Mechanism-Based Inactivation of Cytochrome P450 3A by Evodol

Xenobiotica. 2023 Apr 24:1-33. doi: 10.1080/00498254.2023.2207200. Online ahead of print.ABSTRACT1. Evodol is one of the furanoids isolated from the fruits of Evodia rutaecarpa that has been widely prescribed for the treatment of gastrointestinal diseases in China. The aim of this study was to investigate the inhibitory effect of evodol on CYP3A.2. A 30-min preincubation of evodol with human liver microsomes raised an obvious left IC50 shift, 3.9-fold for midazolam 1'-hydroxylation and 3.2-fold for testosterone 6β-hydroxylation. Evodol inactivated CYP3A in a time-, concentration- and NADPH-dependent manner, with KI and kinact of 5.1 μM and 0.028 min-1 for midazolam 1'-hydroxylation and 3.0 μM and 0.022 min-1 for testosterone 6β-hydroxylation.3. Co-incubation of ketoconazole attenuated the inactivation while inclusion of glutathione (GSH) and catalase/superoxide dismutase displayed no such protection.4. cis-Butene-1, 4-dial (BDA) intermediate derived from evodol were trapped by glutathione and N-acetyl-lysine in microsomes and characterized by HR-MS spectra. The BDA intermediate was believed to play a key role in CYP3A inactivation. CYP3A4 and 2C9 were the primary enzymes contributing to the bioactivation of evodol.5. To sum up, for the first time evodol was characterized as a mechanism-based inactivator of CYP3A.PMID:37092795 | DOI:10.1080/00498254.2023.2207200
Source: Xenobiotica - Category: Research Authors: Source Type: research