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
-
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.).
-
W.P.P. is the Mylan Chair of Pharmacology.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.020768.
-
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
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|