Epidemic Dropsy - Mechanism of Toxicity

Mechanism of Toxicity

Mortality is usually due to heart failure, pneumonia, respiratory distress syndrome or renal failure and is around 5%.Long-term follow-up studies are scanty so the long-term effects of argemone oil toxicity have not been documented. Its been reported that 25% of cases will have oedema beyond 2 months and 10% beyond 5 months.Pigmentation of skin and excessive loss of hair, which lasted 4–5 months following the disease. The majority of patients completely recover in about 3 months.

ROS and Oxidative stress : Studies in the blood of dropsy patients has revealed that there is extensive ROS production (singlet oxygen and hydrogen peroxide) in the argemone oil intoxication leading to depletion of total antioxidants in the body and especially lipid soluble antioxidants such as vitamin E and A (tocopherol and retinol). There is an extensive damage to the anti-oxidant defense system (anti-oxidant enzymes and anti-oxidants) of blood. Prior, in vitro studies have shown that reactive oxygen species (ROS) are involved in AO induced toxicity causing peroxidative damage of lipids in various hepatic sub-cellular fractions including microsomes and mitochondria of rats. The damage in hepatic microsomal membrane causes loss of activity of cytochrome P-450 and other membrane bound enzymes responsible for xenobiotic metabolism which leads to delayed bioelimination of sanguinarine and enhances its cumulative toxicity. Several lines of evidence have been shown to explain the mechanism of toxicity of argemone oil/alkaloid. The toxicity of sanguinarine has been shown to be dependent on the reactivity of its iminium bond with nucleophilic sites like thiol groups, present at the active sites of the enzymes and other vital proteins and thus suggesting the electrophilic nature of the alkaloid.

Pulmonary Toxicity: The decrease in glycogen levels following argemone oil intoxication could be due to enhanced glycogenolysis leading to the formation of glucose-1-phosphate, which enters the glycoltic pathway resulting in accumulation of pyruvate in the blood of experimental animals and dropsy patients. The enhancement of glycogenolysis can further be supported by the interference of sanguinarine in the uptake of glucose through blocking of sodium pump via Na+-K+-ATPase and thereby inhibiting the active transport of glucose across intestinal barrier. It is well established that increased pyruvate concentration in blood uncouples oxidative phosphorylation, and this may be responsible for thickening of interalveolar septa and disorganized alveolar spaces in lungs of argemone oil-fed rats and the breathlessness as has been observed in human victims.

Cardiac Failure:The inhibition of Na+-K+-ATPase activity of heart by sanguinarine is due to interaction with the cardiac glycoside receptor site of the enzyme,which may be responsible for producing degenerative changes in cardiac muscle fibers in the auricular wall of rats fed argemone oil and could be related to tachycardia and cardiac failure in Epidemic Dropsy patients.

Delayed clearance:Destruction of hepatic cytochrome P450 significantly affects the metabolic clearance by liver,. The retention of sanguinarine in the GI tract, liver, lung, kidney, heart, and serum even after 96 hrs of exposure indicates these as the likely target sites of argemone oil toxicity.