Intraperitoneal administration of coumarin causes tissue-selective depletion of cytochromes p450 and cytotoxicity in the olfactory mucosa

Coumarin is a naturally occurring fragrant compound widely used in consumer products and also as a therapeutic agent. The effects of intraperitoneal (ip) and oral administration of coumarin on cytochrome P450 (P450) expression in olfactory mucosa were examined. A single ip injection of coumarin at 50 mg/kg resulted in a significant reduction of levels of CYP2A and CYP2G in the olfactory mucosa of Wistar rats and C57BL/6 mice at 48 hr following injection. Dose-response analysis of coumarin effects indicated that Wistar rats were more sensitive than C57BL/6 mice. A significant suppression of nasal CYP2A levels was observed at 25 mg/kg in rats, but not in mice. Depletion of P450 content was not observed in liver of either rats or mice at 50 mg/kg, indicating tissue-selective effects. Decreased P450 levels were observed at 24 hr, 48 hr, and 7 days following treatment, with minimal levels seen at 48 hr. The decrease in P450 levels was accompanied by necrosis, cell loss, and basal cell metaplasia in the olfactory mucosa. Intraperitoneal injection of 7-hydroxycoumarin or 3,4-dihydrocoumarin at 50 mg/ kg did not result in depletion of nasal P450, indicating that the toxicity is not mediated by P450-catalyzed coumarin 7-hydroxylation and supporting the hypothesis that the formation of coumarin 3, l-epoxide may be responsible for the toxicity. Oral treatment with coumarin in drinking water led to a small, yet significant induction of CYP2A protein and coumarin hydroxylase activity in the nasal mucosa of mice, but not rats. Thus, ip administration of coumarin causes tissue-selective depletion of P450 and cytotoxicity in the olfactory mucosa of Wistar rats and C57BL/6 mice. It remains to be determined whether similar toxicity occurs following coumarin administration by other routes.