Interaction of omeprazole with DNA in rat tissues.
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.
Phillips
D H
DH
Haddow Laboratories, Institute of Cancer Research, Belmont, Sutton, Surrey, UK.
Hewer
A
A
Osborne
M R
MR
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000032:analysis / Q000302:isolation & purification; D004249:DNA Damage / Q000235:genetics*; D006882:Hydroxyapatites; D008297:Male; D015394:Molecular Structure; D009853:Omeprazole / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012997:Solvents
D006882:Hydroxyapatites; D012997:Solvents; D004247:DNA; D009853:Omeprazole