Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes.
1. Using human mononuclear leucocytes as target cells, we have investigated the bioactivation of dapsone (DDS) to a cytotoxic metabolite in the presence of microsomes from nine human livers. Values for NADPH dependent toxicity ranged from 8.8-27% (15.8 +/- 5.9%) and were similar to those for microsomes from control mice, 16-24% (19.0 +/- 4.8%). 2. Microsomes prepared from mice induced with either phenobarbitone or beta-naphthoflavone did not produce significantly more NADPH dependent toxicity than microsomes prepared from control mice. 3. Cytotoxicity was abolished not only by ascorbic acid, but also by sub-physiological concentrations of N-acetylcysteine and glutathione. 4. DDS was metabolised in vitro to a hydroxylamine (metabolic conversion 3.1 +/- 1.5%), which was oxidised further to a cytotoxic metabolite which also became irreversibly bound to protein.
Coleman
M D
MD
Department of Pharmacology and Therapeutics, New Medical School, Liverpool.
Breckenridge
A M
AM
Park
B K
BK
D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003622:Dapsone / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D014343:Trypan Blue
D009249:NADP; D003622:Dapsone; D014343:Trypan Blue