title: Human hepatoma cell lines on gas foaming templated alginate scaffolds for in vitro drug-drug interaction and metabolism studies.
abstract: Liver in vitro systems that allow reliable prediction of major human in vivo metabolic pathways have a significant impact in drug screening and drug metabolism research. In the present study, a novel porous scaffold composed of alginate was prepared by employing a gas-in-liquid foaming approach. Galactose residues were introduced on scaffold surfaces to promote cell adhesion and to enhance liver specific functions of the entrapped HepG2/C3A cells. Hepatoma cells in the gal-alginate scaffold showed higher levels of liver specific products (albumin and urea) and were more responsive to specific inducers (e.g. dexamethasone) and inhibitors (e.g. ketoconazole) of the CYP3A4 system than in conventional monolayer culture. HepG2/C3A cells were also more efficient in terms of rapid elimination of testosterone, used as a model substance, at rates comparable to those of in vivo excretion. In addition, an improvement in metabolism of testosterone, in terms of phase II metabolite formation, was also observed when the more differentiated HepaRG cells were used. Together the data suggest that hepatocyte/gas templated alginate-systems provide an innovative high throughput platform for in vitro drug metabolism and drug-drug interaction studies, with broad fields of application, and might provide a valid tool for minimizing animal use in preclinical testing of human relevance.
authors.affiliation: Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, 00185 Rome, Italy; Laboratorio Antidoping FMSI, L.go Giulio Onesti 1, 00197 Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Stampella
authors.affiliation: Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Rizzitelli
authors.affiliation: Laboratorio Antidoping FMSI, L.go Giulio Onesti 1, 00197 Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Donati
authors.affiliation: Laboratorio Antidoping FMSI, L.go Giulio Onesti 1, 00197 Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mazzarino
authors.affiliation: Laboratorio Antidoping FMSI, L.go Giulio Onesti 1, 00197 Rome, Italy.
authors.forename: X
authors.initials: X
authors.lastname: de la Torre
authors.affiliation: Laboratorio Antidoping FMSI, L.go Giulio Onesti 1, 00197 Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Botrè
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
authors.forename: M F
authors.initials: MF
authors.lastname: Giardi
authors.affiliation: Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Dentini
authors.affiliation: Department of Chemistry, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: andrea.barbetta@uniroma1.it.
authors.forename: A
authors.initials: A
authors.lastname: Barbetta
authors.affiliation: Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy. Electronic address: mara.massimi@univaq.it.
authors.forename: M
authors.initials: M
authors.lastname: Massimi
mesh_terms: D000464:Alginates / Q000737:chemistry*; D004347:Drug Interactions; D020723:Glucuronic Acid / Q000737:chemistry; D056945:Hep G2 Cells; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D008855:Microscopy, Electron, Scanning; D013739:Testosterone / Q000378:metabolism*; D054457:Tissue Scaffolds
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D013739:Testosterone; D020723:Glucuronic Acid
keywords: Alg-GAL; CYP3A4 induction; CYP3A4 inhibition; HepG2/C3A cells; HepaRG cells; Testosterone