Abstract
Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues, including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, and the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first-pass intestinal metabolism and involvement in drug-drug interaction. To fully characterize its role in drug metabolism, selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs were screened for the inhibition of CYP2J2, and we discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC50 values of 0.42 μM and 0.94 μM, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrates of CYP2J2 and show no time-dependent inhibition toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed-type inhibitor, and flunarizine competitively inhibits CYP2J2. The Ki for telmisartan is 0.19 μM, with an α value, an indicator of the type of inhibition mechanism, of 2.80, and flunarizine has a Ki value of 0.13 μM. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting.
Footnotes
This work was supported by National Key Project [Grants 2010CB945501, 2010CB912604], National Science Foundation of China [Grant 21173082], Shanghai Rising-Star Program [Grant 11QA1402000], National Natural Science Foundation of China [Grants 10974054, 20933002], and Shanghai Pujiang Program [Grant 09PJ1404000].
- Received August 8, 2012.
- Accepted October 2, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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