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Pharmaceutics 2017, 9(4), 40; doi:10.3390/pharmaceutics9040040

Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues

1
Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada
2
Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada
3
Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada
*
Author to whom correspondence should be addressed.
Received: 31 August 2017 / Revised: 18 September 2017 / Accepted: 22 September 2017 / Published: 26 September 2017
(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)
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Abstract

Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals (n = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes. Expression levels of cyp3a11 and cyp3a25 mRNA were decreased in the liver (>2–14-fold) and kidneys (>2-fold) of HFD groups which correlated with a significant reduction in midazolam metabolism (by 21- and 5-fold in hepatic and kidney microsomes, respectively, p < 0.001). HFD was associated with decreased activities of cyp2b and cyp2c subfamilies in all organs tested except in the kidneys (for tolbutamide). Other cyp450 hepatic activities were minimally or not affected by HFD. Taken together, our data suggest that substrate-dependent and tissue-dependent modulation of cyp450 metabolic capacities by early phases of T2D are observed, which could modulate drug disposition and pharmacological effects in various tissues. View Full-Text
Keywords: Keywords: cytochromes P450; drug metabolism; mRNA; diet induced obesity; diabetes Keywords: cytochromes P450; drug metabolism; mRNA; diet induced obesity; diabetes
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MDPI and ACS Style

Maximos, S.; Chamoun, M.; Gravel, S.; Turgeon, J.; Michaud, V. Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues. Pharmaceutics 2017, 9, 40.

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