title: 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 microM) 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 (r2 = 0.83) between the haemotoxicity and the Hammett constant, sigma(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.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: R
authors.initials: R
authors.lastname: Mahmud
authors.forename: M D
authors.initials: MD
authors.lastname: Tingle
authors.forename: J L
authors.initials: JL
authors.lastname: Maggs
authors.forename: M T
authors.initials: MT
authors.lastname: Cronin
authors.forename: J C
authors.initials: JC
authors.lastname: Dearden
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000818:Animals; D003622:Dapsone / Q000633:toxicity*; D006413:Hematopoietic System / Q000187:drug effects*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013451:Sulfonic Acids / Q000633:toxicity*
chemical_list: D013451:Sulfonic Acids; D003622:Dapsone