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Peter J. Mc Guire, MS, MBBCh
George A. Diaz, MD, PhD

It’s a part of life. We breathe in oxygen and breathe out carbon dioxide. The oxygen is used to get energy from the breakdown of sugar or fat molecules, and the carbon dioxide removes waste. During this life-sustaining process, a small amount of oxygen is converted into free radicals, for example reactive oxygen species (ROS). Fortunately, our body has an antioxidant defense system which detoxifies free radicals and prevents them from causing damage. If the defense system can’t keep up with demand or if there is an overproduction of reactive oxygen species, the result is “oxidative stress,” a term which refers to the accumulation of potentially toxic forms of oxygen and other atoms beyond the body’s capacity to detoxify them.

During periods of oxidative stress, the toxins can damage various cell components, including proteins, fats in cell membranes, and DNA by reacting with and altering their chemical composition. When this happens, cellular functions can become progressively impaired. When the impairment of cellular function is widespread, the effects can be detected at the level of tissues and organs. A theory has been proposed (the free radical theory of aging) that oxidative stress leads to the gradual accumulation of cellular damage and subsequent tissue degeneration associated with aging. In support of this hypothesis, oxidative stress has been demonstrated in many different disease processes including diabetes, cancer, heart disease, Alzheimer’s disease.

A number of nutrients aid in the antioxidant process, including vitamins C, E, and beta carotene. Supplementation of these nutrients has become relatively common, though the benefit of these supplements is not well established and there is some evidence that at high levels they actually become pro-oxidants, creating more free radicals instead of detoxifying them.

In studies of several different inborn errors of metabolism, evidence of oxidative stress (increased levels of ROS combined with a decrease in antioxidant defenses) has been reported. Laboratory studies of clinical samples from patients with MSUD, as well as animal models of MSUD, have suggested that increased levels of oxidative stress occur in this disease. The cause of the oxidative stress is still being debated. However, it has recently been suggested that in MSUD, as well as in other inborn errors of metabolism, the accumulation of compounds resulting from the inherited enzyme deficiency “poisons” the normal processes occurring in the mitochondria, resulting in the increased production of ROS which overwhelms the antioxidant defense system. Indeed, decreased levels of blood antioxidants have been described in patients with MSUD. Vitamin E (also known as tocopherol) was found to prevent the “mitochondrial sickness” induced by treating rat brain slices with high levels of branched-chain amino acids (valine, isoleucine, leucine) seen in an animal model.

Despite these interesting preliminary studies, the role of oxidative stress in MSUD has not been established definitively. While the role of oxidative stress in common diseases has been an area of intense research activity, investigation of the role of oxidative stress in inborn errors of metabolism has not been as extensive. It has been postulated that some of the neurologic features seen in MSUD may be due to oxidative stress. However, these speculations must be treated with caution as they require further validation. Moreover, the benefit of antioxidants in inborn errors of metabolism is also unproven. Conflicting studies in the literature on the effect of antioxidants in heart attack and stroke suggest that the role of antioxidants in human disease needs further evaluation. Due to the potential for pro-oxidant effects of certain antioxidants, their use via supplementation in MSUD cannot be recommended at this time. A diet containing fruits and vegetables serves as a source of natural antioxidants.

The results of recent work supporting a connection between branched-chain amino acid metabolism and oxidative stress suggest that further research may provide new insights into the pathways involved in the MSUD disease process. It also emphasizes the importance of including ample fruits and vegetables in the diet (see accompanying article on “Getting More Essential Nutrients into the MSUD Diet” by Alex Larkin, RD).

References

Barschak, A. G., A. Sitta, et al. (2006). "Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease." Metab Brain Dis 21(4): 279-86.

Bridi, R., J. Araldi, et al. (2003). "Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease." Int J Dev Neurosci 21(6): 327-32.

Bridi, R., C. A. Braun, et al. (2005). "Alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats." Metab Brain Dis 20(2): 155-67.

Bridi, R., A. Latini, et al. (2005). "Evaluation of the mechanisms involved in leucine-induced oxidative damage in cerebral cortex of young rats." Free Radic Res 39(1): 71-9.

Ribeiro CA, Sgaravatti AM, Rosa RB, Schuck PF, Grando V, Schmidt AL, Ferreira GC, Perry ML, Dutra-Filho CS, Wajner M. Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res. 2008 Jan;33(1):114-24.

Pérez de Obanos MP, López-Zabalza MJ, Arriazu E, Modol T, Prieto J, Herraiz MT, Iraburu MJ. Reactive oxygen species (ROS) mediate the effects of leucine on translation regulation and type I collagen production in hepatic stellate cells. Biochim Biophys Acta. 2007 Nov;1773(11):1681-8.

Funchal C, Latini A, Jacques-Silva MC, Dos Santos AQ, Buzin L, Gottfried C, Wajner M, Pessoa-Pureur R. Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006 Dec;49(7):640-50.

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