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Succinate dehydrogenase inhibitors: in silico flux analysis and in vivo metabolomics investigations show no severe metabolic consequences for rats and humans.
Kamp, H; Wahrheit, J; Stinchcombe, S; Walk, T; Stauber, F; Ravenzwaay, B V.
Afiliação
  • Kamp H; BASF SE, Ludwigshafen, Germany.
  • Wahrheit J; BASF SE, Ludwigshafen, Germany.
  • Stinchcombe S; BASF SE, Ludwigshafen, Germany.
  • Walk T; BASF Metabolome Solutions GmbH, Berlin, Germany.
  • Stauber F; BASF SE, Ludwigshafen, Germany.
  • Ravenzwaay BV; BASF SE, Ludwigshafen, Germany. Electronic address: Bennard.ravenzwaay@basf.com.
Food Chem Toxicol ; 150: 112085, 2021 Apr.
Article em En | MEDLINE | ID: mdl-33636213
Succinate dehydrogenase complex II inhibitors (SDHIs) are widely used fungicides since the 1960s. Recently, based on published in vitro cell viability data, potential health effects via disruption of the mitochondrial respiratory chain and tricarboxylic acid cycle have been postulated in mammalian species. As primary metabolic impact of SDH inhibition, an increase in succinate, and compensatory ATP production via glycolysis resulting in excess lactate levels was hypothesized. To investigate these hypotheses, genome-scale metabolic models of Rattus norvegicus and Homo sapiens were used for an in silico analysis of mammalian metabolism. Moreover, plasma samples from 28-day studies with the SDHIs boscalid and fluxapyroxad were subjected to metabolome analyses, to assess in vivo metabolite changes induced by SDHIs. The outcome of in silico analyses indicated that mammalian metabolic networks are robust and able to compensate different types of metabolic perturbation, e.g., partial or complete SDH inhibition. Additionally, the in silico comparison of rat and human responses suggested no noticeable differences between both species, evidencing that the rat is an appropriate testing organism for toxicity of SDHIs. Since no succinate or lactate accumulation were found in rats, such an accumulation is also not expected in humans as a result of SDHI exposure.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Succinato Desidrogenase / Compostos de Bifenilo / Niacinamida / Amidas Limite: Animals / Female / Humans / Male Idioma: En Revista: Food Chem Toxicol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Succinato Desidrogenase / Compostos de Bifenilo / Niacinamida / Amidas Limite: Animals / Female / Humans / Male Idioma: En Revista: Food Chem Toxicol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido