title: Application of the DataChip/MetaChip technology for the evaluation of ajoene toxicity in vitro.
abstract: The DataChip is a universal platform for three-dimensional (3D) cell cultures on a micropillar chip, which can be applicable to a variety of human cells to simulate organ-specific toxicity. In addition, the MetaChip is developed for various combinations of drug metabolizing enzymes that can be spotted into the microwell chip and incubated with 3D human cells to simulate systematic compound metabolism in the human liver on a microscale format. Ajoenes have been known for various therapeutics activities, including anticancer effects, but there was limited information available in regard to their metabolism and cytotoxicity. In the present work, the metabolism-mediated toxicity of ajoenes was evaluated on a DataChip/MetaChip platform. In detail, we tested cytotoxicity of E- and Z-ajoene on 3D cultured Hep3B human hepatoma cells coupled with mixtures of drug metabolizing enzymes. Metabolic profiles of ajoenes were assessed with 23 representative drug metabolizing enzymes on the MetaChip. As a result, cytotoxicity of E-ajoene was significantly augmented in the presence of cytochrome P450 (CYP) isoforms, such as CYP2E1 and CYP3A5. Both E- and Z-ajoene were drastically detoxified in the presence of Phase II enzymes, including major UGTs, SULTs, NATs, and GSTs. Interestingly, All Mix, an artificial human liver microsome containing representative P450 mixture and phase II enzyme mixture, attenuated P450-induced cytotoxicity of ajoenes. Conclusively, we were able to confirm the metabolism-medicated toxicity of ajoenes on the chip.
authors.affiliation: Central R&D Institute, Samsung Electro-Mechanics Co (SEMCO), Suwon, Republic of Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Lee
authors.forename: Moo-Yeal
authors.initials: MY
authors.lastname: Lee
authors.forename: Bosung
authors.initials: B
authors.lastname: Ku
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Yi
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.forename: Mihi
authors.initials: M
authors.lastname: Yang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D018929:Cell Culture Techniques; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004220:Disulfides / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D046228:Microarray Analysis / Q000295:instrumentation / Q000379:methods*; D008862:Microsomes, Liver / Q000187:drug effects; D009928:Organ Specificity; D013454:Sulfoxides; D018675:Toxicity Tests / Q000295:instrumentation / Q000379:methods*
chemical_list: D004220:Disulfides; D004798:Enzymes; D013454:Sulfoxides; C048980:ajoene; D019392:Cytochrome P-450 CYP2E1; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A