Opportunities and challenges in using human hepatocytes in cytochromes P450 induction assays

Dvořák, Zdeněk

doi:10.1517/17425255.2016.1125881

Cited by 14 publications

(13 citation statements)

References 48 publications

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“…Recently, human hepatocyte-like cells differentiated from human embryonic stem (ES) cells and induced-pluripotent stem (iPS) cells have gained much attention not only due to their promise for regenerative medicines, but also due to their potential for modeling drug metabolism and pathogen infection in vitro 1011121314. For example, human hepatocyte-like cells differentiated from these stem cells can be stably supplied thanks to the indefinite proliferation potential of ES and iPS cells.…”

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confidence: 99%

Human induced-pluripotent stem cell-derived hepatocyte-like cells as an in vitro model of human hepatitis B virus infection

Sakurai

Mitani

Yamamoto

et al. 2017

Sci Rep

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In order to understand the life cycle of hepatitis B virus (HBV) and to develop efficient anti-HBV drugs, a useful in vitro cell culture system which allows HBV infection and recapitulates virus-host interactions is essential; however, pre-existing in vitro HBV infection models are often problematic. Here, we examined the potential of human induced-pluripotent stem (iPS) cell-derived hepatocyte-like cells (iPS-HLCs) as an in vitro HBV infection model. Expression levels of several genes involved in HBV infection, including the sodium taurocholate cotransporting polypeptide (NTCP) gene, were gradually elevated as the differentiation status of human iPS cells proceeded to iPS-HLCs. The mRNA levels of these genes were comparable between primary human hepatocytes (PHHs) and iPS-HLCs. Following inoculation with HBV, we found significant production of HBV proteins and viral RNAs in iPS-HLCs. The three major forms of the HBV genome were detected in iPS-HLCs by Southern blotting analysis. Anti-HBV agents entecavir and Myrcludex-B, which are a nucleoside analogue reverse transcriptase inhibitor and a synthetic pre-S1 peptide, respectively, significantly inhibited HBV infection in iPS-HLCs. These data demonstrate that iPS-HLCs can be used as a promising in vitro HBV infection model.

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confidence: 99%

Human induced-pluripotent stem cell-derived hepatocyte-like cells as an in vitro model of human hepatitis B virus infection

Sakurai

Mitani

Yamamoto

et al. 2017

Sci Rep

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“…First, we have shown that the EC matrix selectively promotes the expression levels of metabolizing enzymes including phase I metabolizing enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2E1 and CYP3A4), a phase II metabolizing enzyme (NAT2) and transporters (ABCC2, SLC22A5 and DPP4) in hASC‐HLCs. These proteins have been extensively studied in hepatocytes because of their implication in drug metabolism and toxicologic processes in adult hepatocytes . More importantly, the activities of CYP2C9 and CYP3A4 in the hASC‐HLCs cultured on the EC matrix were found to be significantly increased compared to those in the cells cultured on the collagen I‐coated substrate.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell‐derived matrix promotes the metabolic functional maturation of hepatocyte via integrin‐Src signalling

Guo

et al. 2017

J Cellular Molecular Medi

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The extracellular matrix (ECM) microenvironment is involved in the regulation of hepatocyte phenotype and function. Recently, the cell‐derived extracellular matrix has been proposed to represent the bioactive and biocompatible materials of the native ECM. Here, we show that the endothelial cell‐derived matrix (EC matrix) promotes the metabolic maturation of human adipose stem cell‐derived hepatocyte‐like cells (hASC‐HLCs) through the activation of the transcription factor forkhead box protein A2 (FOXA2) and the nuclear receptors hepatocyte nuclear factor 4 alpha (HNF4α) and pregnane X receptor (PXR). Reducing the fibronectin content in the EC matrix or silencing the expression of α5 integrin in the hASC‐HLCs inhibited the effect of the EC matrix on Src phosphorylation and hepatocyte maturation. The inhibition of Src phosphorylation using the inhibitor PP2 or silencing the expression of Src in hASC‐HLCs also attenuated the up‐regulation of the metabolic function of hASC‐HLCs in a nuclear receptor‐dependent manner. These data elucidate integrin‐Src signalling linking the extrinsic EC matrix signals and metabolic functional maturation of hepatocyte. This study provides a model for studying the interaction between hepatocytes and non‐parenchymal cell‐derived matrix.

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“…Human Hepatocytes. Unlike HLMs, human hepatocytes contain native receptors and drug metabolizing enzymes, as well as transporters, and remain the gold standard for assessing the induction of drug metabolizing enzymes, particularly the P450s, by NCEs and other xenobiotics (Fahmi and Ripp, 2010;Dvorak, 2016; https://www.fda. gov/regulatory-information/search-fda-guidance-documents/vitro-druginteraction-studies-cytochrome-p450-enzyme-and-transporter-mediateddrug-interactions).…”

Section: Traditional Chinese Medicinementioning

confidence: 99%

Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

Paine

2020

Drug Metab Dispos

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Natural products have been used by humans since antiquity for both egregious and beneficial purposes. Regarding the latter, these products have long been valued as a rich source of phytochemicals and developed into numerous life-saving pharmaceutical agents. Today, the sales and use of natural products with purported medicinal qualities continue to increase worldwide. However, natural products are not subject to the same premarket testing requirements as pharmaceutical agents, creating critical gaps in scientific knowledge about their optimal use. In addition, due to the common misperception that "natural" means "safe," patients may supplement or replace their prescription medications with natural products, placing themselves at undue risk for subefficacious pharmacotherapy or potentially toxic exposure. Collectively, with few exceptions, researchers, health care providers, and educators lack definitive information about how to inform consumers, patients, and students in the health professions on the safe and optimal use of these products. Recognition of this deficiency by key stakeholders, including the three pillars of biomedical research-industry, academia, and government-has facilitated multiple collaborations that are actively addressing this fundamental knowledge gap. This special issue contains a collection of articles highlighting the challenges faced by researchers in the field and the use of various experimental systems and methods to improve the mechanistic understanding of the disposition and drug interaction potential of natural products. Continued refinement of existing, and development of new, approaches will progress toward the common overarching goal of improving public health. SIGNIFICANCE STATEMENT Natural products with purported medicinal value constitute an increasing share of the contemporary health care market. Natural products are not subject to the same premarket testing requirements as drug products, creating fundamental scientific knowledge gaps about the safe and effective use of these products. Collaborations among industrial, academic, and governmental researchers in multiple disciplines are anticipated to provide the definitive information needed to fill these gaps and improve public health.

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Opportunities and challenges in using human hepatocytes in cytochromes P450 induction assays

Cited by 14 publications

References 48 publications

Human induced-pluripotent stem cell-derived hepatocyte-like cells as an in vitro model of human hepatitis B virus infection

Human induced-pluripotent stem cell-derived hepatocyte-like cells as an in vitro model of human hepatitis B virus infection

Endothelial cell‐derived matrix promotes the metabolic functional maturation of hepatocyte via integrin‐Src signalling

Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions

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