1. Linderane (LDR), a furan-containing sesquiterpenoid, is found in Lindera aggregata (Sims) Kosterm, a common traditional Chinese herbal medicine. We thoroughly studied the irreversible inhibitory effect of LDR on cytochrome P450 2C9 (CYP2C9).
METHODS AND RESULTS:
2. LDR caused a time- and concentration-dependent inactivation of CYP2C9. In addition, the inactivation of CYP2C9 by LDR was NADPH-dependent and irreversible. More than 50% of CYP2C9 activity was lost after its incubation with LDR at the concentration of 10 μM for 15 min at 30 °C. The maximal rate constant for inactivation (kinact) was found to be 0.0419 min(-1), and the concentration required for half-maximal inactivation (KI) was 1.26 μM, respectively. Glutathione (GSH), catalase, and superoxide dismutase (SOD) failed to protect CYP2C9 against inactivation by LDR. Diclofenac, a substrate of CYP2C9, prevented the enzyme from inactivation produced by LDR. The estimated partition ratio of the inactivation was approximately 227. 3. Two reactive intermediates, including furanoepoxide and γ-ketoenal, might be responsible for the observed enzyme inactivation. The formation of the intermediates was verified by chemical synthesis.
CONCLUSIONS:
Multiple P450 enzymes, including CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5, were found to be involved in the metabolic activation of LDR. In conclusion, LDR was characterized as a mechanism-based inactivator of CYP2C9. |
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