Structural basis for the haemotoxicity of dapsone: the importance of the sulphonyl group

Abstract

The structural basis of dapsone (4,4′-diaminodiphenyl sulphone) haemotoxicity has been determined by investigation of the in vitro bioactivation of a series of 4-substituted arylamines. In the presence of rat liver microsomes, dapsone (100 μM) was the most potent former of methaemoglobin in human erythrocytes (44.8 ± 6.7%). Substitution of the sulphone group with sulphur (11.6 ± 1.4% methaemoglobin), oxygen (4.5 ± 1.1.%), nitrogen (0.0 ± 3.2%), carbon (13.6 ± 0.8%) or a keto group (34.0 ± 6.1%) resulted in a decrease in methaemoglobin formation. Only one compound, 4,4′-diaminodiphenylamine, generated significant ( P < 0.001) amounts of methaemoglobin (25.6 ± 2.5%) in the absence of NADPH. To assess further the role of the 4-substituent in methaemoglobinaemia, the toxicity of a series of 4-substituted aniline derivatives was also studied. Of the anilines studied, 4-nitroaniline caused the most methaemoglobin (36.5 ± 8.0%), whilst aniline caused the least (0.3 ± 0.5%). Overall, there was a significant correlation ( r 2 = 0.83) between the haemotoxicity and the Hammett constant, σ p, suggesting that it is the electron-withdrawing properties of the substituent that influence the methaemoglobin formation. In the presence of microsomes prepared from two human livers, dapsone was the most haemotoxic bis arylamine, whereas 4-iodoaniline was the most potent methaemoglobin former (60.6 and 73.6%) and aniline the least potent (1.1 and 2.4%). As a whole, these results indicate that the sulphonyl group, which is essential for the pharmacological activity of dapsone, is also largely responsible for the haemotoxicity seen with this drug.