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Drug Metabolism and Disposition Fast Forward
First published on May 12, 2008; DOI: 10.1124/dmd.108.020768

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Received for publication February 8, 2008.
Revised May 5, 2008.
Accepted for publication May 7, 2008.

Metabolism of the cysteine S-conjugate of busulfan involves a {beta}-lyase reaction

Arthur JL Cooper 1, Islam R. Younis 2, Zoya V Niatsetskaya 3, Boris F Krasnikov 1, John T Pinto 1, William P Petros 2, Patrick S Callery 2*

1 New York Medical College 2 West Virginia University 3 Burke Medical Research Institute

* Address correspondence to: E-mail: pcallery{at}hsc.wvu.edu

Abstract

The present work documents the first example of an enzyme-catalyzed {beta}-elimination of a thioether from a sulfonium cysteine S-conjugate. {beta}-(S-Tetrahydrothiophenium)-L-alanine (THT-A) is the cysteine S-conjugate of busulfan. THT-A slowly undergoes a non-enzymatic {beta}-elimination reaction at pH 7.4 and 37°C to yield tetrahydrothiophene, pyruvate and ammonia. This reaction is accelerated by a) rat liver, kidney and brain homogenates, b) isolated rat liver mitochondria, and c) pyridoxal 5'-phosphate (PLP). A PLP-dependent enzyme in rat liver cytosol that catalyzes a {beta}-lyase reaction with THT-A was identified as cystathionine {gamma}-lyase. This unusual drug metabolism pathway represents an alternate route for intermediates in the mercapturate pathway.


Key words: anticancer agents, enzyme mechanism, glutathione, glutathione conjugates, glutathione metabolism, mass spectrometry, phase II drug metabolism


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Home page
 J. Pharmacol. Exp. Ther.Home page
I. R. Younis, M. Elliott, C. J. Peer, A. J. L. Cooper, J. T. Pinto, G. W. Konat, M. Kraszpulski, W. P. Petros, and P. S. Callery
Dehydroalanine Analog of Glutathione: An Electrophilic Busulfan Metabolite That Binds to Human Glutathione S-Transferase A1-1
J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 770 - 776.
[Abstract] [Full Text] [PDF]


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