Abstract：Manganese (Mn) is a widespread environmental and occupational pollutant, its target organ is the brain. Mn accumulates in the substantia nigar, striatum, globus paildus, and caudate nucleues, and causes injury in extrapyramidal system. One of the mechanisms on manganism is something that breaks the balance of oxidation-antioxidation system, and that results in over prodution of reactive oxygen species (ROS) then induces oxidative damage. Glutathione (GSH) is an important endogenous antioxidant. Mangansim can cause GSH synthesis dysfunction. Nuclear Factor- Erythroid 2 Related Factor 2 (Nrf2) is a transcription factor with antioxidation characteristics, which increases synthesis of endogenous GSH levels. This review will focus on four respects, including exposure pathway and neurotoxicity of Mn, Mn and oxidative stress, the effect of manganism on GSH, and the regulatory role of Nrf2 in Mn-induced GSH synthesis dysfunction.
宋奇繁, 邓宇. Nrf2对锰致GSH合成障碍的调控作用[J]. 实用预防医学, 2015, 22(12): 1527-1530.
SONG Qifan, DENG Yu. Regulatory role of Nrf2 in manganese-induced GSH synthesis dysfunction. , 2015, 22(12): 1527-1530.
[1] ATDSR (Agency for Toxic Substances and Disease Registry 2000 Toxicological profile for manganese ). U.S. Department of Health And Human Services Public Health Service. Available at http://www.atsdr.cdc.gov/toxprofiles/tp 151.html. [2] Zheng W, Kim H, Zhan Q. Comparative toxicokinetics of manganese chloride and methylcyclopentadienyl manganese tricarbonyl (MMT) in Sprague-Dawley rats[J]. Toxicol Sei, 2000, 54(2): 295-301. [3] Dorman DC, Andersen ME, Roper JM, et al. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT-Part I: Program Implementation and Lessons Learned[J]. J Toxicol, 2012, 2012: 946742. [4] Sidoryk-Wegrzynowicz M. Impairment of glutamine/glutamate-γ-aminobutyric acid cycle in manganese toxicity in the central nervous system[J]. Folia Neuropathol, 2014, 52(4): 377-382. [5] Roth JA. Correlation between the biochemical pathways altered by mutated parkinson-related genes and chronic exposure to manganese[J]. Neurotoxicology, 2014, 44: 314-325. [6] Haynes EN, Sucharew H, Kuhnell P, et al. Manganese Exposure and Neurocognitive Outcomes in Rural School-Age Children: The Communities Actively Researching Exposure Study (Ohio, USA)[J]. Environ Health Perspect, 2015 Apr 22. [7] Bakthavatsalam S, Das Sharma S, Sonawane M, et al. A zebrafish model of manganism reveals reversible and treatable symptoms that are independent of neurotoxicity[J]. Dis Model Mech, 2014, 7(11), 1239-1251. [8] Rama Rao KV, Reddy PV, Hazell AS, et al. Manganese induces cell swelling in cultured astrocytes[J]. Neurotoxicology, 2007, 28(4): 807-812. [9] Wang F, Wang C, Jiang Y, et al. Protective role of sodium para-amino salicylic acid against manganese-induced hippocampal neurons damage[J]. Environ Toxicol Pharmacol, 2014, 37(3): 1071-1078. [10] 张芳林, 徐兆发, 徐斌, 等. 锰致脑线粒体损伤机制的研究进展[J]. 实用预防医学, 2007, 14(6): 1951-1953. [11] Nishigori C, Hattori Y, Toyokuni S. Role of reactive oxygen species in skin carcinogenesis[J]. Antioxid Redox Signal, 2004, 6(3): 561-570. [12] Shen XM, Dryhurst G. Iron- and manganese-catalyzed autoxidation of dopamine in the presence of L-cysteine: possible insights into iron-and manganese-mediated dopaminergic neurotoxicity[J]. Chem Res Toxicol, 1998, 11(7): 824-837. [13] Dringen R. Metabolism and functions of glutathione in brain[J]. Prog Neurobiol, 2000, 62(6): 649-671. [14] Perl DP, Olanow CW. The neuropathology of manganese-induced Parkinsonism[J]. J Neuropathol Exp Neurol, 2007, 66(8): 675-682. [15] Rama Rao KV, Reddy PV, Hazell AS, et al. Manganese induces cell swelling in cultured astrocytes[J]. Neurotoxicology, 2007, 28(4): 807-812. [16] Zhao F, Cai T, Liu M, et al. Manganese induces dopaminergic neurodegeneration via microglial activation in a rat model of manganism[J]. Toxicol Sci, 2009, 107(1): 156-164. [17] Liu M, Cai T, Zhao F, et al. Effect of microglia activation on dopaminergic neuronal injury induced by manganese, and its possible mechanism[J]. Neurotox