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TGFβ1-mediated suppression of cytochrome P450(CYP) induction responses in rat hepatocyte-fibroblast co-cultures. | LitMetric

TGFβ1-mediated suppression of cytochrome P450(CYP) induction responses in rat hepatocyte-fibroblast co-cultures.

Toxicol In Vitro

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, MD9, #04-11, Singapore 117597, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #04-01, 31 Biopolis Way, Singapore 138669, Singapore; NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), #05-01, 28 Medical Drive, Singapore 117576, Singapore; Singapore-MIT Alliance for Research and Technology, 3 Science Drive 2, S16-05-08, Singapore 117543, Singapore; Mechanobiology Institute, 5A Engineering Drive 1, T-Lab #05-01, Singapore 117411, Singapore; Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA; Department of Gastroenterology, Southern Medical University, Guangzhou, China. Electronic address:

Published: August 2018

AI Article Synopsis

Article Abstract

Co-culture of hepatocyte and fibroblasts has shown distinct advantages in enhancing certain liver specific functions and maintaining hepatic polarity. However, the utility of hepatocyte co-culture models for studies, such as drug-drug interaction studies, has not been completely elucidated. In this study the induction of Cyp1a2, Cyp2b1/2, and Cyp3a2, the three major cytochrome P450 (CYP) isoforms in the rat liver, was evaluated in randomly mixed co-cultures and micropatterned co-cultures. We found that in both co-culture configurations, the drug-induced Cyp1a2, Cyp2b1/2, Cyp3a2 mRNA and activity were suppressed relative to those in monocultured hepatocytes. Further, we observed a significant increase in TGFβ1 production in the co-cultures. Addition of 100 pg/ml TGFβ1 to hepatocyte monocultures resulted in the suppression of Cyp1a2, Cyp2b1/2, and Cyp3a2 induction. These findings implicate TGFβ1 as one of the important factors impairing drug induced CYP induction in co-cultures and suggests that caution needs to be exercised in the use of hepatocyte-fibroblast co-cultures for CYP induction studies.

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http://dx.doi.org/10.1016/j.tiv.2018.01.015DOI Listing

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