Activity and mRNA expression levels of selected cytochromes P450 in various sections of the human small intestine

British Journal of Clinical Pharmacology
Valérie ClermontVeronique Michaud

Abstract

To characterize mRNA expression levels (17 cytochromes P450) and activity (9 isoforms) of major cytochromes P450 expressed throughout the human small intestine. Tissue samples were obtained from 9 deceased subjects and intestinal sections (n = 10) were isolated for each subject. Relative mRNA expression levels were determined using quantitative real-time PCR. Intestinal microsomes were prepared from 5 subsections: duodenum, jejunum (proximal and mid-jejunum) and ileum (proximal and mid-ileum) regions. In vitro incubations were performed with various cytochrome P450 probe substrates: bupropion (CYP2B6), repaglinide (CYP2C8), tolbutamide (CYP2C9), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), chlorzoxazone (CYP2E1), ebastine (CYP2J2), midazolam (CYP3A4/5) and lauric acid (CYP4A11). Metabolite formation was assessed using validated liquid chromatography-tandem mass spectrometry assays. Cytochrome P450 mRNA levels ranked as follows: CYP3A4 > CYP2C9 > CYP2C19 > CYP2J2 > CYP4F2. Cytochrome P450 mRNA transcripts showed different patterns in their relative expression from 1 region to the other but CYP3A4, CYP2C9, CYP2C19 and CYP2J2 displayed the highest levels of mRNA expression (>5%) in all intestinal sections. Cytochrome P450 activiti...Continue Reading

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Citations

Jan 22, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Narciso CoutoGeoffrey Warhurst
Nov 26, 2020·Journal of Clinical Pharmacology·Mazyar MahmoudiWalter E Haefeli
Feb 4, 2021·Drug Development Research·Daniela FanniMirko Manchia
Dec 17, 2020·Pharmaceutics·Florian KlompStefan Oswald

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