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CYP3A gene expression in human gut epithelium
J C Kolars1, K S Lown, P Schmiedlin-Ren
1Department of Internal Medicine, Veterans Administration Medical Center, Ann Arbor, MI 48109.
Abstract:
CYP3A4, a major Phase I xenobiotic metabolizing enzyme present in liver, is also present in human small bowel epithelium where it appears to catalyse significant 'first pass' metabolism of some drugs. To determine whether CYP3A4 or the related enzymes CYP3A3, CYP3A5, and CYP3A7 are present in other regions of the digestive tract, we used CYP3A-specific antibodies to examine histological sections and epithelial microsomes obtained from a human organ donor. CYP3A-related proteins were detected in epithelia throughout the digestive tract and in gastric parietal cells, in pericentral hepatocytes, and in ductular cells of the pancreas. Immunoblot analysis suggested that the major CYP3A protein present in liver, jejunum, colon, and pancreas was CYP3A4 or CYP3A3, whereas CYP3A5 was the major protein present in stomach. Both CYP3A4 and CYP3A5 mRNA were detectable in all regions of the digestive tract using the polymerase chain reaction (PCR); however, only CYP3A4 could be detected by Northern blot analysis. CYP3A7 mRNA was consistently detected only in the liver by PCR and CYP3A3 mRNA was not detected in any of the tissues. We conclude that CYP3A4 and CYP3A5 are present throughout the human digestive tract and that differences in the expression of these enzymes may account for inter-organ differences in the metabolism of CYP3A substrates.
Insights
Cytochrome P450 3A4 (CYP3A4) and CYP3A5 are present throughout the human digestive tract. Their varying expression may explain differences in drug metabolism across organs.
Area of Science:
- Pharmacology
- Gastroenterology
- Biochemistry
Background:
- Cytochrome P450 3A4 (CYP3A4) is a key enzyme in drug metabolism, primarily found in the liver and small intestine.
- Its presence in the digestive tract suggests a role in 'first pass' drug metabolism.
Purpose of the Study:
- To investigate the presence and distribution of CYP3A4 and related enzymes (CYP3A3, CYP3A5, CYP3A7) in various regions of the human digestive tract.
- To understand potential inter-organ variations in drug metabolism.
Main Methods:
- Histological examination of tissue sections and epithelial microsomes from a human organ donor using CYP3A-specific antibodies.
- Immunoblot analysis to identify specific CYP3A proteins.
- Polymerase chain reaction (PCR) and Northern blot analysis to detect CYP3A mRNA.
Main Results:
- CYP3A-related proteins were detected throughout the digestive tract, gastric parietal cells, hepatocytes, and pancreatic ductular cells.
- CYP3A4/CYP3A3 was predominant in the liver, jejunum, colon, and pancreas; CYP3A5 was dominant in the stomach.
- CYP3A4 and CYP3A5 mRNA were found in all digestive tract regions, but only CYP3A4 mRNA was detectable by Northern blot.
Conclusions:
- CYP3A4 and CYP3A5 are expressed throughout the human digestive tract.
- Differential expression of these enzymes across organs may contribute to variations in the metabolism of drugs processed by CYP3A.