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Paper supported long-term 3D liver co-culture model for the assessment of hepatotoxic drugs.

ABSTRACT: Preservation of hepatic phenotype and functions in vitro has always been a great challenge for the reconstruction of liver tissue engineering and in pharmaceutical research studies. Human induced hepatocytes (hiHeps) generated from fibroblasts can be reproducible with almost normal levels of liver specific functions, which are considered as a new source of hepatocytes for biomedical applications. Moreover, paper has served as an attractive biocompatible material for cell-based applications. In this study, we established a simple paper-based scaffold array for creating a 3D liver co-culture model that enabled the assessment of drug induced hepatotoxicity. The hiHeps co-cultured with HUVECs exhibited a 3D like morphology and maintained the liver specific functions of producing albumin and urea for up to 2 months. In addition, the hiHeps in this co-cultured model maintained a higher expression of cytochrome P450 genes as compared with a monolayer culture on a plate and a single culture on paper of hiHeps, revealing a marked enhancement of hepatic functions in the 3D liver co-culture model. Moreover, the 3D liver co-culture model was exposed to acetaminophen (APAP) and pioglitazone, exhibiting near physiological hepatotoxic responses compared to those of the monolayer cultures. Taken together, the low-cost and bioactive paper scaffold could offer great opportunities as 3D in vitro platforms for tissue engineering applications and high-throughput drug testing.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6061007 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Paper supported long-term 3D liver co-culture model for the assessment of hepatotoxic drugs.

Wang Yaqing Y Su Wentao W Wang Li L Jiang Lei L Liu Yang Y Hui Lijian L Qin Jianhua J

Toxicology research 20170928 1

Preservation of hepatic phenotype and functions <i>in vitro</i> has always been a great challenge for the reconstruction of liver tissue engineering and in pharmaceutical research studies. Human induced hepatocytes (hiHeps) generated from fibroblasts can be reproducible with almost normal levels of liver specific functions, which are considered as a new source of hepatocytes for biomedical applications. Moreover, paper has served as an attractive biocompatible material for cell-based application ...[more]

PMID: 30090558

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Project description:The hepatotoxicity of bromobenzene (BB) is directly related to the covalent binding of both initially formed epoxide and secondary quinone metabolites to at least 45 different liver proteins. 4-Bromophenol (4BP) is a significant BB metabolite and a precursor to reactive quinone metabolites; yet, when administered exogenously, it has negligible hepatotoxicity as compared to BB. The protein adducts of 4BP were thus labeled as nontoxic [Monks, T. J., Hinson, J. A., and Gillette, J. R. (1982) Life Sci. 30, 841-848]. To help identify which BB-derived adducts might be related to its cytotoxicity, we sought to identify the supposedly nontoxic adducts of 4BP and eliminate them from the BB target protein list. Administration of [(14)C]-4BP to phenobarbital-induced rats resulted in covalent binding of 0.25, 0.33, and 0.42 nmol equiv 4BP/mg protein in the mitochondrial, microsomal, and cytosolic fractions, respectively. These values may be compared to published values of 3-6 nmol/mg protein from a comparable dose of [(14)C]-BB. After subcellular fractionation and 2D electrophoresis, 47 radioactive spots on 2D gels of the mitochondrial, microsomal, and cytosolic fractions were excised, digested, and analyzed by LC-MS/MS. Twenty-nine of these spots contained apparently single proteins, of which 14 were nonredundant. Nine of the 14 are known BB targets. Incubating freshly isolated rat hepatocytes with 4BP (0.1-0.5 mM) produced time- and concentration-dependent increases in lactate dehydrogenase release and changes in cellular morphology. LC-MS/MS analysis of the cell culture medium revealed rapid and extensive sulfation and glucuronidation of 4BP as well as formation of a quinone-derived glutathione conjugate. Studies with 7-hydroxycoumarin, (-)-borneol, or D-(+)-galactosamine showed that inhibiting the glucuronidation/sulfation of 4BP increased the formation of a GSH-bromoquinone adduct, increased covalent binding of 4BP to hepatocyte proteins, and potentiated its cytotoxicity. Taken together, our data demonstrate that protein adduction by 4BP metabolites can be toxicologically consequential and provide a mechanistic explanation for the failure of exogenously administered 4BP to cause hepatotoxicity. Thus, the probable reason for the low toxicity of 4BP in vivo is that rapid conjugation limits its oxidation and covalent binding and thus its toxicity.

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Paper supported long-term 3D liver co-culture model for the assessment of hepatotoxic drugs.

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Paper supported long-term 3D liver co-culture model for the assessment of hepatotoxic drugs.

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