Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes
Section snippets
Reagents and general procedures
[7-14C]Benzoic acid and sodium [14C]formate were purchased from Moravek Biochemicals (Brea, CA) with specific activities of 53 and 56 Ci/mol, respectively. [7-13C]Benzoic acid and sodium [13C]formate were purchased from Cambridge Isotopes Laboratories (Andover, MA). Compounds 2, 4, 6–9 and cyclopropylamine were obtained from Aldrich (Milwaukee, WI). NADPH, glucose-6-phosphate and glucose-6-phosphate dehydrogenase were purchased from Sigma (St. Louis, MO). Aminopyrine was from Mallinckrodt (St.
Results
Incubation of varying concentrations of 1 with rat liver microsomes and NADPH leads to a time-, concentration-, and cofactor-dependent loss of cytochrome P450 activity as assessed by the aminopyrine N-demethylase (APD) assay. A replot of the reciprocals of the slopes of Fig. 3 vs. the reciprocals of inhibitor concentration [34] leads to the kinetic constants reported in Table 1. As described in earlier literature, the loss of APD activity in microsomes incubated with 1 does not proceed to
Discussion
The discovery of 1 as a suicide substrate for cytochrome P450 enzymes was based on the observation of time- and cofactor-dependent loss of the aminopyrine N-demethylase and p-nitroanisole O-demethylase activities of PB rat liver microsomes [35], [42]. Results presented in Fig. 3 confirm the time-dependence and also indicate the concentration dependence of the inactivation process. They also confirm that as originally described, the inactivation of APD activity does not go to completion but
Acknowledgments
We thank Drs. Yakov Koen and Emily Scott and Ms. Xin Wang for assistance and advice concerning enzyme expression and purification. We also thank Dr. M.A. Correia for providing (with kind permission from Dr. T. Omura) plasmid EL2 for CYP2C11 expression, Dr. F.P. Guengerich for providing an E. coli strain expressing CYP2E1, and Dr. C.B. Kasper for providing an E. coli strain expressing P450 oxidoreductase. We also thank Pfizer Global Research and Development for generous financial support of this
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