Metabolism of ciamexon by human liver microsomes: an investigation into the formation of stable, chemically reactive and cytotoxic metabolites.

1. The in vitro generation of stable, protein-reactive and cytotoxic metabolites from ciamexon by human liver microsomes has been assessed. Stable metabolites were characterized by h.p.l.c./mass spectrometry, protein reactive metabolites by radiometric analysis and cytotoxic metabolites by assessment of cell viability after exposure to metabolites formed in situ. 2. Human livers were obtained from renal transplant donors. All 16 livers investigated metabolized ciamexon in a NADPH-dependent reaction, the major metabolite being the 6-hydroxy-methyl derivative. The hydroxylase activity of the livers varied from 34-577 pmol mg-1 min-1, with a mean activity of 306 +/- 156 pmol mg-1 min-1. The further oxidation product, 6-carboxy ciamexon, was also detected in some incubations. A third, unidentified, polar metabolite was present in all incubations (3.34-11.11% of incubated radioactivity). 3. Only very low levels (less than 1%) of radioactivity became irreversibly bound to microsomal protein, which suggests that ciamexon undergoes little or no oxidative bioactivation in vitro. 4. Human liver microsomes did not metabolize ciamexon to a cytotoxic species, whereas microsomes prepared from mouse livers did generate a cytotoxic species. The degree of toxicity was enhanced if animals were pre-treated with either phenobarbitone or beta-naphthoflavone.