Metabolic Activation of Methyldopa and Other Catechols

Abstract

The antihypertensive agent methyldopa (MD) is reported to produce mild, clinically covert, hepatic injury in 14% of recepients when liver function tests are monitored. Recent reports have shown that MD also may initiate chronic active liver disease, occasionally with a fatal outcome. We have studied metabolic activation of MD as a possible mechanism of MD hepatitis. Human and rodent liver microsomes convert MD to a reactive metabolite that binds covalently to protein in the presence of NADPH and O_2. The binding is inhibited by a CO: O₂ atmosphere, as well as by superoxide dismutase, ascorbic acid, ethylene diamine and glutathione, suggesting that MD is being oxidized by cytochrome P-450-generated superoxide anion to a reactive semiquinone and/or quinone. Emerging evidence indicate that synthetic estrogens may induce neoplastic changes in the liver. Hydroxylated estrogens are also activated to covalently bound products by liver microsomes in the presence of NADPH and O₂, presumably via oxidation of the catechol nucleus by cytochrome P-450-generated superoxide anion. Oxyhemoglobin of red blood cells can be visualized as a bound form of superoxide anion. Human red blood cells activate MD to covalently bound products, this reaction may be responsible for immunological disorders such as a positive Coombs test and immune hemolysis.