Mechanism-based inactivation of cytochrome P450 3A4 by 4-ipomeanol.
Earlier phase I and II clinical studies showed that 4-ipomeanol produced selective hepatotoxicity. To investigate the mechanism of bioactivation of 4-ipomeanol, we thoroughly studied the interaction of 4-ipomeanol with human cytochrome P450 3A4 (EC 1.14.14.1). 4-Ipomeanol produced a time- and concentration-dependent inactivation of P450 3A4. More than 80% of the P450 3A4 activity was lost after its incubation with 4-ipomeanol at the concentration of 75 microM in 12 min. The inactivation was characterized by a rate of inactivation (kinact) of 0.15 min(-1) and by an inactivation potency (KI) of 20 microM. In addition, the inhibition of P450 3A4 by 4-ipomeanol was NADPH-dependent and irreversible. Glutathione, catalase, and superoxide dismutase failed to protect P450 3A4 from inactivation by 4-ipomeanol. The presence of testosterone, a substrate of P450 3A4, protected the enzyme from inactivation. The estimated partition ratio of the inactivation was approximately 257. Covalent binding studies demonstrated that reactive metabolites of 4-ipomeanol modified P450 3A4 but not P450 reductase (EC 1.6.2.4). The stoichiometry of binding between reactive metabolites of radiolabeled 4-ipomeanol and P450 3A4 was approximately 1.5:1. In addition to P450 3A4, reactive metabolites of 4-ipomeanol were found to covalently bind to other proteins. 4-Ipomeanol failed to inactivate P450 1A2 in human liver microsomes. In conclusion, 4-ipomeanol irreversibly inhibited P450 3A4, and it was characterized as a mechanism-based inactivator of P450 3A4. This finding facilitates the understanding of the mechanism of bioactivation of 4-ipomeanol by human hepatic enzymes.[1]References
- Mechanism-based inactivation of cytochrome P450 3A4 by 4-ipomeanol. Alvarez-Diez, T.M., Zheng, J. Chem. Res. Toxicol. (2004) [Pubmed]
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