Toxicology protein expression

Lantz RC, Petrick JS, Hays AM. Altered protein expression following in utero exposure to arsenic. Society of Toxicology, 2005. 

New biomarkers will be useful in hepatotoxicity risk assessment if the data quality and validity can be established. The FDA defines a valid biomarker as one that can be measured in an analytical test system with well-established performance characteristics and has an established scientific framework or body of evidence that elucidates the significance of the test results [160]. Although there is no formerly agreed upon path, biomarker validation should include appropriate end-points for study (i.e., toxicology, histopathology, bioanalytical chemistry, etc.) and dose- and time-dependent measurements. An assessment of species, sex and strain susceptibility is also important to evaluate across species differences. More specific considerations for validation of gene and protein expression technologies are reviewed by Corvi et al. and Rifai et al. [144, 147]. 

Korte J.J, M.D. Kahl, K.M. Jensen, M.S. Pasha, L.G. Parks, G.A. LeBlanc, and G.T. Ankley (2000). Fathead minnow vitellogenin Complementary DNA sequence and messenger RNA and protein expression after 17 3-estradiol treatment. Environmental Toxicology and Chemistry 19 972-981. 

Kennedy S (2002) The role of proteomics in toxicology identification of biomarkers of toxicity by protein expression analysis. Biomarkers 7 269-290 Li J, Zhang Z, Rosenzweig J, Wang YY, Chan DW (2002) Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. Clinical Chemistry 48 1296-1304... 

For the investigation of expression changes due to xenobiotic/toxin exposure, proteins have to be extracted from samples of body fluids, tissues or cells. For this purpose, many protein extraction protocols have been developed and adapted to different sample types (Link 1999). All protocols follow the main objective to recover as much of the proteome as possible with as little contamination by other biomaterials as possible. Sample preparation has to be performed prior to any proteomics technology used in investigative studies, or predictive toxicology. Depending on the method used for protein expression analysis, fractionation steps have to follow or have to be implemented in the extraction procedures (Wilkins et al. 1997 Rabilloud 2000 Liebler 2002). 

For transporters, relatively low protein expression level and limited transport capacity makes for nonlinear, enzyme-like transport kinetics that is, the transport rate saturates with increasing substrate concentration. This phenomenon is the basis for the competitive interactions generally found for chemicals that are handled by one or more common transporters this is usually manifest as inhibition of the transport of one chemical by a structural analog. The extent to which these competitive interactions are important depends on the concentrations of the chemicals involved, their relative affinities for the common transporter, and their phar-macological/toxicological profiles (effects, effective concentrations, therapeutic index). Competition for transport is discussed below in the context of drug-drug interactions. 

As most new in vitro toxicology tests and assays use human cells, tissues, and proteins expressed in various cells, species specificity can also be investigated fairly early. When animal experiments signal unexpected toxic effects, one can sift through the extensive in vitro data and determine if the expected target molecule shares homology between the human and animal species. 

Kennedy S (2002) The role of proteomics in toxicology Identification of biomarkers of toxicity by protein expression analysis. Biomarkers 7(4) 269-290. 

A previously published review on the role of proteomics in toxicology [74] covered the earlier toxicoproteomics literature, so the review in Table 5.1 will cover more recent citations with minimal overlap. Table 5.2 summarizes data from primary literature that reports on the effects of toxic agents on global protein expression. Entries are summarized by author, proteomic platform, chemicals or toxicants tested, the tissue analyzed, and a very brief statement of results and potential markers of toxic effect. 

Drake MG, Witzmann FA, Hyde J, Witten ML. JP-8 jet fuel exposure alters protein expression in the lung. Toxicology 2003 191(2-3) 199-210. 

Additional parameters that are readily incorporated into a stand-alone immune function test such as the KLH-TDAR model include ex vivo lymphocyte proliferation, cytokine protein expression, and immunophenotype analysis any or all of which can enhance hazard identification and characterization of a potential immunotoxicant. While the KLH-TDAR is an example of a combined immune function screen and mechanistic study, the ex vivo methodologies described herein are generally applicable to toxicology studies that do not include an immunization protocol. Moreover, the methodologies are not species-specific however, responsiveness to various stimulants to induce ex vivo lymphocyte proliferation and cytokine production may differ across species and strain, requiring procedural optimization for a given species and ex vivo test. 

Yamamoto, T., T. Eukushima, R. Kikkawa, H. Yamada, and 1. Horri. 2005. Protein expression analysis of rat testes Induced testicular toxicity with several reproductive toxicants. Journal of Toxicological Sciences 30 111-126. 

Limonciel, A., Wilmes, A., Aschauer, L., Radford, R., Bloch, K. M., McMorrow, T., Pfaller, W., van Delft, J. H., Slattery, C., Ryan, M. R, Lock, E. A., and Jennings, P. (2012) Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells. Archives of Toxicology 86, 1741-1751. 

A xenobiotic is said to be stored when it is not available to sites of metabolism or action and is not available for excretion. In other words, it is held in an inert position from a toxicological point of view, where it is not able to express toxic action or to be acted upon by enzymes. A xenobiotic is stored when it is located in a fat depot (adipose tissue), bound to an inert protein or other cellular macromolecule, or simply held in a membrane that does not have any toxicological function (i.e., it does not contain or represent a site of toxic action, neither does it contain enzymes that can degrade the xenobiotic). 

Horiguchi, T., Nishikawa, T., and Ohta, Y. et al. (2007). Retinoid X receptor gene expression and protein content in tissues of the rock sheU Thais clavigera. Aquatic Toxicology 84, 379-388. 

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