Biodistribution of ellagic acid and dose-related inhibition of lung tumorigenesis in A/J mice.
Ellagic acid (EA), derived from fruit ellagitannins, is known to be antimutagenic and anticarcinogenic in various animal tumor models. In this study, EA at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet. In contrast, two related compounds, esculin and esculetin, had no effect on lung tumorigenesis. The biodistribution of EA was studied as a function of dose and time after gavage of EA. The levels of EA in the lung were directly proportional to the dose of EA between 0.2 and 2.0 mmol. The maximum level of EA, corresponding to 21.3 nmol/g, was observed 30 minutes after gavage with 2.0 mmol of EA/kg body wt, which corresponds to only 70 ppm of the administered dose. The levels in liver tissues were 10-fold lower and reached a maximum 30 minutes after gavage. At this interval, the blood level of EA was 1 nmol/ml. The inclusion of EA in cyclodextrin doubles the level of EA in lung tissues. These results demonstrate that EA localizes preferentially in lung tissues and confirm that EA administered orally can inhibit lung tumorigenesis.
Boukharta
M
M
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec City, Canada.
Jalbert
G
G
Castonguay
A
A
D000818:Animals; D002273:Carcinogens; D003505:Cyclodextrins / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004610:Ellagic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D009602:Nitrosamines; D014018:Tissue Distribution
D002273:Carcinogens; D003505:Cyclodextrins; D004337:Drug Carriers; D009602:Nitrosamines; D004610:Ellagic Acid; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone