Étude des propriétés de deux séries de substances d'origine naturelle : les cucurbitacines et les parabènes : analyse de leur biotransformation chez l'homme et mesure du pouvoir cytotoxique des cucurbitacines sur une lignée cellulaire de chondrosarcome humain

Abstract : Cucurbitacins and parabens are natural compounds belonging to cyclic triterpenoid and alkyl ester of 4-hydroxybenzoic acid, respectively. They are known for their potential valuable pharmacological effects. The aim of this work was to study the biotransformation of a series of three cucurbitacins and six parabens in human liver, in vitro, essentially by glucuronidation and hydrolysis reactions, and by comparision with other natural substances structurally related, and to characterize the cytotoxicity effect of cucurbitacins on a human chondrosarcoma cell line, SW 1353. The results showed that cucurbitacins I and D showed more cytotoxicity than cytochalasin D and led to cell apoptosis after 12h of treatment at 1 ?M. Cucurbitacin E showed its cytotoxic effect at 10 µM. The in vitro study of cucurbitacins biotransformation in man showed that these substances are sulfated, glucuronidated (radiochemical methods). Moreover, cucurbitacin E was actively hydrolyzed (Km 22 µM and Vmax 571 nmol/mg protein/min) leading to cucurbitacin I in man liver. On the other hand, they are weakly hydroxylated. Oleanolic acid, ursolic acid and erythrodiol, chemically related to cucurbitacins, were glucuronidated at the same rate in human liver microsomes, however, with affinities 100 times greater. Parabens were quickly hydrolyzed in human liver microsomes by esterases and hydrolysis decreased with side chain length. Parabens, caffeic acid, tyrosol and hydroxytyrosol were actively glucuronidated by the UGTs of both families 1A and 2B. However, p-hydroxybenzoic acid is not a good substrate for UGTs
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Suzanne Abbas. Étude des propriétés de deux séries de substances d'origine naturelle : les cucurbitacines et les parabènes : analyse de leur biotransformation chez l'homme et mesure du pouvoir cytotoxique des cucurbitacines sur une lignée cellulaire de chondrosarcome humain. Médecine humaine et pathologie. Université de Lorraine, 2012. Français. ⟨NNT : 2012LORR0135⟩. ⟨tel-01749356⟩

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