Aminochrome Toxicity is Mediated by Inhibition of Microtubules Polymerization Through the Formation of Adducts with Tubulin.
In this study, we investigated the role of adducts formation between aminochrome and tubulin and its interference in microtubules assembly and stability in aminochrome-induced toxicity in SH-SY5Y cells. We also investigated whether changes in the microtubules structures are an early event that could affect tubulin expression. We demonstrated in vitro that aminochrome tubulin adducts inhibit tubulin polymerization and that aminochrome induces microtubules disassembly. Moreover, when the SH-SY5Y cells were incubated with aminochrome, we observed an increase in soluble tubulin, indicating depolymerization of microtubules. Aminochrome generates disruption of the microtubules network, leading to changes in the morphology of the cells inducing cell death, in a dose- and time-dependent manner. Interestingly, these changes preceded cell death and were partly inhibited by paclitaxel, a microtubule-stabilizing agent. Furthermore, we observed that aminochrome increased early tubulin expression before significant cell death occurred. Consequently, all these antecedents suggest that aminochrome toxicity is mediated by early disruption of microtubules network, where the adduct formation between aminochrome and tubulin could be responsible for the inhibition in the assembly microtubules and the loss of microtubules stability. Possibly, the early changes in tubulin expression could correspond to compensatory mechanisms against the toxic effects of aminochrome.
Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, 8380453, Santiago, Chile.
Andrea
A
Briceño
Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, 8380453, Santiago, Chile.
Patricia
P
Muñoz
Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Limonares 190, 2561780, Viña del Mar, Chile.
Patricia
P
Brito
Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, 8380453, Santiago, Chile.
Sandro
S
Huenchuguala
Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, 8380453, Santiago, Chile.
Juan
J
Segura-Aguilar
Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, 8380453, Santiago, Chile. iparis@santotomas.cl.|Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Limonares 190, 2561780, Viña del Mar, Chile. iparis@santotomas.cl.
Irmgard B
IB
Paris
D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D045563:Indolequinones / Q000633:toxicity*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000633:toxicity*
D045563:Indolequinones; D014404:Tubulin; D050257:Tubulin Modulators; C091584:aminochrome 1
Aminochrome; Dopamine; Microtubules polymerization; Neurodegeneration; Parkinson’s disease; Tubulin