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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creator | Wang, Furun Jiang, Xue Yang, Zengxu Fu, Shuang Yao, Shi Wang, Lingchao Lv, Yue Zhang, Wenpeng Ding, Rigao Zhuang, Xiaomei |
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. |
doi_str_mv | 10.3390/ijms232112948 |
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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.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms232112948</identifier><identifier>PMID: 36361734</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Animal models ; Biodistribution ; Cell lines ; Coronaviruses ; Dengue fever ; Disease ; Enzymes ; Exposure ; Infections ; Inflammation ; Inhalation ; Intracellular ; Lipopolysaccharides ; Lungs ; MDR1 protein ; Metabolism ; Microsomes ; Monensin ; Permeability ; Pharmacokinetics ; Pneumonia ; Respiration ; Testosterone ; Tetrandrine ; Trapping ; Turnover rate ; Viral infections</subject><ispartof>International journal of molecular sciences, 2022-11, Vol.23 (21), p.12948</ispartof><rights>2022 by the authors. 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/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c348t-ac50217c3ffed0c6531f6c2612adeab5b536fe2f400a4bc5764fcaf9b049ae9b3</cites><orcidid>0000-0001-8085-0504</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9655037/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9655037/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Wang, Furun</creatorcontrib><creatorcontrib>Jiang, Xue</creatorcontrib><creatorcontrib>Yang, Zengxu</creatorcontrib><creatorcontrib>Fu, Shuang</creatorcontrib><creatorcontrib>Yao, Shi</creatorcontrib><creatorcontrib>Wang, Lingchao</creatorcontrib><creatorcontrib>Lv, Yue</creatorcontrib><creatorcontrib>Zhang, Wenpeng</creatorcontrib><creatorcontrib>Ding, Rigao</creatorcontrib><creatorcontrib>Zhuang, Xiaomei</creatorcontrib><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><title>International journal of molecular sciences</title><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.</description><subject>Animal models</subject><subject>Biodistribution</subject><subject>Cell lines</subject><subject>Coronaviruses</subject><subject>Dengue fever</subject><subject>Disease</subject><subject>Enzymes</subject><subject>Exposure</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Inhalation</subject><subject>Intracellular</subject><subject>Lipopolysaccharides</subject><subject>Lungs</subject><subject>MDR1 protein</subject><subject>Metabolism</subject><subject>Microsomes</subject><subject>Monensin</subject><subject>Permeability</subject><subject>Pharmacokinetics</subject><subject>Pneumonia</subject><subject>Respiration</subject><subject>Testosterone</subject><subject>Tetrandrine</subject><subject>Trapping</subject><subject>Turnover rate</subject><subject>Viral infections</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkk1v1DAQhiMEoqVw5G6JC5eAv-JsLkhVtZSVtmqlXc7WxBnvepXYwU6qbn8UvxGXVhXl5JHmeR_bmimKj4x-EaKhX91hSFxwxngjF6-KUyY5LylV9et_6pPiXUoHSjNYNW-LE6GEYrWQp8Xv837C6GFywZNgyXXcgS83IxpnnSHLuzGkOSJxnqxvNuXKd7PBjtx4nIfgHZArZ5CAzRIy7ZGs_B76Z9sWpwi-i87nTiKX4TbflePtkVzhBG3o3b3zO7L098cByWYex4gpPaRzjKyPKaQwQE-2EcYxk--LNxb6hB-ezrPi5_fl9uJHub6-XF2cr0sj5GIqwVSUs9oIa7GjRlWCWWW4Yhw6hLZqK6EscispBdmaqlbSGrBNS2UD2LTirPj26B3ndsDOoM8f6fUY3QDxqAM4_bLj3V7vwq1uVFVRUWfB5ydBDL9mTJMeXDLY9-AxzEnzWlQLpWrFM_rpP_QQ5jyS_i8llaRiQTNVPlImhpQi2ufHMKofNkG_2ATxB9BaqkU</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Wang, Furun</creator><creator>Jiang, Xue</creator><creator>Yang, Zengxu</creator><creator>Fu, Shuang</creator><creator>Yao, Shi</creator><creator>Wang, Lingchao</creator><creator>Lv, Yue</creator><creator>Zhang, Wenpeng</creator><creator>Ding, Rigao</creator><creator>Zhuang, Xiaomei</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>COVID</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8085-0504</orcidid></search><sort><creationdate>20221101</creationdate><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><author>Wang, Furun ; 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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.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>36361734</pmid><doi>10.3390/ijms232112948</doi><orcidid>https://orcid.org/0000-0001-8085-0504</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animal models Biodistribution Cell lines Coronaviruses Dengue fever Disease Enzymes Exposure Infections Inflammation Inhalation Intracellular Lipopolysaccharides Lungs MDR1 protein Metabolism Microsomes Monensin Permeability Pharmacokinetics Pneumonia Respiration Testosterone Tetrandrine Trapping Turnover rate Viral infections |
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 |
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