Metabolism of the cysteine S-conjugate of busulfan involves a beta-lyase reaction.
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.
Cooper
Arthur J L
AJ
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, USA.
Younis
Islam R
IR
Niatsetskaya
Zoya V
ZV
Krasnikov
Boris F
BF
Pinto
John T
JT
Petros
William P
WP
Callery
Patrick S
PS
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002066:Busulfan / Q000493:pharmacokinetics*; D003545:Cysteine / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008190:Lyases / Q000378:metabolism*; D011732:Pyridoxal Phosphate / Q000378:metabolism; D051381:Rats
D018906:Antineoplastic Agents, Alkylating; D011732:Pyridoxal Phosphate; D008190:Lyases; D002066:Busulfan; D003545:Cysteine