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Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes.
Author(s) -
Coleman MD,
Breckenridge AM,
Park BK
Publication year - 1989
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1989.tb03517.x
Subject(s) - microsome , metabolite , microsoma , glutathione , chemistry , biochemistry , cytotoxicity , cytotoxic t cell , dapsone , toxicity , enzyme , in vitro , pharmacology , biology , immunology , organic chemistry
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.