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Maggs, J. L., Bishop, L. P. D., Batty, K. T., Dodd, C. C., Ilett, K. F., O'Neill, P. M., Edwards, Geoffrey and Park, B. K. (2004) 'Hepatocellular bioactivation and cytotoxicity of the synthetic endoperoxide antimalarial arteflene'. Chemico-Biological Interactions, Vol 147, Issue 2, pp. 173-184.
Full text not available from this repository.Abstract
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 < 0.05) toxic to isolated hepatocytes with reference to extramitochondrial reductase activity (tetrazolium reduction) but not enzyme leakage when the cells were exposed to drug concentrations >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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | arteflene hepatocytes cyclohexyl radical rat-liver in-vitro artemisinin derivatives ro-42-1611 arteflene biliary metabolites dihydroartemisinin localization prostacyclin glutathione mechanism |
| Subjects: | QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials |
| Faculty: Department: | Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group |
| Digital Object Identifer (DOI): | https://doi.org/10.1016/j.cbi.2003.12.005 |
| Depositing User: | Martin Chapman |
| Date Deposited: | 13 Nov 2012 15:02 |
| Last Modified: | 17 Jul 2020 10:57 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/2138 |
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