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Increased Divalent Metal Transporter 1 Expression Might Be Associated with the Neurotoxicity of L-DOPA

Department of Applied Biology and Chemical Technology, and National Key Laboratory of Chinese Medicine and Molecular Pharmacology (Shenzhen), Hong Kong Polytechnic University, Kowloon, Hong Kong (Y.-Z.C., Y.K., J.-R.D., G.M.H., K.-P.H., L.Z., Y.-J.X., Q.W., L.-Z.L., C.-Y.W., Z.-M.Q.); the Biotechnology Laboratory, Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada (Y.K.); and the Key Laboratory of Nerve Regeneration, Nanton University, Nanton, Jiangsu, People's Republic of China (L.Z., X.-S.G., Z.-M.Q.)

Based on the available data, we speculated that changes in brain iron metabolism induced by L-DOPA might be associated with the neurotoxicity of L-DOPA. To investigate this possibility, the effects of L-DOPA on the expression of iron influx proteins [transferrin receptor (TfR) and divalent metal transporter 1 (DMT1)], iron efflux protein (ferroportin 1), and iron uptake in C6 glioma cells were determined in this study using Northern blot and Western blot analysis and the calcein method. The findings showed that treatment of C6 cells with different concentrations of L-DOPA (0-100 µM) did not affect the expression of mRNA and protein of TfR and DMT1 with iron-responsive element (+IRE) and protein of ferroportin 1. However, a significant increase in the expression of DMT1(-IRE) mRNA and protein was found in cells treated, respectively, with 10 and 30 µM L-DOPA (mRNA) and 1, 5, 10 and 30 µM L-DOPA (protein). The increase in DMT(-IRE) protein induced by L-DOPA treatment was in parallel with the increase in DMT(-IRE) mRNA. The levels of DMT1(-IRE) mRNA and protein peaked in the cells treated with 10 µM L-DOPA and then decreased progressively with increasing concentrations of L-DOPA. Further study demonstrated that treatment of the cells with 10 µM L-DOPA induced a significant increase in ferrous uptake by C6 glioma cells. The findings suggested that the increased DMT1(-IRE) expression might be partly associated with the neurotoxicity of L-DOPA. Clinical relevance of the findings needs to be investigated further.

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