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Hepatocellular bioactivation and cytotoxicity of the synthetic endoperoxide antimalarial arteflene

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.

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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: 06 Feb 2018 13:03
URI: http://archive.lstmed.ac.uk/id/eprint/2138

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