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.