Oral administration of naturally occurring coumarins leads to altered phase I and II enzyme activities and reduced DNA adduct formation by polycyclicaromatic hydrocarbons in various tissues of SENCAR mice

Several naturally occurring coumarins, to which humans are routinely expose d in the diet, were previously found to inhibit P450-mediated metabolism of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) in vitro, block DNA adduct formation in mouse epidermis and inhibit skin tumor initi ation by B[a]P and/or DMBA when applied topically to mice. The present stud y was designed to investigate the effects of two of these compounds, of the linear furanocoumarin type, when given orally (70 mg/kg per os, four succe ssive daily doses), on P450 and glutathione S-transferase (GST) activities and DNA adduct formation by B[a]P and DMBA in various mouse tissues. Impera torin and isopimpinellin significantly blocked ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD) activities in epidermis at 1 and 24 h after oral dosing. Imperatorin and isopimpinellin modestly inhi bited EROD activities in lung and forestomach at 1 h and significantly inhi bited PROD activities in lung and forestomach at 1 h after the final oral d ose. Twenty-four hours after the final oral dose of imperatorin or isopimpi nellin EROD and PROD activities remained inhibited in epidermis and lung. H owever, forestomach P450 activity had returned to control levels. Interesti ngly, imperatorin and isopimpinellin treatment inhibited liver EROD activit y at 1 h, had no effect on PROD activity at this time point, but elevated b oth these enzyme activities at 24 h. Elevated EROD and PROD activities coin cided with elevated hepatic P450 content. Imperatorin and isopimpinellin tr eatment also increased liver cytosolic GST activity at both 1 and 24 h afte r the final oral dose by 1.6-fold compared with corn oil controls, Oral adm inistration of imperatorin and isopimpinellin also had a protective effect against DNA adduct formation by B[a]P and DMBA, Imperatorin pretreatment de creased formation of DNA adducts by DMBA in forestomach, Pretreatment with isopimpinellin led to reduced DNA adduct levels in liver (B[a]P), lung (B[a ]P) and mammary epithelial cells (DMBA). These results suggest that imperat orin and isopimpinellin may have potential chemopreventive effects when adm inistered in the diet.