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Drug Metabolism and Disposition Fast Forward
First published on December 20, 2007; DOI: 10.1124/dmd.107.016501

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Received for publication May 4, 2007.
Revised December 13, 2007.
Accepted for publication December 14, 2007.

CYP3A4-MEDIATED CARBAMAZEPINE (CBZ) METABOLISM: FORMATION OF A COVALENT CBZ-CYP3A4 ADDUCT AND ALTERATION OF THE ENZYME KINETIC PROFILE

Ping Kang 1, Mingxiang Liao 1, Michael R. Wester 2, J. Steven Leeder 3, Robin E Pearce 4, Maria Almira Correia 1*

1 UCSF 2 Pfizer Global Research & Development, San Diego, CA 3 Section of Developme Pharmacology and Experimental Therapeutics, The Children's Mercy Hospitals & Cl 4 The Children's Mercy Hospitals & Clinics, Kansas City, MO

* Address correspondence to: E-mail: almira.correia{at}ucsf.edu

Abstract

Carbamazepine (CBZ) is a widely prescribed anticonvulsant whose use is often associated with idiosyncratic hypersensitivity. Sera of CBZ-hypersensitive patients often contain anti-CYP3A antibodies including those to a CYP3A23 K-helix peptide that is also modified during peroxidative CYP3A4 heme-fragmentation. We explored the possibility that cytochromes P450 (P450s) such as CYP3A4 bioactivate CBZ to reactive metabolite(s) that irreversibly modify the P450 protein. Such CBZ-P450 adducts, if stable in vivo, could engender corresponding serum P450 autoantibodies. Incubation with CBZ not only failed to inactivate functionally reconstituted, purified recombinant CYP3A4 or CYP3A4 SupersomesTM in a time-dependent manner, but the inclusion of CBZ (0-1 mM) also afforded a concentration-dependent protection to CYP3A4 from inactivation by NADPH-induced oxidative uncoupling. Incubation of CYP3A4 SupersomesTM with 3H-CBZ resulted in its irreversible binding to CYP3A4 protein with a stoichiometry of 1.58 ±0.15 pmol 3H-CBZ bound/pmol CYP3A4. Inclusion of GSH (1.5 mM) in the incubation reduced this level to 1.09. Similar binding (1.0 ± 0.4 pmol 3H-CBZ bound/pmol CYP3A4) was observed after 3H-CBZ incubation with functionally reconstituted, purified recombinant CYP3A4(His)6. The CBZ-modified CYP3A4 retained its functional activity albeit at a reduced level, but its testosterone 6{beta}-hydroxylase kinetics were altered from sigmoidal (a characteristic profile of substrate cooperativity) to near-hyperbolic (Michaelis-Menten) type, suggesting that CBZ may have modified CYP3A4 within its active site.


Key words: CYP3A, cytochrome P450 catalyzed oxidations, drug interactions, human CYP enzymes, idiosyncratic drug reactions, immunogenicity, inactivation, mechanism-based inhibition, reactive intermediate, suicide inhibition


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R. E. Pearce, W. Lu, Y. Wang, J. P. Uetrecht, M. A. Correia, and J. S. Leeder
Pathways of Carbamazepine Bioactivation in Vitro. III. The Role of Human Cytochrome P450 Enzymes in the Formation of 2,3-Dihydroxycarbamazepine
Drug Metab. Dispos., August 1, 2008; 36(8): 1637 - 1649.
[Abstract] [Full Text] [PDF]


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