Abstract
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.
Footnotes
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The work reported herein was supported in part by the National Institutes of Health Grants RO1 ES08421 (to A.J.L.C.) and 5-PO1-CA47741 (to W.P.P.) and by National Institute of Justice Grant IJ-CX-K014 (to P.S.C.).
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W.P.P. is the Mylan Chair of Pharmacology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.020768.
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ABBREVIATIONS: THT-A, β-(S-tetrahydrothiophenium)-l-alanine [(2S)-2-amino-3-(2,3,4,5-tetrahydrothiophen-1-yl)propanoic acid]; PLP, pyridoxal 5′-phosphate; KG, α-ketoglutarate; KMB, α-keto-γ-methiolbutyrate; HPLC, high-performance liquid chromatography; mitAspAT, mitochondrial aspartate aminotransferase; GTK, glutamine transaminase K.
- Received February 2, 2008.
- Accepted May 7, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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