Investigation of Correlation Among Safety Biomarkers in Serum, Histopathological Examination, and Toxicogenomics

This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BL...

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Bibliographic Details
Published in:International journal of toxicology 2011-05, Vol.30 (3), p.300-312
Main Authors: Wang, Tao, Papoutsi, Maria, Wiesmann, Marion, DeCristofaro, Marc, Keselica, M. Craig, Skuba, Elizabeth, Spaet, Robert, Markovits, Judit, Wolf, Armin, Moulin, Pierre, Pognan, Francois, Vancutsem, Paul, Petryk, Lew, Sutton, James, Chibout, Salah-Dine, Kluwe, William
Format: Article
Language:English
Subjects:
Alanine Transaminase - blood
Alanine Transaminase - genetics
Animals
Aspartate Aminotransferases - blood
Aspartate Aminotransferases - genetics
Benzothiazoles - toxicity
Biomarkers - blood
Down-Regulation - drug effects
Gene Expression Profiling
Humans
Liver - drug effects
Liver - enzymology
Liver - pathology
Macaca fascicularis
Pharmacogenetics
Picolinic Acids - toxicity
Rats
Rats, Wistar
RNA, Messenger - genetics
Toxicity Tests
Up-Regulation - drug effects
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Summary:This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations.
ISSN:1091-5818
1092-874X
DOI:10.1177/1091581811401920