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Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models()
Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121301/ https://www.ncbi.nlm.nih.gov/pubmed/27896072 http://dx.doi.org/10.1016/j.ymgmr.2013.12.003 |
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author | Tanaka, Yuta Ishitsuka, Yoichi Yamada, Yusei Kondo, Yuki Takeo, Toru Nakagata, Naomi Higashi, Taishi Motoyama, Keiichi Arima, Hidetoshi Matsuo, Muneaki Higaki, Katsumi Ohno, Kousaku Irie, Tetsumi |
author_facet | Tanaka, Yuta Ishitsuka, Yoichi Yamada, Yusei Kondo, Yuki Takeo, Toru Nakagata, Naomi Higashi, Taishi Motoyama, Keiichi Arima, Hidetoshi Matsuo, Muneaki Higaki, Katsumi Ohno, Kousaku Irie, Tetsumi |
author_sort | Tanaka, Yuta |
collection | PubMed |
description | Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1(+/+)) or Npc1(+/−) mice died by 72 h after the injection. In contrast, all of the Npc1(−/−) mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1(+/+) or Npc1(+/−) mice. However, these pathophysiological changes were significantly alleviated in Npc1(−/−) mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1(−/−) mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1(+/+) or Npc1(+/−) mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells. |
format | Online Article Text |
id | pubmed-5121301 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-51213012016-11-28 Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() Tanaka, Yuta Ishitsuka, Yoichi Yamada, Yusei Kondo, Yuki Takeo, Toru Nakagata, Naomi Higashi, Taishi Motoyama, Keiichi Arima, Hidetoshi Matsuo, Muneaki Higaki, Katsumi Ohno, Kousaku Irie, Tetsumi Mol Genet Metab Rep Research Paper Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann–Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD in Npc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1(+/+)) or Npc1(+/−) mice died by 72 h after the injection. In contrast, all of the Npc1(−/−) mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment in Npc1(+/+) or Npc1(+/−) mice. However, these pathophysiological changes were significantly alleviated in Npc1(−/−) mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1(−/−) mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1(+/+) or Npc1(+/−) mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells. Elsevier 2014-01-11 /pmc/articles/PMC5121301/ /pubmed/27896072 http://dx.doi.org/10.1016/j.ymgmr.2013.12.003 Text en © 2013 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
spellingShingle | Research Paper Tanaka, Yuta Ishitsuka, Yoichi Yamada, Yusei Kondo, Yuki Takeo, Toru Nakagata, Naomi Higashi, Taishi Motoyama, Keiichi Arima, Hidetoshi Matsuo, Muneaki Higaki, Katsumi Ohno, Kousaku Irie, Tetsumi Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() |
title | Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() |
title_full | Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() |
title_fullStr | Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() |
title_full_unstemmed | Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() |
title_short | Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann–Pick Type C disease models() |
title_sort | influence of npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in niemann–pick type c disease models() |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121301/ https://www.ncbi.nlm.nih.gov/pubmed/27896072 http://dx.doi.org/10.1016/j.ymgmr.2013.12.003 |
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