Keratin biomarkers

Thulin P, Nordahl G, Gry M, Yimer G, Aklillu E, Makonnen E, Aderaye G, Lindquist L, Mattsson CM, Ekblom B, Antoine DJ, Park BK, Linder S, Harrill AH, Watkins PB, Glinghammar B, Schuppe-Koistinen I (2013) Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int. doi 10.1111/liv.l2322... 

Even though the microfluidic-MS analysis was performed with low injection volumes, it enabled the identification of five putative biomarkers 39,40 proliferating cell nuclear antigen (PCNA), cathepsin D and keratins K8, K18 and K19 (Table 7.1). All corresponding peptides that identified these proteins had p < 0.001, confirming the reliability of the match. PCNA is a protein involved... 

Antoine, D.J., et al., Molecular forms of HMGBl and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. 7 2012. 

Thulin, P, et al., Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int, 2014. 34 p. 367-78. 

There are intrinsic problems with hair Pb in terms of understanding Pb toxicokinetics in hair or other keratinizing tissue. Hair Pb loadings appear to vary with hair color, highly variable deposition rates, etc. (Barbosa et al., 2005 Mushak, 1992 U.S. ATSDR, 2007 U.S. EPA, 2006). Of particular concern, Pb-hair is poorly correlated with PbB, especially at low Pb levels currently encountered by nonoccupational human populations (Campbell and Toribara, 2001). The latter is to be expected, given what each biomarker is reflecting in time scales of exposures. 

Finally, the issue of firontend purification for the collected test material is perhaps the most important aspect of sample preparation. Currently there are various methods that utilize standard separation techniques to remove most abundant proteins prior to MS, i.e., removal of some 20 high-abundance proteins and better visualization of low-abundance proteins (Sigma-Aldrich kits). However, in most cases the removal of these proteins may in fact compromise the detection of biomarkers or their partners, since in many instances, viral infection leads to overexpression of the most abundant proteins such as the actins, keratins, tubulins, cyclophilins, vimentin, and HSPs among others. Therefore, future attempts at the identification of biomarkers would have to define not only the most high- and low-abundance proteins but also their partners and possible modifications. 

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