Snyderwine E G, Sadrieh N, King R S, Schut H A
Chemical Carcinogenesis Section, Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Food Chem Toxicol. 1998 Dec;36(12):1033-41. doi: 10.1016/s0278-6915(98)00088-x.
2-amino-9H-pyrido[2,3-b]indole (AalphaC) is a heterocyclic amine found at relatively high concentrations in barbecued or grilled meats. In the current study, the mammary gland carcinogenicity of AalphaC was examined in female Sprague-Dawley rats given 10 doses of AalphaC (75 mg/kg, orally, once 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 carcinogenesis. Within 1 year, one out of 20 rats dosed with AalphaC developed a tubulopapillary carcinoma, indicating that the bioassay was largely negative. As DNA adduct formation is considered to play a role in carcinogenesis, AalphaC-DNA adduct levels were measured in the mammary gland and other tissues by the 32P-postlabelling method. Under intensification conditions, one major adduct and up to three minor adducts were detected in isolated mammary gland epithelial cells and other tissues (liver, stomach, small intestine, colon and kidney) of AalphaC-treated rats; the adduct patterns were similar in all tissues examined. The major adduct, comprising 60-100% of total DNA adduct levels in tissues, was chromatographically identical to the principal adduct found in 3'-dGp-AalphaC (synthesized by reacting 3'-phospho-2'-deoxyguanosine (3'-dGp) with N-acetoxy-AalphaC). Of the tissues examined, the highest AalphaC-DNA adduct levels were found in the liver. In male rats given a single dose of AalphaC (75 mg/kg, orally, 3 hr prior to necropsy), no AalphaC-DNA adducts were detected in extrahepatic tissues. In female rats given a single dose or 12 daily doses of AalphaC, hepatic DNA adduct levels were at least 12-13-fold higher than those in any other tissue. Mean total AalphaC-DNA adduct levels in mammary gland epithelial cells and liver from female rats given multiple doses of AalphaC were 3.5 and 50.7 (RAL x 10(7)), respectively. Although factors in addition to DNA adduct formation are likely to play a role in mammary gland carcinogenesis, the results suggest that the weak mammary gland carcinogenicity of AalphaC may in part be associated with low AalphaC-DNA adduct levels in the mammary gland epithelium.
2-氨基-9H-吡啶并[2,3-b]吲哚（AαC）是一种杂环胺，在烧烤肉类中含量相对较高。在本研究中，对给予10剂AαC（75mg/kg，口服，从43日龄开始每天一次）并饲喂特定高脂肪饮食（23.5%玉米油）的雌性斯普拉格-道利大鼠进行了AαC的乳腺致癌性研究，高脂肪饮食是大鼠乳腺致癌的一个强促进因素。在1年内，20只给予AαC的大鼠中有1只发生了管状乳头状癌，表明生物测定在很大程度上呈阴性。由于DNA加合物的形成被认为在致癌过程中起作用，因此通过32P后标记法测量了乳腺和其他组织中的AαC-DNA加合物水平。在强化条件下，在AαC处理大鼠的分离乳腺上皮细胞和其他组织（肝脏、胃、小肠、结肠和肾脏）中检测到一种主要加合物和多达三种次要加合物；在所检查的所有组织中加合物模式相似。主要加合物占组织中总DNA加合物水平的60-100%，其色谱图与在3'-dGp-AαC（通过使3'-磷酸-2'-脱氧鸟苷（3'-dGp）与N-乙酰氧基-AαC反应合成）中发现的主要加合物相同。在所检查的组织中，肝脏中的AαC-DNA加合物水平最高。在给予单剂量AαC（75mg/kg，口服，尸检前3小时）的雄性大鼠中，在肝外组织中未检测到AαC-DNA加合物。在给予单剂量或12剂每日剂量AαC的雌性大鼠中，肝脏DNA加合物水平比任何其他组织中的至少高12-13倍。给予多剂量AαC的雌性大鼠乳腺上皮细胞和肝脏中的平均总AαC-DNA加合物水平分别为3.5和50.7（RAL×10(7)）。尽管除DNA加合物形成外的其他因素可能在乳腺致癌过程中起作用，但结果表明AαC的弱乳腺致癌性可能部分与乳腺上皮中低水平的AαC-DNA加合物有关。
