Formation of DNA adducts of the food-derived mutagen 2-amino-9H-pyrido[2,3-b]indole (A(alpha)C) and bioassay of mammary gland carcinogenicity in Sprague-Dawley rats

2-amino-9H-pyrido[2,3-b]indole (A alpha C) is a heterocyclic amine found at relatively high concentrations in barbecued or grilled meats. In the curre nt study, the mammary gland carcinogenicity of A alpha C was examined in fe male Sprague-Dawley rats given IO doses of A alpha C (75 mg/kg, orally, onc e per day starting at 43 days of age) and placed on a defined high-fat diet (23.5% corn oil), a strong promotional factor for rat mammary gland carcin ogenesis. Within 1 year, one out of 20 rats dosed with A alpha C developed a tubulopapillary carcinoma, indicating that the-bioassay was largely negat ive. As DNA adduct formation is considered to play a role in carcinogenesis , A alpha C-DNA adduct levels were measured in the mammary gland and other tissues by the P-32-postlabelling method. Under intensification conditions, one major adduct and up to three minor adducts were detected in isolated m ammary gland epithelial cells and other tissues (liver, stomach, small inte stine, colon and kidney) of A alpha C-treated rats; the adduct patterns wer e similar in all tissues examined. The major adduct, comprising 60-100% of total DNA adduct levels in tissues, was chromatographically identical to th e principal adduct found in 3'-dGp-A alpha C (synthesized by reacting 3'-ph ospho-2'-deoxyguanosine (3'-dGp) with N-acetoxy-A alpha C). Of the tissues examined, the highest A alpha C-DNA adduct levels were found in the liver. In male rats given a single dose of A alpha C (75 mg/kg, orally, 3 hr prior to necropsy), no A alpha C-DNA adducts were detected in extrahepatic tissu es. In female rats given a single dose or 12 daily doses of A alpha C, hepa tic DNA adduct levels were at least 12-13-fold higher than those in any oth er tissue. Mean total A alpha C-DNA adduct levels in mammary gland epitheli al cells and liver from female rats given multiple doses of A alpha C were 3.5 and 50.7 (RAL x 10(7)), respectively. Although factors in addition to D NA adduct formation are likely to play a role in mammary gland carcinogenes is, the results suggest that the weak mammary gland carcinogenicity of A al pha C may in part be associated with low A alpha C-DNA adduct levels in the mammary gland epithelium. Published by Elsevier Science Ltd.