Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

Abstract Diseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether...

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Autores principales:	Arne Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan G. Hengstler, Lars Kuepfer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dd7f260955f04583b1611c15c14be427
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spelling	oai:doaj.org-article:dd7f260955f04583b1611c15c14be4272021-12-02T16:06:56ZPhysiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage10.1038/s41598-017-04574-z2045-2322https://doaj.org/article/dd7f260955f04583b1611c15c14be4272017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04574-zhttps://doaj.org/toc/2045-2322Abstract Diseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether the surviving tissue undergoes an adaptive response to compensate the loss. To understand the cellular impact of toxic liver damage in an in vivo situation, we here used physiologically-based pharmacokinetic modelling to investigate pharmacokinetics of a specifically designed drug cocktail at three different sampling sites of the body in healthy mice and mice treated with carbon tetrachloride (CCl4). Liver zonation was explicitly quantified in the models through immunostaining of cytochrome P450s enzymes. Comparative analyses between the simulated decrease in clearance capacity and the experimentally measured loss in tissue volume indicated that CCl4-induced impairment of metabolic functions goes beyond the mere loss of metabolically active tissue. The here established integrative modelling strategy hence provides mechanistic insights into functional consequences of toxic liver damage in an in vivo situation, which would not have been accessible by conventional methods.Arne SchenkAhmed GhallabUte HofmannReham HassanMichael SchwarzAndreas SchuppertLars Ole SchwenAlbert BraeuningDonato TeutonicoJan G. HengstlerLars KuepferNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arne Schenk Ahmed Ghallab Ute Hofmann Reham Hassan Michael Schwarz Andreas Schuppert Lars Ole Schwen Albert Braeuning Donato Teutonico Jan G. Hengstler Lars Kuepfer Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
description	Abstract Diseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether the surviving tissue undergoes an adaptive response to compensate the loss. To understand the cellular impact of toxic liver damage in an in vivo situation, we here used physiologically-based pharmacokinetic modelling to investigate pharmacokinetics of a specifically designed drug cocktail at three different sampling sites of the body in healthy mice and mice treated with carbon tetrachloride (CCl4). Liver zonation was explicitly quantified in the models through immunostaining of cytochrome P450s enzymes. Comparative analyses between the simulated decrease in clearance capacity and the experimentally measured loss in tissue volume indicated that CCl4-induced impairment of metabolic functions goes beyond the mere loss of metabolically active tissue. The here established integrative modelling strategy hence provides mechanistic insights into functional consequences of toxic liver damage in an in vivo situation, which would not have been accessible by conventional methods.
format	article
author	Arne Schenk Ahmed Ghallab Ute Hofmann Reham Hassan Michael Schwarz Andreas Schuppert Lars Ole Schwen Albert Braeuning Donato Teutonico Jan G. Hengstler Lars Kuepfer
author_facet	Arne Schenk Ahmed Ghallab Ute Hofmann Reham Hassan Michael Schwarz Andreas Schuppert Lars Ole Schwen Albert Braeuning Donato Teutonico Jan G. Hengstler Lars Kuepfer
author_sort	Arne Schenk
title	Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
title_short	Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
title_full	Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
title_fullStr	Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
title_full_unstemmed	Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
title_sort	physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/dd7f260955f04583b1611c15c14be427
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Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

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