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Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping

The objective of the present study was to define whether inhaled tetrandrine (TET) could be a promising way to achieve the local effect on its therapeutic efficacy based on biodistribution features using the LPS-treated acute lung injury (ALI) model. The tissue distribution profiles of inhaled TET i...

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Autores principales: Wang, Furun, Jiang, Xue, Yang, Zengxu, Fu, Shuang, Yao, Shi, Wang, Lingchao, Lv, Yue, Zhang, Wenpeng, Ding, Rigao, Zhuang, Xiaomei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9655037/
https://www.ncbi.nlm.nih.gov/pubmed/36361734
http://dx.doi.org/10.3390/ijms232112948
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author Wang, Furun
Jiang, Xue
Yang, Zengxu
Fu, Shuang
Yao, Shi
Wang, Lingchao
Lv, Yue
Zhang, Wenpeng
Ding, Rigao
Zhuang, Xiaomei
author_facet Wang, Furun
Jiang, Xue
Yang, Zengxu
Fu, Shuang
Yao, Shi
Wang, Lingchao
Lv, Yue
Zhang, Wenpeng
Ding, Rigao
Zhuang, Xiaomei
author_sort Wang, Furun
collection PubMed
description The objective of the present study was to define whether inhaled tetrandrine (TET) could be a promising way to achieve the local effect on its therapeutic efficacy based on biodistribution features using the LPS-treated acute lung injury (ALI) model. The tissue distribution profiles of inhaled TET in normal and ALI mouse models showed that pulmonary inflammation led to an altered distribution in a tissue-specific way. More TET accumulated in almost all tissues including in the blood. Among them, the increased exposure in the lungs was significantly higher than in the other tissues. However, there was a negative increase in the brain. In vitro turnover rates of TET in mouse liver microsomes (MLM) from normal and LPS-treated mice showed significant differences. In the presence of NADPH, TET demonstrated relatively low hepatic clearance (89 mL/h/kg) in that of normal MLM (140 mL/h/kg). Intracellular uptakes of TET in A549, HepG2, RAW264.7, and C8-D1A cells were significantly inhibited by monensin, indicating that the intracellular accumulation of TET is driven by lysosomal trapping. However, in the presence of LPS, only the lysosomal pH partitioning of TET in A549 cell lines increased (~30%). Bidirectional transport of TET across LLC-PK1 cell expressing MDR1 showed that MDR1 is responsible for the low brain exposure via effluxion (ER = 32.46). From the observed overall agreement between the in vitro and in vivo results, we concluded that the downregulation of the CYP3A together with strengthened pulmometry lysosomal trapping magnified the retention of inhaled TET in the lung. These results therefore open the possibility of prolonging the duration of the local anti-inflammation effect against respiratory disorders.
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spelling pubmed-96550372022-11-15 Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping Wang, Furun Jiang, Xue Yang, Zengxu Fu, Shuang Yao, Shi Wang, Lingchao Lv, Yue Zhang, Wenpeng Ding, Rigao Zhuang, Xiaomei Int J Mol Sci Article The objective of the present study was to define whether inhaled tetrandrine (TET) could be a promising way to achieve the local effect on its therapeutic efficacy based on biodistribution features using the LPS-treated acute lung injury (ALI) model. The tissue distribution profiles of inhaled TET in normal and ALI mouse models showed that pulmonary inflammation led to an altered distribution in a tissue-specific way. More TET accumulated in almost all tissues including in the blood. Among them, the increased exposure in the lungs was significantly higher than in the other tissues. However, there was a negative increase in the brain. In vitro turnover rates of TET in mouse liver microsomes (MLM) from normal and LPS-treated mice showed significant differences. In the presence of NADPH, TET demonstrated relatively low hepatic clearance (89 mL/h/kg) in that of normal MLM (140 mL/h/kg). Intracellular uptakes of TET in A549, HepG2, RAW264.7, and C8-D1A cells were significantly inhibited by monensin, indicating that the intracellular accumulation of TET is driven by lysosomal trapping. However, in the presence of LPS, only the lysosomal pH partitioning of TET in A549 cell lines increased (~30%). Bidirectional transport of TET across LLC-PK1 cell expressing MDR1 showed that MDR1 is responsible for the low brain exposure via effluxion (ER = 32.46). From the observed overall agreement between the in vitro and in vivo results, we concluded that the downregulation of the CYP3A together with strengthened pulmometry lysosomal trapping magnified the retention of inhaled TET in the lung. These results therefore open the possibility of prolonging the duration of the local anti-inflammation effect against respiratory disorders. MDPI 2022-10-26 /pmc/articles/PMC9655037/ /pubmed/36361734 http://dx.doi.org/10.3390/ijms232112948 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Furun
Jiang, Xue
Yang, Zengxu
Fu, Shuang
Yao, Shi
Wang, Lingchao
Lv, Yue
Zhang, Wenpeng
Ding, Rigao
Zhuang, Xiaomei
Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
title Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
title_full Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
title_fullStr Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
title_full_unstemmed Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
title_short Alternation of Organ-Specific Exposure in LPS-Induced Pneumonia Mice after the Inhalation of Tetrandrine Is Governed by Metabolizing Enzyme Suppression and Lysosomal Trapping
title_sort alternation of organ-specific exposure in lps-induced pneumonia mice after the inhalation of tetrandrine is governed by metabolizing enzyme suppression and lysosomal trapping
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9655037/
https://www.ncbi.nlm.nih.gov/pubmed/36361734
http://dx.doi.org/10.3390/ijms232112948
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