Abstract
The human small intestine can be involved in the first-pass metabolism of drugs. Under this condition, members of the CYP450 superfamily are expected to contribute to drug presystemic biotransformation. The aim of this study was to quantify protein expression levels of 16 major CYP450 isoforms in tissue obtained from nine human organ donors in seven subsections of the small intestine, i.e., duodenum (one section, N = 7 tissue samples), jejunum (three subsections (proximal, mid and distal), N = 9 tissue samples) and ileum (three subsections, (proximal, mid and distal), N = 9 tissue samples), using liquid chromatography tandem mass spectrometry (LC-MS/MS) based targeted proteomics. CYP450 absolute protein expression levels were compared to mRNA levels and enzyme activities by using established probe drugs. Proteins corresponding to seven of sixteen potential CYP450 isoforms were detected and quantified in various sections of the small intestine: CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, CYP3A5 and CYP4F2. Wide inter-subject variability was observed, especially for CYP2D6. CYP2C9 (p = 0.004) and CYP2C19 (p = 0.005) expression levels decreased along the small intestine. From the duodenum to the ileum, CYP2J2 (p = 0.001) increased, and a trend was observed for CYP3A5 (p = 0.13). CYP3A4 expression was higher in the jejunum than in the ileum (p = 0.03), while CYP4F2 expression was lower in the duodenum compared to the jejunum and the ileum (p = 0.005). CYP450 protein levels were better correlated with specific isoform activities than with mRNA levels. This study provides new data on absolute CYP450 quantification in human small intestine that could improve physiologically based pharmacokinetic models. These data could better inform drug absorption profiles while considering the regional expression of CYP450 isoforms.
Highlights
The liver and small intestine are involved in drug biotransformation due to their high content of drug metabolizing enzymes [1,2,3,4,5]
As our tissue samples were from nine donors, the classification of cytochrome P450 (CYP450) expression level in a larger cohort could differ for CYP450 with low expression (≤5%)
Our results demonstrated highest correlations between protein expression and enzyme activity than between protein expression and mRNA for CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4 and CYP4F2
Summary
The liver and small intestine are involved in drug biotransformation due to their high content of drug metabolizing enzymes [1,2,3,4,5]. The liver has higher expression levels of total CYP450s than the small intestine, but intestinal metabolism by some CYP450 isoforms, e.g., CYP3A4, could be responsible for the presystemic metabolism of some drugs [3,4,16]. Absolute quantification of major CYP450 isoforms in the human small intestine is needed in order to better understand inter-subject and intrasubject variability in pre-systemic metabolism and drug pharmacokinetics [1,10,18,24,25,26,27]
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