The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice.
Gaucher disease (GD), caused by a defect of acid β-glucosidase (β-Glu), is one of the most common sphingolipidoses. Recently, ambroxol, an FDA-approved drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified as a chemical chaperone for GD. In the present study, we investigated the chaperone activity and toxicity of ambroxol on both cultured GD patient cells and normal mice. We found that ambroxol treatment significantly increased N370S, F213I, N188S/G193W and R120W mutant β-Glu activities in GD fibroblasts with low cytotoxicity. Additionally, we measured the β-Glu activity in the tissues of normal mice which received water containing increasing concentrations of ambroxol ad libitum for one week. No serious adverse effect was observed during this experiment. Ambroxol significantly increased the β-Glu activity in the spleen, heart and cerebellum of the mice. This result showed its oral availability and wide distribution and chaperone activity in the tissues, including the brain, and its lack of acute toxicity. These characteristics of ambroxol would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations.
Division of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Japan. nicholasluan@gmail.com
Zhuo
Z
Luan
Linjing
L
Li
Katsumi
K
Higaki
Eiji
E
Nanba
Yoshiyuki
Y
Suzuki
Kousaku
K
Ohno
D000551:Ambroxol / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D003124:Colorimetry; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D005100:Expectorants / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D005697:Galactosides / Q000493:pharmacokinetics; D005776:Gaucher Disease / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000097:blood / Q000378:metabolism* / Q000652:urine; D009154:Mutation / Q000235:genetics; D012867:Skin / Q000473:pathology; D013997:Time Factors; D001617:beta-Glucosidase / Q000235:genetics
D005100:Expectorants; D005456:Fluorescent Dyes; D005697:Galactosides; D018832:Molecular Chaperones; D000551:Ambroxol; D006923:Hymecromone; C026845:4-methylumbelliferyl-galactopyranoside; D001617:beta-Glucosidase