Genotoxic effects in rodents given high oral doses of ranitidine and sodium nitrite

Abstract

The possible intragastric nitrosation of ranitidine to genotoxic derivatives has been investigated in rats and mice given, by gavage, high single doses of this histamine H ₂ receptor antagonist along with NaNO ₂ Liver DNA fragmentation, as revealed in rats by both DNA alkaline elution and DNA alkaline denaturation followed by hydroxylapatite chromatography, was found to be dependent either on the molar ratio drug/nitrite or on the gastric pH. It occurred only with doses of 175 mg/kg ranitidine HCI + 80 mg/kg NaNO ₂ (molar ratio 1:2.32) or 350 mg/kg ranitidine HCI + 80 mg/kg NaNO ₂ (molar ratio 1:1.16) and concurrent reduction of gastric pH from 5.5 to 2–3 (produced by prolonged fasting). A further reduction of pH elicited by histamine injection increased the amount of DNA damage. DNA fragmentation in gastric mucosa showed a similar dependence on both pH and ranitidine/NaNO ₂ ratio, but was more marked than in liver. Simultaneous administration of ascorbic acid reduced the damage of gastric DNA. Oral administration of 175 mg/kg ranitidine HCl+ 80 mg/kg NaNO in fasted and histamine- injected mice induced a modest but statistically significant in crease in the frequency of sister chromatid exchanges in bone marrow cells.