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.