title: Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug.
abstract: A large number of antibiotics are known to cause drug-induced liver injury in the clinic; however, interpreting clinical risk is not straightforward owing to a lack of predictivity of the toxicity by standard preclinical species and a poor understanding of the mechanisms of toxicity. An example is PF-04287881, a novel ketolide antibiotic that caused elevations in liver function tests in Phase I clinical studies. In this study, a mouse diversity panel (MDP), comprised of 34 genetically diverse, inbred mouse strains, was utilized to model the toxicity observed with PF-04287881 treatment and investigate potential mechanisms that may mediate the liver response. Significant elevations in serum alanine aminotransferase (ALT) levels in PF-04287881-treated animals relative to vehicle-treated controls were observed in the majority (88%) of strains tested following a seven day exposure. The average fold elevation in ALT varied by genetic background and correlated with microscopic findings of hepatocellular hypertrophy, hepatocellular single cell necrosis, and Kupffer cell vacuolation (confirmed as phospholipidosis) in the liver. Global liver mRNA expression was evaluated in a subset of four strains to identify transcript and pathway differences that distinguish susceptible mice from resistant mice in the context of PF-04287881 treatment. The protein ubiquitination pathway was highly enriched among genes associated with PF-04287881-induced hepatocellular necrosis. Expression changes associated with PF-04287881-induced phospholipidosis included genes involved in drug transport, phospholipid metabolism, and lysosomal function. The findings suggest that perturbations in genes involved in protein degradation leading to accumulation of oxidized proteins may mediate the liver injury induced by this drug.
authors: Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors: Merrie
authors: M
authors: Mosedale
authors: Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340, USA.
authors: Hong
authors: H
authors: Wu
authors: Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors: C Lisa
authors: CL
authors: Kurtz
authors: Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340, USA.
authors: Stephen P
authors: SP
authors: Schmidt
authors: Drug Safety Research and Development, Pfizer Global Research and Development, Groton, CT06340, USA. Electronic address: Karissa.Adkins@pfizer.com.
authors: Karissa
authors: K
authors: Adkins
authors: Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA; University of Arkansas for Medical Sciences, Little Rock, AR72205, USA.
authors: Alison H
authors: AH
authors: Harrill
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005260:Female; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D010743:Phospholipids / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013045:Species Specificity
chemical_list: D000900:Anti-Bacterial Agents; D010743:Phospholipids
keywords: Drug-induced liver injury; Mouse diversity panel; Phospholipidosis