Chhabra S K, Anderson L M, Perella C, Desai D, Amin S, Kyrtopoulos S A, Souliotis V L
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, Maryland 21702, USA.
Toxicol Appl Pharmacol. 2000 Dec 1;169(2):191-200. doi: 10.1006/taap.2000.9068.
Use of alcoholic beverages increases risk of cancer at several target sites, including the breast. Of several possible mechanisms for this effect, competitive inhibition by ethanol of hepatic clearance of nitrosamines, resulting in increased dose delivery to posthepatic tissues, gives the quantitatively most pronounced enhancement. We investigated whether this effect would pertain to the mammary gland, and to ethanol and nitrosamines delivered translactationally to sucklings. Ethanol (1.6 g/kg) was administered by gavage to nursing Sprague-Dawley rats 10 min before 5 mg/kg N-nitrosodimethylamine (NDMA) or 50 mg/kg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); treatment was on postnatal days 1, 7, or 14. Tissues taken 4 h later for analysis of O(6)-methylguanine in DNA were liver, blood, and mammary glands from the mothers, and liver, lung, kidney, and blood from the sucklings. Ethanol cotreatment resulted in a marked, 10-fold increase in O(6)-methylguanine adducts from NDMA in mammary gland, as well as smaller but significant increases in this tissue from NNK and in maternal blood cells from both chemicals; adducts in maternal liver decreased slightly. In the sucklings, ethanol cotreatment also lowered adducts in liver after NDMA or NNK treatment. After NDMA, adducts were also detected in suckling lung and kidney and were increased five- to 10-fold after ethanol coexposure. Adducts from either chemical, with or without ethanol, decreased markedly in all suckling tissues with development from postnatal day 1 to day 14. Thus ethanol coexposure with nitrosamines increases O(6)-methylguanine DNA adducts in mammary gland and strongly influences adduct formation in suckling tissues after translactational delivery.
饮用酒精饮料会增加包括乳腺在内的多个靶器官患癌风险。在导致这种影响的几种可能机制中，乙醇对亚硝胺肝脏清除的竞争性抑制作用，使得进入肝后组织的剂量增加，在数量上产生了最为显著的增强效果。我们研究了这种效应是否适用于乳腺，以及经乳汁传递给幼崽的乙醇和亚硝胺的情况。在给哺乳的斯普拉-道利大鼠灌胃给予5毫克/千克N-亚硝基二甲胺（NDMA）或50毫克/千克4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK）前10分钟，经口灌胃给予乙醇（1.6克/千克）；处理在出生后第1、7或14天进行。4小时后采集组织，用于分析DNA中O(6)-甲基鸟嘌呤的是母鼠的肝脏、血液和乳腺，以及幼崽的肝脏、肺、肾脏和血液。乙醇联合处理导致乳腺中NDMA产生的O(6)-甲基鸟嘌呤加合物显著增加10倍，同时该组织中NNK产生的加合物以及两种化学物质在母鼠血细胞中的加合物也有较小但显著的增加；母鼠肝脏中的加合物略有减少。在幼崽中，乙醇联合处理也降低了NDMA或NNK处理后肝脏中的加合物。NDMA处理后，幼崽的肺和肾脏中也检测到加合物，乙醇共同暴露后增加了5至10倍。从出生后第1天到第14天，无论有无乙醇，两种化学物质产生的加合物在所有幼崽组织中均显著减少。因此，乙醇与亚硝胺共同暴露会增加乳腺中O(6)-甲基鸟嘌呤DNA加合物，并强烈影响经乳汁传递后幼崽组织中的加合物形成。
