An investigation into the haematological toxicity of structural analogues of dapsone in-vivo and in-vitro.
With microsomes prepared from a single human liver, 4,4'-diaminodiphenyl sulphone (DDS), 4-acetyl-4-aminodiphenyl sulphone (MADDS), 4-acetyl-4-aminodiphenyl thioether (MADDT) and 4,4'-diacetyldiphenyl thioether (DADDT) caused significantly greater methaemoglobin formation compared with control. In-vitro in the rat, the pattern of toxicity was slightly different:DADDT was not haemotoxic, whilst 3,4'-diaminodiphenyl sulphone (3,4'DDS) and 3,3'-diaminodiphenyl sulphone (3,3'DDS) as well as DDS, MADDS and MADDT were significantly greater than control. 4,4' Acetyl diphenyl sulphone (DADDS), 4,4' diaminodiphenyl thioether (DDT), 4,4'-diaminodiphenyl ether (DDE) and 4,4' diaminooctofluorodiphenyl sulphone (F8DDS) did not cause significant methaemoglobinaemia in either human or rat liver microsomes. DDS, MADDS, and MADDT were not significantly different in haemotoxicity generation in-vitro in the presence of human microsomes. In the rat in-vitro, DDS, MADDS, and 3,4'DDS did not differ significantly in red cell toxicity, and were the most potent methaemoglobin formers. The 3,3'DDS and MADDT derivatives were both significantly less toxic compared with DDS. None of the compounds tested caused haemoglobin oxidation in the absence of NADPH in-vitro. In the whole rat, DDS, MADDS and MADDT caused significantly higher levels of methaemoglobin compared with control. None of the remaining compounds caused methaemoglobin formation which was significantly greater than control. DDS and MADDS were the most potent methaemoglobin formers tested, in-vivo and in-vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Therapeutics, University of Liverpool, UK.
M D
MD
Coleman
M D
MD
Tingle
F
F
Hussain
R C
RC
Storr
B K
BK
Park
D000293:Adolescent; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003622:Dapsone / Q000031:analogs & derivatives / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008708:Methemoglobinemia / Q000139:chemically induced; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D003622:Dapsone; D008706:Methemoglobin