l-Tyrosine Induces DNA Damage in Brain and Blood of Rats
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Mutations in the tyrosine aminotransferase gene have been identified to cause tyrosinemia type II which is inherited in an autosomal recessive manner. Studies have demonstrated that an excessive production of ROS can lead to reactions with macromolecules, such as DNA, lipids, and proteins. Considering that the l-tyrosine may promote oxidative stress, the main objective of this study was to investigate the in vivo effects of l-tyrosine on DNA damage determined by the alkaline comet assay, in brain and blood of rats. In our acute protocol, Wistar rats (30 days old) were killed 1 h after a single intraperitoneal l-tyrosine injection (500 mg/kg) or saline. For chronic administration, the animals received two subcutaneous injections of l-tyrosine (500 mg/kg, 12-h intervals) or saline administered for 24 days starting at postnatal day (PD) 7 (last injection at PD 31), 12 h after the last injection, the animals were killed by decapitation. We observed that acute administration of l-tyrosine increased DNA damage frequency and damage index in cerebral cortex and blood when compared to control group. Moreover, we observed that chronic administration of l-tyrosine increased DNA damage frequency and damage index in hippocampus, striatum, cerebral cortex and blood when compared to control group. In conclusion, the present work demonstrated that DNA damage can be encountered in brain from animal models of hypertyrosinemia, DNA alterations may represent a further means to explain neurological dysfunction in this inherited metabolic disorder and to reinforce the role of oxidative stress in the pathophysiology of tyrosinemia type II.
KeywordsTyrosinemia type II DNA damage Comet assay Oxidative stress
This research was supported by Grants from Programa de Pós-graduação em Ciências da Saúde—Universidade do Extremo Sul Catarinense (UNESC) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
- 1.Buist NRM, Kennaway NG, Fellmann JH (1985). In: Bickel H, Wachtel U (eds) Inherited diseases of amino acid metabolism. Thieme, Stuttgart, pp 203–235Google Scholar
- 3.Mitchell GA, Grompe M, Lambert M, Tanguay RM (2001) Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1977–1982Google Scholar
- 4.Fois A, Borgogni P, Cioni M, Molinelli M, Frezzotti R, Bardelli AM, Lasorella G, Barberi L, Durand P, DoRocco M, Romano C, Parini R, Cirbetta C, Giovanninim G, Riva E, Balato N, Sartorio R, Mollica F, Zammarchi E, Battini ML (1986) Presentation of the data of the Italian registry for oculocutaneous tyrosinemia. J Inherit Metab Dis 9:S262–S263CrossRefGoogle Scholar
- 5.Charfeddine C, Monastiri K, Mokni M, Laadjimi A, Kaabachi N, Perin O, Nilges M, Kassar S, Keirallah M, Guediche MN, Kamoun MR, Tebib N, Ben Dridi MF, Boubaker S, Ben Osman A, Abdelhak S (2006) Clinical and mutational investigations of tyrosinemia type II in northern Tunisia: identification and structural characterization of two novel TAT mutations. Mol Genet Metab 88:184–191PubMedCrossRefGoogle Scholar
- 9.Greengard O, Andersson SM, Raiha NCR, Ohisalo JJ (1970) In biochemical actions of hormones. J Dev Physiol 2:17–27Google Scholar
- 11.Maydan G, Andresen BS, Madsen PP, Zeigler M, Raas-Rothschild A, Zlotogorski A, Gutman A, Korman SH (2006) TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping. J Inherit Metab Dis 29:620–626PubMedCrossRefGoogle Scholar
- 16.Sgaravatti AM, Magnusson AS, de Oliveira AS, Rosa AP, Mescka CP, Zanin FR, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2009) Tyrosine administration decreases glutathione and stimulates lipid and protein oxidation in rat cerebral cortex. Metab Brain Dis 24:415–425PubMedCrossRefGoogle Scholar
- 19.Bongiovanni R, Yamamoto BK, Simpson C, Jaskiw GE (1980) Pharmacokinetics of systemically administered tyrosine: a comparison of serum, brain tissue and in vivo microdialysate levels in the rat. J Neurochem 87(1980):310–317Google Scholar
- 24.Halliwell B, Gutteridge JMC (2001) Oxidative stress: adaptation, damage, repair and death. In: Halliwell B, Gutteridge JMC (eds) Free radicals in biology and medicine. Oxford University Press, Oxford, pp 246–350Google Scholar
- 42.Jana S, Sinha M, Chanda D, Roy T, Banerjee K, Munshi S, Patro BS, Chakrabarti S (2011) Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: implications in dopamine cytotoxicity and pathogenesis of Parkinson’s disease. Biochim Biophys Acta 1812:663–673PubMedCrossRefGoogle Scholar