Hepatocellular bioactivation and cytotoxicity of the synthetic endoperoxide antimalarial arteflene

Arteflene is a synthetic endoperoxide antimalarial. Its peroxide bridge undergoes iron(II)-mediated reduction in vitro which yields a carbon-centered cyclohexyl radical and a mixture of cis- and trans-alpha,beta-unsaturated ketones (enones). The enones are biliary metabolites in rats and therefore surrogate markers of bioactivation. Arteflene is reported to be more cytotoxic to primary rat hepatocytes than some non-endoperoxide antimalarials. Hepatic metabolism of arteflene was investigated in recirculating isolated perfused rat livers, and the drug's metabolism and cytotoxicity were compared using hepatocytes from male rats. Both preparations metabolized [C-14]arteflene to cis- and trans-[ C-14]enone, 8-hydroxyarteflene glucuronide and an unassigned isomeric glucuronide. During a 2 h liver perfusion, the cis- and trans-enones recovered in bile represented 8.1 +/- 3.4 and 11.3 +/- 4.6% (mean +/- S.D., N = 6), respectively, of the [C-14]arteflene (52 muM) added to the perfusate. After a 3 h incubation of [C-14]arteflene (10 muM) with hepatocytes in suspension, the cis- and trans-enones comprised, respectively, 14.8 +/- 7.1 and 2.1 +/- 1.0% (N = 4) of the recovered radioactivity; the corresponding data for cultured hepatocytes being 18.6 +/- 6.9 and 3.3 +/- 2.2%. Arteflene was significantly (P 50 muM for 24 h. Cellular glutathione was depleted under these conditions. Therefore arteflene was acutely cytotoxic, though only at relatively high concentrations, when it was metabolized via a pathway which generates carbon-centered radicals. (C) 2004 Elsevier Ireland Ltd. All rights reserved.