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      The current state of serum biomarkers of hepatotoxicity.

      1 ,   , , ,
      Toxicology
      Elsevier BV

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          Abstract

          The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTalpha) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in early clinical trials.

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          Author and article information

          Journal
          Toxicology
          Toxicology
          Elsevier BV
          0300-483X
          0300-483X
          Mar 20 2008
          : 245
          : 3
          Affiliations
          [1 ] Safety Assessment, Merck Research Laboratories, West Point, PA, USA.
          Article
          S0300-483X(07)00790-1
          10.1016/j.tox.2007.11.021
          18291570
          2a6a11a3-3317-403c-b202-e1d610e84dc6
          History

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