A mouse model to test the in vivo efficacy of chemical chaperones

Bai, Chunxue; Biwersi, Joachim; Verkman, A.S; Matthay, Michael A

doi:10.1016/s1056-8719(98)00034-3

Cited by 59Heat shock proteins researchCystic Fibrosis Research AdvancesIon Transport and Channel Regulation

A mouse model to test the in vivo efficacy of chemical chaperones

Bai, Chunxue, Biwersi, Joachim, Verkman, A.S, Matthay, Michael A·1998·Journal of Pharmacological and Toxicological Methods

DOI 10.1016/s1056-8719(98)00034-3

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Abstract

In vitro studies in transfected cells have indicated that chemical chaperones including glycerol (0.5-1.2 M) and trimethylamine oxide (TMAO, 50-100 mM) can correct defective trafficking of some proteins, including deltaF508 CFTR in cystic fibrosis and AQP2 mutants in nephrogenic diabetes insipidus. To develop a mouse model to test the efficacy of chemical chaperones in vivo, glycerol and TMAO were administered by intraperitoneal (i.p.), subcutaneous (s.c.), and oral routes. Glycerol and TMAO assays that utilized 1-5 microL of tail vein blood were developed. Administration by the i.p. and s.c. routes gave maximum serum glycerol concentrations of approximately 100 mM, levels that were well below the effective in vitro concentrations. Single i.p. or s.c. doses of TMAO (7 g/kg, 8% solution in water) resulted in serum [TMAO] greater than 50 mM, with a long half-life (t1/2 approximately equal to 18-21 h). Sustained high serum and tissue [TMAO] > 52 mM for 3 days was achieved by s.c. administration of TMAO (7 g/kg) in water every 8 h. Although approximately 50% of the mice died with this multiple-dose regimen, the remaining mice had nearly normal liver, renal, and pancreatic function. A lower dose of TMAO (5 g/kg) given by the s.c. route every 8 h resulted in serum [TMAO] concentration of 22 mM, a level that was well tolerated by all mice for 72 h. These mice also had high [TMAO] in urine, 400 mM. These results demonstrate that potentially therapeutic concentrations of TMAO can be sustained in mice in vivo, permitting the testing of chemical chaperones in transgenic mouse models of diseases caused by defective protein trafficking.

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TMAO is reportedly capable of directly inducing conformational changes in proteins and of stabilizing protein folding and acting as a small-molecule protein chaperone.
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From Resveratrol Attenuates Trimethylamine- <i>N</i> -Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota (2016) · cites this paper as [48]

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Authors: Bai, C., Biwersi, J., Verkman, A. S., & Matthay, M. A.
Affiliations: University of California, San Francisco (US)
Corresponding author: Matthay, Michael A
ORCID: Bai, Chunxue
Verkman, A.S
Matthay, Michael A
Venue: Journal of Pharmacological and Toxicological Methods
Publisher: Elsevier BV
Published: 1998-07
Volume: 40
Issue: 1
Pages: 39-45
ISSN: 1056-8719 (ISSN-L)
DOI: 10.1016/s1056-8719(98)00034-3
OpenAlex: W2036368648
Cited by: 59
References: 23
Citations by year: 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 3 · 2014: 1 · 2013: 3 · 2012: 5
FWCI: 0.81
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Pharmacological and Toxicological Methods (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords: chemical chaperones, trimethylamine N-oxide, glycerol, protein trafficking, ΔF508-CFTR, cystic fibrosis, aquaporin-2, nephrogenic diabetes insipidus, mouse model, route of administration, serum drug concentration, drug tolerability, transgenic mouse model
MeSH terms: Animals, Blood Chemical Analysis, Cells, Cultured, Female, Glycerol, Half-Life, Hematocrit, Injections, Intraperitoneal, Injections, Subcutaneous, Male, Methylamines, Protein Binding, Spectrophotometry, Ultraviolet, Oxidants, Molecular Chaperones, Mice

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A mouse model to test the in vivo efficacy of chemical chaperones

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