Unique Cyanide Adduct in Human Serum Albumin: Potential as a Surrogate Exposure Marker
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- 作者：Michael J. Fasco ; Robert F. Stack ; Shijun Lu ; Charles R. Hauer ; III ; Erasmus Schneider ; Michael Dailey ; Kenneth M. Aldous
- 刊名：Chemical Research in Toxicology
- 出版年：2011
- 出版时间：April 18, 2011
- 年：2011
- 卷：24
- 期：4
- 页码：505-514
- 全文大小：967K
- 年卷期：v.24,no.4(April 18, 2011)
- ISSN：1520-5010
文摘
Cyanide (CN = HCN + CN鈭?/sup>) is a renowned poison and neurotoxicant that is prevalent throughout the environment. Despite a plethora of studies conducted over the last half century, relatively little is known of its potential to cause adverse health outcomes at sublethal exposures. CN exposure is normally determined from blood, but because CN is rapidly metabolized and cleared from this compartment (t1/2 < 1 h), it is common for several half-lives to have passed before blood samples are drawn for analysis. This variable, coupled with a very narrow toxic index and metabolic diversity within the human population, has rendered accurate assessment of CN exposure, and consequently any predictions of possible adverse health outcomes, highly problematic. Prior studies by us showed the potential of Cys-SCN adducts within human serum albumin (HSA) to act as retrospective surrogates of CN exposure. Here, we report the discovery of a stable, SCN adduct at Cys567 formed by the reaction of CN with the C-terminal Cys558Cys567 disulfide bond of HSA. Treatment of HSA purified from human serum with base in guanidine hydrochloride releases a readily detectable, uniquely modified, C-terminal-19-mer peptide from Cys567-SCN moieties in all the samples examined thus far. Inclusion of a HSA-Cys567-S13C15N labeled internal standard permits quantitation of the Cys567-SCN adduct by LC-MS/MS in selective reaction monitoring (SRM) of the surrogate peptide with high sensitivity and good precision. Reaction of CN in vitro with the Cys558Cys567 disulfide bond in HSA is specific, rapid, and concentration dependent within a putative, physiologically relevant range. Data from various human sera demonstrate the potential usefulness of this adduct as a biomarker of CN exposure.