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Titolo:
STRUCTURAL BASIS FOR THE HAEMOTOXICITY OF DAPSONE - THE IMPORTANCE OFTHE SULFONYL GROUP
Autore:
MAHMUD R; TINGLE MD; MAGGS JL; CRONIN MTD; DEARDEN JC; PARK BK;
Indirizzi:
UNIV LIVERPOOL,DEPT THERAPEUT & PHARMACOL,POB 147 LIVERPOOL L69 3BX MERSEYSIDE ENGLAND UNIV LIVERPOOL,DEPT THERAPEUT & PHARMACOL LIVERPOOL L69 3BX MERSEYSIDE ENGLAND LIVERPOOL JOHN MOORES UNIV,SCH PHARM LIVERPOOL L3 3AF MERSEYSIDE ENGLAND
Titolo Testata:
Toxicology
fascicolo: 1, volume: 117, anno: 1997,
pagine: 1 - 11
SICI:
0300-483X(1997)117:1<1:SBFTHO>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VITRO; METHEMOGLOBIN FORMATION; AROMATIC-AMINES; HEMATOLOGICAL TOXICITY; N-OXIDATION; METABOLISM; HYDROXYLAMINE; HEMOGLOBIN; INVITRO; MODEL;
Keywords:
DAPSONE; ANILINE; METHEMOGLOBIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
44
Recensione:
Indirizzi per estratti:
Citazione:
R. Mahmud et al., "STRUCTURAL BASIS FOR THE HAEMOTOXICITY OF DAPSONE - THE IMPORTANCE OFTHE SULFONYL GROUP", Toxicology, 117(1), 1997, pp. 1-11

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 mu M) was the most potent former of methaemoglobin in human erythrocytes (44.8 +/- 6.7%). Substitution of thesulphone 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 wasa significant correlation (r(2) =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. Copyright (C) 1997 Elsevier Science Ireland Ltd.

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Documento generato il 04/07/20 alle ore 04:53:19