Biomarkers toxicity identification

Jiang H, Lu J, Ji J. Circadian rhythm of dihydrouracil/uracil ratios in biological fluids a potential biomarker for dihydropyrimidine dehydrogenase levels. Br J Pharmacol 2004 141 616-623. van Kuilenburg AB, Haasjes J, Riehel DJ et al. Clinieal implieations of dihydropyrimidine dehydrogenase (DPD) defleieney in patients with severe 5-fluorouraeil-assoeiated toxicity identification of new mutations in the DPD gene. Clin Cancer Res 2000 6 4705 712. 

The development, validation, and implementation of translational biomarkers that allow for renal toxicity identification, risk assessment, and risk management are of extreme value. The ideal biomarker or panel of biomarkers should demonstrate the necessary sensitivity and specificity to predict toxicity in preclinical models and in a clinical setting. One of the major challenges in assessing DDCI is the limited translatabUity between preclinical models and the clinical setting mainly due to the suboptimal inappropriate tools currently available. 

Dare TO, Davies HA, Turton JA, et al. Apphcation of surface-enhanced laser desorption/ionization technology to the detection and identification of urinary parvalbumin-alpha a biomarker of compoimd-induced skeletal muscle toxicity in the rat. Electrophoresis 2002 23 3241-51. 

The various organs of the immune system such as spleen, lymph nodes, thymus and bone marrow containing the cells involved in the various immune responses offer the possibility to harvest these cells and perform in vitro assays for evaluation of effects on the immune system. When part of an in vivo animal study this may indicate a direct toxic effect of pharmaceuticals, that is, immunosuppression (Table 18.2). So, it is feasible to obtain cell suspensions for further evaluation such as determination of cellular subsets of T and B leukocytes by fluorescent activated cell sorter analysis (FACS analysis), and determination of natural killer (NK) cell activity of the spleen cell population. An advantage of this approach is that it may lead to identification of a biomarker to be used in clinical studies. In addition, in vitro stimulation of spleen cells with mitogens activating specific subsets may indicate potential effects on the functionality of splenic cell populations. Concanavalin A (Con A) and phytohemagglutinin (PHA) activate Tcells, while lipopolysaccharide (LPS) activates primarily B cell populations. Blood is collected for total white blood cell (WBC) determination and blood cell differential count. In addition, serum can be obtained for determination of serum immunoglobulins. 

Consequently, proteomics is a valuable tool for identification and validation of drug targets in early phases, the investigation of the mechanism of pharmacological drug activity and toxicity, and hence, individualized drug therapy. Use of biomarkers may lead to development of nonanimal models. 

As the use of metabonomics advances, there are several challenges facing scientists using this tool that must be addressed in order to make it more mainstream and more relevant to predicting toxicity, and useful for hazard identification, human risk assessment and clinical medicine. First, advancing the use of metabonomics to identify mechanisms of toxicity is essential, and such efforts should help to increase the overall usefulness, validity, and relevance of toxicity prediction and biomarker development. Second, the use of metabonomic evaluations in the course of chronic toxicity rather than the heretofore emphasis on acute studies will help to establish its place in following the... 

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... 

Using the toxicogenomic techniques described, some significant data have been obtained but to determine the functional significance of these data, additional studies need to be done. Use of these new technologies and their specificity and sensitivity to assess nephrotoxicity remains controversial, but in the future they may allow the identification of useful biomarkers that would be predictive of future responses to toxicant insults and the region of the kidney affected. Identification of specific biomarkers associated with the future development of loss of kidney function, fibrosis, or recovery would be useful in the rapid evaluation of potentially nephrotoxic agents. 

In summary, acetylcholinesterase and butyr-ylcholinesterase are not the only proteins modified by OP exposure in humans. Neiuotoxicity from low doses of OPs may be explained by OP modification of heretofore imiden-tified proteins. Toxic symptoms from low-dose exposure to a particular OP are not identical to toxic symptoms from another OP, suggesting that the set of proteins modified by a particular OP does not overlap completely with the set of proteins modified by a different OP. Identification of new biomarkers of OP exposure could lead to new assays for OP exposure, and could lead to an understanding of the causes of low-dose toxicity. 

Gao J, Ann Garulacan L, Storm SM, et al. Identification of in vitro protein biomarkers of idiosyncratic liver toxicity. Toxicol In Vitro. 2004 18(4) 533-541. 

Identification of novel biomarkers of toxicity Previously, the detection of novel biomarkers of toxic effect has mainly been serendipitous. However, it is now possible to use a combined NMR-expert systems approach to systematically explore the relationships between biofluid composition and toxicity and to generate novel combination biomarkers of toxicity. Pattern recognition maps can be examined for evidence of clustering of data according to site and type of toxic lesion. 

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