Effects of mid-respiratory chain inhibition on mitochondrial function in vitro and in vivo

Toxicology Research
Ashley J BroomJonathan J Lyon

Abstract

Relating the in vitro mitochondrial effects of drug candidates to likely in vivo outcomes remains challenging. Better understanding of this relationship, alongside improved methods to assess mitochondrial dysfunction in vivo, would both guide safer drug candidate selection and better support discovery programmes targeting mitochondria for pharmacological intervention. The aim of this study was to profile the in vivo effects of a compound with suspected complex III electron transport chain (ETC) inhibitory activity (GSK932121A) at doses associated with clinical signs, and relate findings back to in vitro data with the same compound. Control liver mitochondria or HepG2 cells were treated in vitro with GSK932121A to assess mitochondrial effects on both calcium retention capacity (CRC) and oxygen consumption rate (OCR) respectively. The same assessments were then performed on liver mitochondria isolated from Crl:CD(SD) rats, 5 hours following intraperitoneal (IP) administration of GSK932121A. Lactate/pyruvate assessment, hepatic microscopy, blood gas analysis, glutathione profiling and transcriptomics were used to characterise the acute toxicity. In vivo, GSK932121A caused hypothermia, increased levels of hepatocellular oxidative s...Continue Reading

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Citations

Jun 13, 2017·Expert Opinion on Drug Metabolism & Toxicology·Richard J WeaverB Kevin Park
May 11, 2021·The Journal of Allergy and Clinical Immunology·Luís AlmeidaTim Sparwasser

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Datasets Mentioned

BETA
GSE65374

Methods Mentioned

BETA
light microscopy
chips
transmission
Assay
transmission electron microscopy
protein assay

Software Mentioned

Array Studio

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