Res, 2009, 16(1): 42-49. [18] Zhang P, Hatter A, Liu B. Manganese chloride stimulates rat microglia to release hydrogen peroxide[J]. Toxicol Lett, 2007, 173(2): 88-100. [19] Lee A, Pow DV. Astrocytes: Glutamate transport and alternate splicing of transporters[J]. Int J Biochem Cell Biol, 2010, 42(12): 1901-1906. [20] Ross JR, Porter BE, Buckley PT, et al. mRNA for the EAAC1 subtype of glutamate transporter is present in neuronal dendrites in vitro and dramatically increases in vivo after a seizure[J]. Neurochem Int, 2011, 58(3): 366-375. [21] Albrecht P, Lewerenz J, Dittmer S, et al. Mechanisms of oxidative glutamate toxicity: the glutamate/cystine antiporter system xc- as a neuroprotective drug target[J]. CNS Neurol Disord Drug Targets, 2010, 9(3): 373-382. [22] Hansen JM, Harris C. Glutathione during embryonic development[J]. Biochim Biophys Acta. 2014 Dec 16. pii: S0304-4165(14)00400-0. doi:10.1016/j.bbagen.2014.12.001. [23] Desole MS, Esposito G, Migheli R, et al. Glutathione deficiency potentiates manganese toxicity in rat striatum and brainstem and in PC12 cells[J]. Pharmacol Res, 1997, 36(4): 285-292. [24] Desole MS, Serra PA, Esposito G, et al. Glutathione deficiency potentiates manganese-induced increases in compounds associated with high-energy phosphate degradation in discrete brain areas of young and aged rats[J]. Aging (Milano), 2000, 12(6): 470-477. [25] Zhang F, Xu Z, Gao J, et al. In vitro effect of manganese chloride exposure on energy metabolism and oxidative damage of mitochondria isolated from rat brain[J]. Environ Toxicol Pharmacol, 2008, 26(2): 232-236. [26] Santos AP, Lucas RL, Andrade V, et al. Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity[J]. Toxicol Appl Pharmacol, 2012, 258(3): 394-402. [27] Wang M, Sun J, Xue F, et al. The effect of intracellular amino acids on GSH production by high-cell-density cultivation of Saccharomyces cerevisiae[J]. Appl Biochem Biotechnol, 2012, 168(1): 198-205. [28] 邓宇, 米超, 李乐慧, 等. 褪黑素对锰致小鼠运动障碍及纹状体损伤的影响[J]. 中国工业医学杂志, 2013, 26(6): 403-408. [29] Erikson KM, Dobson AW, Dorman DC, et al. Manganese exposure and induced oxidative stress in the rat brain[J]. Sci Total Environ, 2004, 334-335: 409-416. [30] Erikson KM, Dorman DC, Lash LH, et al. Duration of airborne-manganese exposure in rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity[J]. Neurotoxicology, 2008, 29(3): 377-385. [31] Erikson KM, Dorman DC, Lash LH, et al. Manganese inhalation by rhesus monkeys is associated with brain regional changes in biomarkers of neurotoxicity[J]. Toxicol Sci, 2007, 97(2): 459-466. [32] Satoh T, Harada N, Hosoya T, et al. Keap1/Nrf2 system regulates neuronal survival as revealed through study of keap1 gene-knockout mice[J]. Biochem Biophys Res Commun, 2009, 380(2): 298-302. [33] Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism[J]. J Biochem Mol Biol, 2004, 37(2): 139-143. [34] Kotlo KU, Yehiely F, Efimova E, et al. Nrf2 is an inhibitor of the Fas pathway as identified by Achilles’ Heel Method, a new function-based approach to gene identification in human cells[J]. Oncogen, 2003, 22( 6): 797-806. [35] Li J, Jin J, Li M, et al. Role of Nrf2 in protection against triptolide-induced toxicity in rat kidney cells[J]. Toxicol Lett, 2012, 213(2): 194-202. [36] Escartin C, Won SJ, Malgorn C, et al. Nuclear factor erythroid 2-related factor 2 facilitates neuronal glutathione synthesis by upregulating neuronal excitatory amino acid transporter 3 expression[J]. J Neurosci, 2011, 31(20): 7392-7401. [37] Ji L, Liu R, Zhang XD, et al. N-acetylcysteine attenuates phosgene-induced acute lung injury via up-regulation of Nrf2-expression[J]. Inhal Toxicol, 2010, 22(7): 535-542. [38] Lee HJ, Han J, Jang Y, et al. Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis[J]. Biochem Biophys Res Commun, 2015, 457(1): 95-100. [39] Pullarkat V, Meng Z, Tahara SM, et al. Proteasome inhibition induces both antioxidant and hb f responses in sickle cell disease via the nrf2 pathway[J]. Hemoglobin, 2014, 38(3): 188-195.
2015, Vol. 22 
