Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene: a key role for C239 in quenching reactive intermediates.

@article{Pearson2007DifferentialTI,
  title={Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene: a key role for C239 in quenching reactive intermediates.},
  author={Josh T. Pearson and Jan L. Wahlstrom and Leslie J. Dickmann and Santosh Kumar and James R. Halpert and Larry C. Wienkers and Robert S. Foti and Dan A. Rock},
  journal={Chemical research in toxicology},
  year={2007},
  volume={20 12},
  pages={
          1778-86
        }
}
The role of C239 as the active-site residue responsible for forming the covalent linkage with raloxifene during P450 3A4 time-dependent inactivation (TDI) was recently identified. The corresponding residue in CYP3A5 is S239, and when the potential for TDI in P450 3A5 was investigated, only reversible inhibition was observed against midazolam and testosterone, with median inhibitory concentration (IC50) values of 2.4 and 2.9 microM, respectively. In a similar fashion, when C239 was replaced with… CONTINUE READING
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