In vitro Metabolism of Grandisin, a Lignan with Anti-chagasic Activity

Abstract

Tetrahydrofuran lignans represent a well-known group of phenolic compounds capable of acting as antiparasitic agents. In the search for new medicines for the treatment of Chagas disease, one promising compound is grandisin which has shown significant activity on trypomastigote forms of Trypanosoma cruzi. In this work, the in vitro metabolism of grandisin was studied in the pig cecum model and by biomimetic phase I reactions, aiming at an ensuing a preclinical pharmacokinetic investigation. Although grandisin exhibited no metabolization by the pig microbiota, one putative metabolite was formed in a biomimetic model using Jacobsen catalyst. The putative metabolite was tested against T. cruzi revealing loss of activity in comparison to grandisin.

Key words

tetrahydrofuran lignans - grandisin - in vitro metabolism - Piper solmsianum - Piperaceae - Jacobsen catalyst

• References

• 1 Gertsch J, Tobler RT, Brun R, Sticher O, Heilmann J. Antifungal, antiprotozoal, cytotoxic and piscicidal properties of justicidin B and a new arylnaphthalide lignan from Phyllanthus piscatorum . Planta Med 2003; 69: 420-424
• 2 Emmanuel FM, Gentile D, Clive M, Eian DM. A comparative in vitro kinetic study of [14C]-eugenol and [14C]-methyleugenol activation and detoxification in human, mouse, and rat liver and lung fractions. Xenobiotica 2012; 42: 429-441
• 3 Murray T, Kang J, Astheimer L, Price WE. Tissue distribution of lignans in rats in response to diet, dose-response, and competition with isoflavones. J Agric Food Chem 2007; 55: 4907-4912
• 4 Engemann A, Hübner F, Rzeppa S, Humpf HU. Intestinal metabolism of two A-type procyanidins using the pig cecum model: Detailed structure elucidation of unknown catabolites with Fourier transform mass spectrometry (FTMS). J Agric Food Chem 2010; 60: 749-757
• 5 Hein EM, Rose K, vanʼt Slot G, Friedrich AW, Humpf H-U. Deconjugation and degradation of flavonol glycosides by pig cecal microbiota characterized by fluorescence in situ hybridization (FISH). J Agric Food Chem 2008; 56: 2281-2290
• 6 Keppler K, Hein EM, Humpf HU. Metabolism of quercetin and rutin by the pig caecal microflora prepared by freeze preservation. Mol Nutr Food Res 2006; 50: 686-695
• 7 Keppler K, Humpf HU. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorg Med Chem 2005; 13: 5195-5205
• 8 Seefelder W. Fumonisine und deren Reaktionsprodukte in Lebensmitteln: Vorkommen, Bedeutung, biologische Aktivität und Metabolismus [dissertation]. Würzburg: Bayerische Julius-Maximilians-Universität; 2002
• 9 vanʼt Slot G, Humpf HU. Degradation of catechin, epigallocatechin-3-gallate (EGCG) and related compounds by the intestinal microbiota in the pig cecum-model. J Agric Food Chem 2009; 57: 8041-8048
• 10 vanʼt Slot G, Mattern W, Rzeppa S, Grewe D, Humpf HU. Complex flavonoids in coca: synthesis and degradation by intestinal microbiota. J Agric Food Chem 2010; 58: 8879-8886
• 11 Mac Leod TCO, Faria AL, Barros VP, Queiroz MEC, Assis MD. Primidone oxidation catalyzed by metalloporphyrins and Jacobsen catalyst. J Mol Catal A Chem 2008; 296: 54-60
