Analysis of gene expression profiles from the liver of rats treated with the mitochondrial electron transport chain complex III inhibitor GSK932121A (50mg/kg) or vehicle control

ABSTRACT: BACKGROUND: Correlating in vitro mitochondrial data to outcomes in vivo remains a challenge and improving methods to assess mitochondrial function in vivo would both guide safer candidate selection and support the growing number of discovery programmes targeting mitochondria for pharmacological intervention. OBJECTIVES: The aim was to assess the toxicity profile of a compound with complex III electron transport chain inhibitory activity (GSK932121A) in order to identify markers and mechanisms of mitochondrial perturbation in vivo. METHODS:Crl:CD(SD) rats were dosed IP with GSK932121A for up to 5 hours depending upon the severity of observed clinical signs. Respirometry, microscopy, lactate/pyruvate and transcriptomics profiling were used to aid identification of a mode of action and this data was compared with functional data in isolated mitochondria. RESULTS AND DISCUSSION: GSK932121A administered in vivo caused hypothermia and a metabolic shift in energy production provoking an increased lactate/pyruvate ratio, microvesicular steatosis and glycogen depletion; alongside gene expression changes indicative of a fasted state. Our data improves current understanding of the toxicological consequences of drug induced respiratory chain inhibition and guides endpoint selection for future investigative safety studies with mitochondrially active molecules. 50mg/kg GSK932121A treated rat livers (n=10) were used to assess differential gene expression when compared with 0mg.kg GSK932121A Vehicle Control (n=12). Two samples were excluded from the 50mg/kg group due to low plasma exposure to GSK932121A

ORGANISM(S): Rattus norvegicus

SUBMITTER: Ashley Broom 

PROVIDER: E-GEOD-65374 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress