TY - JOUR T1 - Metabolism of the Cysteine <em>S</em>-Conjugate of Busulfan Involves a β-Lyase Reaction JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1546 LP - 1552 DO - 10.1124/dmd.108.020768 VL - 36 IS - 8 AU - Arthur J. L. Cooper AU - Islam R. Younis AU - Zoya V. Niatsetskaya AU - Boris F. Krasnikov AU - John T. Pinto AU - William P. Petros AU - Patrick S. Callery Y1 - 2008/08/01 UR - http://dmd.aspetjournals.org/content/36/8/1546.abstract N2 - The present work documents the first example of an enzyme-catalyzed β-elimination of a thioether from a sulfonium cysteine S-conjugate. β-(S-Tetrahydrothiophenium)-l-alanine (THT-A) is the cysteine S-conjugate of busulfan. THT-A slowly undergoes a nonenzymatic β-elimination reaction at pH 7.4 and 37°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 β-lyase reaction with THT-A was identified as cystathionine γ-lyase. This unusual drug metabolism pathway represents an alternate route for intermediates in the mercapturate pathway. The American Society for Pharmacology and Experimental Therapeutics ER -