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

Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York (A.J.L.C., B.F.K., J.T.P.); School of Pharmacy, West Virginia University, Morgantown, West Virginia (I.R.Y., W.P.P., P.S.C.); and Burke Medical Research Institute, White Plains, New York (Z.V.N.)

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 -lyase. This unusual drug metabolism pathway represents an alternate route for intermediates in the mercapturate pathway.