Evaluation of in Vitro Mitochondrial Toxicity Assays and Physicochemical Properties for Prediction of Organ Toxicity Using 228 Pharmaceutical Drugs.
Chem Res Toxicol
; 32(1): 156-167, 2019 01 22.
Article
em En
| MEDLINE
| ID: mdl-30525499
ABSTRACT
Mitochondrial toxicity has been shown to contribute to a variety of organ toxicities such as liver, cardiac, and kidney. In the past decades, two high-throughput applicable screening assays (isolated rat liver mitochondria; glucose-galactose grown HepG2 cells) to assess mitochondrial toxicity have been deployed in many pharmaceutical companies, and numerous publications have demonstrated its usefulness for mechanistic investigations. However, only two publications have demonstrated the utility of these screens as a predictor of human drug-induced liver injury. In the present study, we screened 73 hepatotoxicants, 46 cardiotoxicants, 49 nephrotoxicants, and 60 compounds not known to cause human organ toxicity for their effects on mitochondrial function(s) in the assays mentioned above. Predictive performance was evaluated using specificity and sensitivity of the assays for predicting organ toxicity. Our results show that the predictive performance of the mitochondrial assays are superior for hepatotoxicity as compared to cardiotoxicity and nephrotoxicity (sensitivity 63% vs 33% and 28% with similar specificity of 93%), when the analysis was done at 100* Cmax (drug concentration in human plasma level). We further explored the association of mitochondrial toxicity with physicochemical properties such as calculated log partition coefficient (cLogP), topological polar surface area, ionization status, and molecular weight of the drugs and found that cLogP was most significantly associated mitochondrial toxicity. Since these assays are amenable to higher throughput, we recommend that chemists use these assays to perform structure activity relationship early in the drug discovery process, when chemical matter is abundant. This assures that compounds that lack the propensity to cause mitochondrial dysfunction (and associated organ toxicity) will move forward into animals and humans.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Mitocôndrias Hepáticas
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Preparações Farmacêuticas
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Coração
/
Rim
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Fígado
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Chem Res Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos