Evaluation of Human Hepatocytes Under Prolonged Culture in a Novel Medium for the Maintenance of Hepatic Differentiation: Results with the Model Pro-inflammatory Cytokine Interleukin 6
Albert P. Li,
A major challenge for the evaluation of cytokine-induced down regulation of CYP gene
expression in primary cultured hepatocytes is the spontaneous decrease in expression of the genes with
culture duration. Based on our recent discovery that hepatocytes cultured for 7 days in a novel medium,
Li’s Differentiation Maintenance Medium (LDMM), would retain gene expression for markers of
differentiation and most CYP isoforms at levels similar to those of the first day of culture, we examined
the effects of the prototypical pro-inflammatory cytokine IL-6 in the "LDMM-stabilized (LS)" human
hepatocyte model. The LS-human hepatocyte cultures were found to be responsive to IL-6 induction of the
inflammatory gene marker, C-reactive protein (CRP), suggesting the expression of IL-6 receptors and the subsequent
signaling pathways. Results from two independent laboratories with human hepatocytes from three donors demonstrated
dose-dependent down regulation of the gene expression of several CYPs, i.e. 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4.
The results suggest that the LS-human hepatocytes may represent a physiologically relevant experimental model for
mechanistic investigation of the down-regulatory effects of inflammatory cytokines.
Biography:Dr. Albert Li (Ph. D., Biomedical Sciences) is CEO and President of In Vitro ADMET Laboratories, Columbia,
MD and Malden, MA. He is a pioneer in hepatocyte cryopreservation and application of hepatocytes in the assessment of
ADMET drug properties. He has published over 160 scientific articles and edited 6 books.
Keywords: C-reactive protein, CRP, Cytochrome P450, cytokine, CYP, gene expression, hepatocytes, IL-6, interleukin 6.
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