Albumin adducts

Absorption kinetic studies on fasted rats dosed by lipid-emulsion gavage revealed rapid appearance of triehloroethylene in the blood (typieally peaking at 15 minutes post-exposure) followed by rapid disappearance (Templin et al. 1993). Rats similarly dosed with radiolabelled trichloroethylene showed rapid serum albumin adduction which peaked at 4-8 hours, then decayed with a half-life consistent with that of albumin itself (Stevens et al. 1992). However, some of the detected radioactivity may have been due to trichloroethylene metabolites rather than the parent compound. 

Sepai, 0., Henschler, D. Sabbioni, G. (1995a) Albumin adducts, hemoglobin adducts and urinary metabolites in workers exposed to 4,4 -methylenedianiline diisocyanate. Carcinogenesis, 16, 2583-2587... 

The albumin adduct of styrene oxide, S-(2-hydroxyl-l-phenylethyl)cysteine,... 

Wild CP, Jiang YZ, Allen SJ, Jansen LA, Hall AJ, Montesano R (1990) Aflatoxin-albumin adducts in human sera from different regions of the world. Carcinogenesis, 11(12) 2271-2274. 

Sulfur mustard forms adducts with the blood proteins hemoglobin and albumin. Adducts with histidine residues are the most abundant after exposure of hemoglobin in vitro to sulfur mustard. Analysis of adducted histidine by GC/MS is hampered by poor thermal stability of volatile derivatives. A sensitive method was developed using LC/ESI/MS/MS after... 

The analytical procedure for S-[2-[(hydroxyethyl) thio]ethyl-Cys-Pro-Phe was successfully applied to blood samples from nine Iranian casualties of the Iraq-Iran war, all exhibiting skin injuries compatible with exposure to sulfur mustard. The blood samples were collected 8-9 days after the alleged exposure and stored at — 70 °C. The albumin adduct was detected in all cases, at levels estimated as corresponding to those after in vitro exposure of human blood to mustard concentrations ranging from 0.4-1.8 xM. 

Noort and colleagues (2008) investigated the persistence of sulfur mustard adducts to albumin and hemoglobin in rats. The albumin adduct (S -2-hydroxyethylthioethyl)-Cys-Pro-Tyr was detectable up to 7 days after the exposure, while the adduct to the N-terminal valine in hemoglobin was still detected after 28 days. The decrease of adduct concentration corresponded with albumin half-life and the hfetime of the rat erythrocyte, respectively. 

Li et al. (2008) have shown that soman covalently binds to albumin at tyrosine 411. The adduct is stable (/i/2 = 20 days). However, though the concentration of albumin in plasma is very high, its reactivity with soman is too slow to play a major role in detoxification of the agent. The authors concluded that soman-albumin adducts could be usefid for the diagnosis of soman exposure. Tarhoni et al. (2008) also found that OP pesticides covalently bind to albumin and that the adduct is stable for more than 7 days. 

Blood Albumin adduct, cysteine adduct Digestion with pronase LC-MS/MS Noort et al. (1999, 2004)... 

Blood Albumin adduct Detected as thiodigylcol after alkaline hydrolysis GC-MS Capacio et al. (2004) Lawrence et al. (2008)... 

These examples show that OPs can bind covalently to albumin under physiological conditions, and that the resultant adducts are relatively stable. OP-albumin adducts could therefore be useful as biomarkers of OP exposure. In addition, unlike cholinesterases, the soman-albumin conjugate does not age (Li et al, 2008a), making it possible to discriminate between sarin and soman exposure. OP-albumin adducts have not yet been reported in humans exposed to OPs. 

Lovley, D.R., Anaerobic benzene degradation, Biodegradation 11, 107—116, 2000 Snyder, R., Xenobiotic metabolism and the mechanism(s) of benzene toxicity. Drug Metab. Rev. 36, 531—547, 2004 Rana, S.V. and Verma, Y., Biochemical toxicity of benzene, J. Environ. Biol. 26,157—168, 2005 Lin, Y.S., McKelvey, W., Waidyanatha, S., and Rappaport, S.M., Variability of albumin adducts of 1,4-benzoquinone, a toxic metabolite of benzene, in human volunteers. Biomarkers 11,14-27, 2006 Baron, M. and Kowalewski, V.J., The liquid water-benzene system, J. Phys. Chem. A Mol. Spectrosc. Kinet. Environ. Gen. Theory 100, 7122-7129, 2006 Chambers, D.M., McElprang, D.O., Waterhouse, M.G., and Blount, B.C., An improved approach for accurate quantiation of benzene, toluene, ethylbenzene, zylene, and styrene in blood, Anal. Chem. 78, 5375-5383, 2006. 

Barr JR, Young CL, Woolfit AR, et al. Comprehensive quantitative tandem MS analysis of urinary metabolites and albumin adducts following an accidental human exposure to sulfur mustard. In Proceedings ofthe 53rd Conference ofthe American Society of Mass Spectrometry, San Antonio, TX, June 2005. 

Similar to sulphur mustard, IIN-2 binds covalently with the cysteine-34 residue of human serum albumin in vitro. Although no detection following in vivo exposures has been reported, analogous albumin adducts have been demonstrated in cancer patients being treated... 

The albumin adduct with HN-2 can be detected by LC-MS-MS using a similar methodology to that used for the sulphur mustard adduct (Noort et al, 2002b). HPLC with UV detection (LOD, 10 ng/ml) has been reported for the HN-2 N7-... 

Albumin adducts can be detected by LC-MS-MS as phosphylated tyrosine, after digestion of the albumin fraction with Pronase and SPE cleanup (Harrison et al., 2000b). 

Lind, P., Dalene, M., Lindstrom, V., Grubb, A., and Sharping, G., Albumin adducts in plasma from workers exposed to toluene diisocyanate, Analyst, 122, 151-154, 1997. 

Presently the first year collection of seunples has occurred and preliminary data on aflatoxin consumption, albumin adduct binding and urine excretion of adducts analyzed. The data are very preliminary in nature, but we hope that over the next three years a more complete picture of aflatoxin metabolism in people will be elucidated. 

Summary Primary hepatocellular carcinoma is one of the most common cancers in the world and is prevalent on the continents of Africa and Asia. A number of classical epidemiological studies have determined that the exposure status of people to aflatoxin B1 is an important risk factor in the etiology of liver cancer. However, these studies have only relied upon the criteria of presumptive intake data, rather than information obtained from quantitative analyses of food samples, biological fluids and from people exposed to aflatoxin. Information obtained by monitoring exposed individuals for specific DNA adducts and metabolites will define the pharmacokinetics of aflatoxin B1 in people, thereby facilitating risk assessments. Preliminary data, reported here, support the concept that measurement of the major, rapidly excised AFB-N7-Gua adduct in urine and quantification of the more persistent aflatoxin albumin adduct are appropriate dosimeters for estimating exposure status and possibly risk in individuals consuming this mycotoxin. 

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