Toxicity biomarkers

Costa LG, et al. Paraoxonase (PON 1) as a biomarker of susceptibility for organophos-phate toxicity. Biomarkers. 2003 8 1-12. 

Future Directions in the Discovery of Toxicity Biomarkers through Computational Approaches 737... 

Can be used in both preclinical and clinical studies and may also be disease, efficacy, or toxicity biomarkers. 

Interestingly, the number of examples of toxicity biomarkers discovered using nuclear magnetic resonance (NMR)-based and MS-based metabonomics is quite impressive. In metabonomics studies in which a severe toxicity is observed, almost always the relative urinary concentrations of Krebs cycle intermediates are decreased and a concomitant decrease in urinary levels of hippuric acid is observed. These compounds have been proposed to be nonspecific markers of toxicity as they reflect a combination of complex changes in an organism [11,48-51], Taurine has been known to be a specific marker for liver toxicity as its urinary levels are typically increased with necrosis and fatty liver. Several bile acids in the serum such as cholic, glycolic, and taurocholic acids have also been demonstrated to be sensitive markers of liver dysfunction [50], In the literature, there are a few preclinical and clinical examples of... 

This chapter will attempt to describe the various options available to validate commercial assays used in chug development appropriately to meet the expectations and requirements of each study in which they may be used. In particular, we will examine the use of commercial kits for pharmacodynamic (PD), efficacy and toxicity (biomarkers), and pharmacokinetic (PK) assessments. The PK assessment assays will focus on those molecules that are developed as therapeutic chugs, but which are also compounds that exist endogenously in humans. These chugs are often called new biological entities (NBEs) and examples include growth hormone, insulin, and erythropoietin. 

Sensitive detection of toxic effect is of key importance. Toxicity biomarkers report effects that precede significant tissue damage and organ failure. The classic examples include detection of liver enzymes in the blood. 

Further validation of these potential retinal miRNA biomarkers will be needed in additional toxicological species, for example, dog and monkey, following treatments with a variety of retinal toxicants, as well as possible studies in laser-induced choroid neovascularization (CNV) and streptozotocin-induced diabetic retinopathy ocular disease models (Rittenhouse et al., 2014). Understanding the temporal and spatial relationships between retinal injuries and circulating miRNAs will be critical to fuUy understand the specificity, sensitivity, predictivity, and reliability of these biomarkers. Further evaluation of the translatability of circulating miRNA toxicity biomarkers in humans will be exciting as the next tier of retinal miRNA biomarker research. Finally, in addition to retinal miRNA biomarkers, there is the need to establish and validate other ocular tissue-specific miRNA biomarkers, for cornea, iris/ciliary body, and lens. 

CURRENT STATUS OF PRECLINICAL IN VIVO TOXICITY BIOMARKERS... 

Fuchs TC, Frick K, Emde B, Czasch S, von Landenberg F, Hewitt P. (2012) Evaluation of novel acute urinary rat kidney toxicity biomarker for subacute toxicity studies in preclinical trials. Toxicol Pathol. 40(7) 1031-1048. 

McBumey R.N., Hines W.M., Von Tnngeln L.S., et al. 2009. The liver toxicity biomarker study phase I design and preliminary results. Toxicol. Pathol. 37(l) 52-64. 

Total LDH activity was significantly enhanced in EDL, diaphragm, and serum by carbofuran (1.5 mg/ kg, s.c.) or methyl parathion [5mg/kg, administered intraperitoneally (i.p.)] within Ih of injection. Each AChE inhibitor caused marked elevation of all five iso-enz3unes in serum, with maximum increases in LDH-1 and LDH-4 (threefold). Unlike serum, muscle LDH isoenzymes depicted variable patterns by carbofuran or methyl parathion intoxication. A significant decline in ATP appears to be the mechanism involved in leakage of cytoplasmic/mitochondrial enzymes into circulation (Gupta et al., 1994). For further details on muscle toxicity biomarkers, see Gupta et al. (2014). 

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