• 12 Mansuy D. Brief historical overview and recent progress on cytochromes P450: adaptation of aerobic organisms to their chemical environment and new mechanisms of prodrug bioactivation. Ann Pharm Fr 2011; 69: 62-69
• 13 Niehues M, Barros VP, Emery FS, Dias-Baruffi M, Assis MD, Lopes NP. Biomimetic in vitro oxidation of lapachol: A model to predict and analyse the in vivo phase I metabolism of bioactive compounds. Eur J Med Chem 2012; 54: 804-812
• 14 Pigatto MC, de Lima MDA, Galdino SL, Pitta ID, Vessecchi R, Assis MD, dos Santos JS, Costa TD, Lopes NP. Metabolism evaluation of the anticancer candidate AC04 by biomimetic oxidative model and rat liver microsomes. Eur J Med Chem 2011; 46: 4245-4251
• 15 Lopes NP, Blumenthal EED, Cavalheiro AJ, Kato MJ, Yoshida M. Lignans, gamma-lactones and propiophenones of Virola surinamensis . Phytochemistry 1996; 43: 1089-1092
• 16 Lopes NP, Chicaro P, Kato MJ, Albuquerque S, Yoshida M. Flavonoids and lignans from Virola surinamensis twigs and their in vitro activity against Trypanosoma cruzi . Planta Med 1998; 64: 667-669
• 17 Schmidt TJ, Khalid SA, Romanha AJ, Alves TMA, Biavatti MW, Brun R, Da Costa FB, de Castro SL, Ferreira VF, de Lacerda MVG, Lago JHG, Leon LL, Lopes NP, das Neves Amorim RC, Niehues M, Ogungbe IV, Pohlit AM, Scotti MT, Setzer WN, de NC Soeiro M, Steindel M, Tempone AG. The potential of secondary metabolites from plants as drugs/leads against protozoan neglected diseases – part II. Curr Med Chem 2012; 19: 2176-2228
• 18 Fundação de Amparo à Pesquisa do Estado de São Paulo. Acef SA, Silva MLA, Silva R, Rodrigues V, Pereira-Júnior OS, Silva-Filho AA, Donate PM, Albuquerque S, Bastos JK. Processo de obtenção de derivados sintéticos e semi-sintéticos de lignanas, suas atividades antiparasitárias e respectivas formulações farmacêuticas, englobando o método terapêutico utilizando tais lignanas no tratamento de parasitoses. BR Patent PI0503951-7; 2005.
• 19 WHO, Media Center. Chagas disease (American trypanosomiasis). Fact sheet N°340. Available at http://www.who.int/mediacentre/factsheets/fs340/en/index.html Accessed June 10, 2012
• 20 Verza M, Arakawa NS, Lopes NP, Kato MJ, Pupo MT, Said S, Carvalho I. Biotransformation of a tetrahydrofuran lignan by the endophytic fungus Phomopsis sp . J Braz Chem Soc 2009; 20: 195-200
• 21 Côrtes C, Gagnon N, Benchaar C, da Silva D, Santos GTD, Petit HV. In vitro metabolism of flax lignans by ruminal and faecal microbiota of dairy cows. J Appl Microbiol 2008; 105: 1585-1594
• 22 Messiano GB, Santos RAS, Ferreira LS, Simões RA, Kato MJ, Lopes NP, Pupo MT, Oliveira ARM. In vitro metabolism study of the bioactive lignan (−)-grandisin. Planta Med 2012; 78: 1139
• 23 Ramos CS, Vanin SA, Kato MJ. Metabolism of (−)-grandisin from Piper solmsianum in Coleoptera and Lepidoptera species. Phytochemistry 2008; 69: 2157-2161
• 24 Saad JM, Soepadamo E, Fang XP, Mclaughlin JL, Fanwick PE. (−)-Grandisin from Cryptocarya crassinervia . J Nat Prod 1991; 54: 1681-1683
• 25 Holloway D, Scheinmann F. Extractives from Litsea species. II. Two lignans from Litsea grandis and L. gracilipes . Phytochemistry 1974; 13: 1233-1236
• 26 Martins RCC, Latorre LR, Sartorelli P, Kato MJ. Phenylpropanoids and tetrahydrofuran lignans from Piper solmsianum . Phytochemistry 2000; 55: 843-846