BeriBeri is a neurological and cardiovascular disease that is the result of thia

Question

BeriBeri is a neurological and cardiovascular disease that is the result of thiamine deficiency. The disease can result in lactic acidosis and elevated alpha-ketoglutarate levels in the blood. Interestingly both mercury and arsenite poisoning can lead to symptoms and blood work that mirror BeriBeri. Both mercury and arsenite have high reactivity for free sulfhydryls and form covalent bonds with them. Given this information explain how a thiamine deficiency or mercury/arsenite poisoning lead to lactic acidosis. A full answer will describe the mechanism of their (thiamine deficiency and mercury/arsenite poisoning) action. (5 points)

Explanation / Answer

Arsenic poisoning interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme pyruvate dehydrogenase (PDH) complex which catalyzes the reaction Pyruvate + CoA-SH + NAD+ PDH Acetyl-Co-A + NADH + CO2

. With the enzyme inhibited, the energy system of the cell is disrupted resulting in a cellular apoptosis episode. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with arsenic, can raise lactate levels and lead to lactic acidosis. Arsenic in cells clearly stimulates the production of hydrogen peroxide (H2 O2 ). When the H2O2 reacts with Fenton metals such as iron, it produces a highly reactive hydroxyl radical. Inorganic Arsenic trioxide found in ground water particularly affects Voltage-gated potassium channels , disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged qt interval, high blood pressure central nervous system dysfunction and death. Arsenic trioxide is a ubiquitous element present in American drinking water.Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing fibrinolysis. Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis.

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