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Interaction of omeprazole with DNA in rat tissues
D H Phillips1, A Hewer, M R Osborne
1Haddow Laboratories, Institute of Cancer Research, Belmont, Sutton, Surrey, UK.
Abstract:
There has been concern recently over the possible genotoxicity of omeprazole, a potent inhibitor of gastric acid secretion in humans. In order to investigate its possible DNA binding activity in vivo, 14C-labelled omeprazole was administered to male PVG rats, 8-10 weeks old, orally by gavage at a dose of 30 mg/kg. At various times after treatment, animals were killed and DNA isolated from the fundic and antral regions of the glandular stomach, and from the duodenum, ileum and colon. Scintillation counting of the DNA samples revealed a reproducible association of 14C that was not extractable with organic solvents and could not be removed from the DNA by column cartridge chromatography. DNA samples were digested enzymically to deoxyribonucleosides and analysed by reversed-phase high performance liquid chromatography (HPLC). With DNA from each tissue, most of the radioactivity eluted in a peak that was chromatographically distinct from normal nucleosides and from omeprazole itself. Chromatography following partial digestion of DNA gave rise to the same radioactivity elution profiles, whilst chromatography on hydroxyapatite resulted in retention of most of the radioactivity on the column using conditions under which DNA was eluted. These findings suggest either the formation in rat tissues of chemically-labile covalent omeprazole-DNA adducts or, more likely, a strong non-covalent interaction. The apparent DNA binding occurs rapidly in vivo and is short-lived, the maximum levels of radioactive incorporation (equivalent of up to 36 pmol omeprazole/mg DNA) occurring at 0.5 h in fundus, 0.5-1 h in antrum, 1 h in duodenum, 2 h in ileum and at 4-8 h in colon.
Insights
Concerns about omeprazole genotoxicity were investigated. Studies in rats suggest omeprazole may bind to DNA in vivo, possibly through strong non-covalent interactions, but this binding is transient.
Area of Science:
- Pharmacology
- Toxicology
- Molecular Biology
Background:
- Omeprazole, a widely used proton pump inhibitor, has raised concerns regarding potential genotoxicity.
- Investigating the in vivo DNA binding activity of omeprazole is crucial for understanding its safety profile.
Purpose of the Study:
- To determine if omeprazole binds to DNA in mammalian tissues.
- To characterize the nature and kinetics of any potential omeprazole-DNA interaction in vivo.
Main Methods:
- Administration of 14C-labeled omeprazole to male PVG rats.
- Isolation of DNA from various gastrointestinal tissues (stomach, duodenum, ileum, colon).
- Analysis of radioactivity associated with DNA using scintillation counting, HPLC, and hydroxyapatite chromatography.
Main Results:
- Reproducible association of radioactivity with DNA was observed, not removable by organic solvents or standard chromatography.
- HPLC analysis revealed a distinct radioactive peak, separate from normal nucleosides and omeprazole.
- Radioactivity was retained on hydroxyapatite columns under conditions where DNA eluted, suggesting interaction with DNA.
Conclusions:
- Findings suggest either chemically-labile covalent omeprazole-DNA adducts or, more likely, strong non-covalent interactions.
- The observed DNA binding is rapid, transient, and tissue-specific, with peak levels occurring at different time points post-administration.