping. An in vitro ALDH1A1 activity assay was then developed using TA as the probe substrate. With this system, 47 clinically relevant TCMs and their major monomeric components were systematically screened for ALDH1A1 inhibitory activity and mechanism. Selected potent inhibitors were further evaluated for in vivo drug–drug interaction potential in rats
Results: 1) TA was mainly oxidized to TAA by ALDH1A1, and a TA?based assay for ALDH1A1 activity was successfully established. 2) Multiple TCMs and their monomer components exhibited significant inhibitory activity against ALDH1A1. Among them, 12 monomers showed IC50 < 3 μM, and five compounds, including diosmetin and acacetin, had IC50 < 1 μM. Mechanistic studies revealed that ginsenosides Rh3 and Rh4 were time-dependent inhibitors, whereas most others were non-time-dependent inhibitors. Diosmetin and dicoumarol exhibited competitive inhibition; myricetin and isoxanthohumol showed non-competitive inhibition; and acacetin and quercetin displayed mixed-type inhibition. 3) In vivo, dicoumarol, ginsenoside Rh3, and Rh4 significantly inhibited IS‑5‑MN degradation and altered its pharmacokinetic profiles.
Conclusion: A reliable TA?based ALDH1A1 activity assay was established. Multiple TCM components inhibit ALDH1A1 and impair IS?5?MN metabolism, representing potential clinical DDI risks.
