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Investigating the Mechanistic Basis for Hepatic Toxicity Induced by an Experimental Chemokine Receptor 5 (CCR5) Antagonist Using a Compendium of Gene Expression Profiles

¹ Rosetta Inpharmatics LLC (A wholly owned subsidiary of Merck & Co., Inc.), 401 Terry Ave. N, Seattle, WA 98109
² Calistoga Pharmaceuticals Inc., 2101 4th Ave., Suite 1960, Seattle, WA 98121

Correspondence: Address correspondence to: Paul D. Cornwell, Eli Lilly & Co., Inc. 2001 W. Main St. (GL47), Greenfield, IN 46140, USA; e-mail:CornwellPD{at}lilly.com Current Address for Paul D. Cornwell: Eli Lilly & Co., Inc., 2001 W. Main St., Greenfield, IN 46140;

A compendium of hepatic gene expression signatures was used to identify a mechanistic basis for the hepatic toxicity of an experimental CCR5 antagonist (MrkA). Development of MrkA, a potential HIV therapeutic, was discontinued due to hepatotoxicity in preclinical studies. Rats were treated with MrkA at 3 dose levels (50, 250, and 500 mg/kg) for 1, 3, or 7 days. Hepatic toxicity (vacuolation, consistent with steatosis, and elevated serum transaminase levels) was observed at 250 and 500 mg/kg, but not at 50 mg/kg. Hepatic gene expression profiles were compared to a compendium of hepatic expression profiles. MrkA was similar to 3 β-oxidation inhibitors (valproate, cyclopropane carboxylate, pivalate), 8 PPAR agonists (fenofibrate, bezafibrate and 6 fibrate analogues), and 3 other diverse compounds (diethylnitrosamine, microcystin LR & actinomycin D). These data indicate MrkA to be a mitochondrial inhibitor, and activation of PPAR-regulated transcription was thought to be due to an accumulation of endogenous ligands. While mitochondrial inhibition was likely responsible for steatosis, canonical pathway analysis revealed that progression to liver injury may be mediated by activation of the innate immune system primarily through NF-kB pathways. These results demonstrate the utility of a gene expression response compendium in developing transcriptional biomarkers and identifying the mechanistic basis for toxicity.

Key Words: Chemokine receptor • liver • rat • microarray • steatosis • mitochondria

Abbreviations: CCR5, chemokine receptor 5 • MrkA, experimental chemokine receptor 5 antagonist • PPAR, peroxisome proliferator activated receptor alpha • GGT, -glutamyltransferase • AST, aspartate amino-transferase • ALT, alanine aminotransferase • CK, creatinine kinase • H&E, hemotoxylin and eosin • PPAR, peroxisome proliferator activated receptor gamma

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