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Title: Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver

Abstract

Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75 × 10{sup 4} between the hydrophobic and hydrophilic phases. Due to this high affinity for the cellular membranes dinoseb underwent flow-limited distribution in the liver. Transformation was slow but uptake into the liver space was very pronounced. For an extracellular concentration of 10 μM, the equilibrium intracellular concentration was equal to 438.7 μM. In general dinoseb stimulated catabolism and inhibited anabolism. Half-maximal stimulation of oxygen uptake in the whole liver occurred at concentrations (2.8–5.8 μM) at least ten times above those in isolated mitochondria (0.28 μM). Gluconeogenesis and ureagenesis were half-maximally inhibited at concentrations betweenmore » 3.04 and 5.97 μM. The ATP levels were diminished, but differently in livers from fed and fasted rats. Dinoseb disrupts metabolism in a complex way at concentrations well above its uncoupling action in isolated mitochondria, but still at concentrations that are low enough to be dangerous to animals and humans even at sub-lethal doses. - Highlights: • Dinoseb presents high affinity for the hydrophobic region of the lipid bilayers. • Its cellular concentration may exceed the extracellular one by a factor of 43.9. • One order of magnitude separates the active concentrations in mitochondria and liver. • Hepatic metabolism is disrupted in the concentration range up to 10 μM.« less

Authors:
; ; ; ; ; ;
Publication Date:
OSTI Identifier:
22722903
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 329; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AFFINITY; ANABOLISM; CONCENTRATION RATIO; DISTRIBUTION; ECOLOGICAL CONCENTRATION; ENZYMATIC HYDROLYSIS; KINETICS; LAYERS; LIPIDS; LIVER; MITOCHONDRIA; MOLECULAR DYNAMICS METHOD

Citation Formats

Salla, Gabriela Bueno Franco, Bracht, Lívia, Sá-Nakanishi, Anacharis Babeto de, Parizotto, Angela Valderrama, Bracht, Fabrício, Peralta, Rosane Marina, and Bracht, Adelar. Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.06.013.
Salla, Gabriela Bueno Franco, Bracht, Lívia, Sá-Nakanishi, Anacharis Babeto de, Parizotto, Angela Valderrama, Bracht, Fabrício, Peralta, Rosane Marina, & Bracht, Adelar. Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver. United States. doi:10.1016/J.TAAP.2017.06.013.
Salla, Gabriela Bueno Franco, Bracht, Lívia, Sá-Nakanishi, Anacharis Babeto de, Parizotto, Angela Valderrama, Bracht, Fabrício, Peralta, Rosane Marina, and Bracht, Adelar. Tue . "Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver". United States. doi:10.1016/J.TAAP.2017.06.013.
@article{osti_22722903,
title = {Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver},
author = {Salla, Gabriela Bueno Franco and Bracht, Lívia and Sá-Nakanishi, Anacharis Babeto de and Parizotto, Angela Valderrama and Bracht, Fabrício and Peralta, Rosane Marina and Bracht, Adelar},
abstractNote = {Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75 × 10{sup 4} between the hydrophobic and hydrophilic phases. Due to this high affinity for the cellular membranes dinoseb underwent flow-limited distribution in the liver. Transformation was slow but uptake into the liver space was very pronounced. For an extracellular concentration of 10 μM, the equilibrium intracellular concentration was equal to 438.7 μM. In general dinoseb stimulated catabolism and inhibited anabolism. Half-maximal stimulation of oxygen uptake in the whole liver occurred at concentrations (2.8–5.8 μM) at least ten times above those in isolated mitochondria (0.28 μM). Gluconeogenesis and ureagenesis were half-maximally inhibited at concentrations between 3.04 and 5.97 μM. The ATP levels were diminished, but differently in livers from fed and fasted rats. Dinoseb disrupts metabolism in a complex way at concentrations well above its uncoupling action in isolated mitochondria, but still at concentrations that are low enough to be dangerous to animals and humans even at sub-lethal doses. - Highlights: • Dinoseb presents high affinity for the hydrophobic region of the lipid bilayers. • Its cellular concentration may exceed the extracellular one by a factor of 43.9. • One order of magnitude separates the active concentrations in mitochondria and liver. • Hepatic metabolism is disrupted in the concentration range up to 10 μM.},
doi = {10.1016/J.TAAP.2017.06.013},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 329,
place = {United States},
year = {2017},
month = {8}
}