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Abstract

Mild hypothermia is largely used in medical applications but few studies are available on this effect on drug metabolism of hepatocytes. Rat primary hepatocytes were cultured at 37°C or 32°C during 24 or 48 hours thanks to our Integrated Dynamic Cell Cultures in Microsystem (IDCCM) device. Although no apoptosis was detected in both temperature cultures, hepatocytes remained better differentiated until the end of the perfusion in hypothermic culture. A modulation of their ploidy was observed in response to hypothermia by enhancing the cytokinesis of multiploidic hepatocytes. Quantitative RT-PCR analysis revealed a time-dependent and temperature sensitivity of the expression of several drug metabolism-related genes (CYP1A2, CYP3A2, CYP2B1, CYP2D2, CYP2E1, GSTA2, UGT1A6, ABCB1b, and ABCC2). Whereas the CYP1A2 activity remained lower in hypothermic cultures, hepatocytes remained inducible by prototypical inducers (3-methylcholanthrene, rifampicin). ABCB1 expression was upregulated by hypothermia suggesting the inefficiency of rifampicin observed during drug treatment of critical care patients. Together, these results suggest new insights on the effects of hypothermia on cellular functions and this impact on drug responses of hepatocytes. Further experiments with clinically relevant drug-related CYP450 (CYP3A, CYP2C, CYP2D) could be performed to have a clinical relevance with therapeutic hypothermia.

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Cellular Responses of Hepatocytes Induced by Hypothermia: Modulation of Cytokinesis and Drug Metabolism-Related Functions

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