Metabolism of the Cysteine S-Conjugate of Busulfan Involves a Beta-Lyase Reaction

Authors

Arthur J L Cooper, New York Medical CollegeFollow
Islam R. Younis
Zoya V. Niatsetskaya
Boris F. Krasnikov, New York Medical CollegeFollow
John T. Pinto, New York Medical CollegeFollow
William P. Petros
Patrick Callery

First Page

1546

Last Page

1552

Document Type

Article

Publication Date

8-1-2008

Department

Biochemistry and Molecular Biology

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 nonenzymatic beta-elimination reaction at pH 7.4 and 37 degrees C to yield tetrahydrothiophene, pyruvate, and ammonia. This reaction is accelerated by 1) rat liver, kidney, and brain homogenates, 2) isolated rat liver mitochondria, and 3) 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.

Recommended Citation

Cooper, A. J., Younis, I. R., Niatsetskaya, Z. V., Krasnikov, B. F., Pinto, J. T., Petros, W. P., et al. (2008). Metabolism of the cysteine S-conjugate of busulfan involves a beta-lyase reaction. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 36(8), 1546-1552. doi:10.1124/dmd.108.020768

Publisher's Statement

Originally published in Drug Metabolism and Disposition: The Biological Fate of Chemicals. https://doi.org/10.1124/dmd.108.020768