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Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes
Cerny, Matthew A. Hanzlik, Robert P.
Cerny, Matthew A.
Hanzlik, Robert P.
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Abstract
The inactivation of cytochrome P450 enzymes by cyclopropylamines has been attributed to a mechanism involving initial one-electron oxidation at nitrogen followed by scission of the cyclopropane ring leading to covalent modification of the enzyme. Herein, we report that in liver microsomes N-cyclopropylbenzylamine (1) and related compounds inactivate P450 to a large extent via formation of metabolic intermediate complexes (MICs) in which a nitroso metabolite coordinates tightly to the heme iron, thereby preventing turnover. MIC formation from 1 does not occur in reconstituted P450 systems with CYP2B1/2, 2C11 or 2E1, or in microsomes exposed to gentle heating to inactivate the flavin-containing monooxygenase (FMO). In contrast, N-hydroxy-N-cyclopropylbenzylamine (3) and N-benzylhydroxylamine (4) generate MICs much faster than 1 in both reconstituted and microsomal systems. MIC formation from nitrone 5 (PhCH = N(O)cPr) is somewhat faster than from 1, but very much faster than the hydrolysis of 5 to a primary hydroxylamine. Thus the major overall route from 1 to a P450 MIC complex would appear to involve FMO oxidation to 3, further oxidation by P450 and/or FMO to nitrone 5′ (C2H4C = N(O)CH2Ph), hydrolysis to 4, and P450 oxidation to α-nitrosotoluene as the precursor to oxime 2 and the major MIC from 1.
Description
NOTICE: this is the author’s version of a work that was accepted for publication in Archives of Biochemistry and Biophysics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Archives of Biochemistry and Biophysics, Volume 436, Issue 2, 15 April 2005 doi:10.1016/j.abb.2005.02.020
Date
2005-04-15
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Elsevier
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Keywords
Cytochrome p450, Flavin-containing monooxygenase, Metabolic intermediate complex, Mechanismbased inactivation, Suicide substrate
Citation
M. A. Cerny and R. P. Hanzlik, "Cyclopropylamine inactivation of cytochromes P450. Role of metabolic intermediate complexes." Arch. Biochem. Biophys. 436, 265-275 (2005). http://dx.doi.org/10.1016/j.abb.2005.02.020