Role of antioxidant treatment on DNA and lipid damage in the brain of rats subjected to a chemically induced chronic model of tyrosinemia type II

Abstract

Tyrosine levels are abnormally elevated in tissues and body fluids of patients with inborn errors of tyrosine metabolism. Tyrosinemia type II, which is caused by tyrosine aminotransferase deficiency, provokes eyes, skin, and central nervous system disturbances in affected patients. However, the mechanisms of brain damage are still poorly known. Considering that studies have demonstrated that oxidative stress may contribute, along with other mechanisms, to the neurological dysfunction characteristic of hypertyrosinemia, in the present study we investigated the effects of antioxidant treatment (NAC and DFX) on DNA damage and oxidative stress markers induced by chronic administration of L-tyrosine in cerebral cortex, hippocampus, and striatum of rats. The results showed elevated levels of DNA migration, and thus DNA damage, after chronic administration of L-tyrosine in all the analyzed brain areas, and that the antioxidant treatment was able to prevent DNA damage in cerebral cortex and hippocampus. However, the co-administration of NAC plus DFX did not prevent the DNA damage in the striatum. Moreover, we found a significant increase in thiobarbituric acid-reactive substances (TBA-RS) and DCFH oxidation in cerebral cortex, as well as an increase in nitrate/nitrite levels in the hippocampus and striatum. Additionally, the antioxidant treatment was able to prevent the increase in TBA-RS levels and in nitrate/nitrite levels, but not the DCFH oxidation. In conclusion, our findings suggest that reactive oxygen and nitrogen species and oxidative stress can play a role in DNA damage in this disorder. Moreover, NAC/DFX supplementation to tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the current treatment of this disease.

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

“…Interestingly, L-tyrosine influences developmental decisions and longevity in Caenorhabditis elegans [407,408] and potentiates the detrimental effects of oxidative stress either by decreasing glutathione and stimulating lipid and protein oxidation in rat cerebral cortex [409] or by increasing the thiobarbituric acid reactive species levels in the hippocampus and the carbonyl levels in the cerebellum, hippocampus, and striatum [410]. Moreover, chronic administration of Ltyrosine increased DNA damage frequency and damage index in the hippocampus, striatum, cerebral cortex, and blood [411,412]. Recent studies demonstrated that chronic administration of L-tyrosine inhibited the activity of complex I, II-III, and IV in the striatum, which can be prevented by antioxidant treatment [413,414].…”

Effect of genistein and coenzyme Q10 in oxidative damage and mitochondrial membrane potential in an attenuated type II mucopolysaccharidosis cellular model

“…The study indicated that MPS II patients showed DNA damage and that ERT is able to protect against this process. DNA damage is largely described in EIM, such as phenylketonuria, tyrosinemia type II, MPS IVA, MPS II among others 7,9,46–48 …”

“…DNA damage is largely described in EIM, such as phenylketonuria, tyrosinemia type II, MPS IVA, MPS II among others. 7,9,[46][47][48] A previous study demonstrated DNA damage significantly greater in HEK-293 KO HP 10 MP II cells when compared with WT control cells. In turn, the coenzyme Q10 in 10 μm concentration decreased in vitro the DNA damage in these cells, hypothesizing that the DNA damage to this homozygous cell model is of oxidative origin.…”

Tyrosine aminotransferase is involved in the oxidative stress response by metabolizing meta-tyrosine in Caenorhabditis elegans

“…1A) (30,31). In relation to oxidative stress, multiple studies have reported a potential enhancement of oxidative stress with either a reduction in tyrosine aminotransferase or administration of tyrosine (32)(33)(34)(35)(36)(37). Furthermore, rats treated with mercury had greater tyrosine aminotransferase activity subsequent to higher transcriptional expression (38), and heat stress resulted in increased tyrosine aminotransferase activity in chickens (39).…”