Josyula S, Schut H A
Department of Pathology, Medical College of Ohio, Toledo 43614-5806, USA.
Nutr Cancer. 1998;32(3):139-45. doi: 10.1080/01635589809514732.
Meats cooked at high temperatures contain mutagenic heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). In female Fischer 344 rats, IQ is a multiorgan carcinogen, whereas PhIP induces mammary adenocarcinomas. For IQ and PhIP, N-hydroxylation, catalyzed by microsomal cytochrome P-450 1A1 and/or 1A2, and then esterification, especially O-acetylation, are the principal steps leading to DNA adduct formation. Conjugated linoleic acid (CLA) is a mixture of conjugated linoleic acid isomers found in various meat and dairy products. We have examined the effect of dietary CLA on DNA adduct formation by PhIP and IQ in female Fischer 344 rats. Four-week-old animals were maintained on AIN-76A diet without or with CLA (4% wt/wt) and treated with IQ or PhIP (50 mg/kg by gavage) after two weeks. Animals were killed (4/group) one, four, and eight days later. DNA isolated from mammary epithelial cells, liver, colon, and white blood cells was analyzed for carcinogen-DNA adducts by 32P-postlabeling assays. On Day 1, dietary CLA significantly inhibited adduct formation (82.0%) in mammary epithelial cells in IQ--but not in PhIP-treated rats. In the colon, dietary CLA significantly inhibited PhIP-DNA adduct formation (18.7%) on Day 8 but increased IQ-DNA adduct formation (30.5%) on Day 8. Dietary CLA had no effect on adduct levels in liver or white blood cells. Calf thymus DNA was incubated with N-hydroxy-PhIP or -IQ in the presence of acetyl-CoA. Enzymatic activation was catalyzed by liver or mammary cytosol. A two-week pretreatment with 2% (wt/wt) dietary CLA had no effect on O-acetyltransferase-catalyzed IQ- or PhIP-DNA adduct formation. It is concluded, under certain conditions, that dietary CLA can lower IQ- and PhIP-DNA adduct formation. Overall, however, the major mode of action of CLA is probably by a mechanism other than the inhibition of the N-hydroxylation and subsequent O-acetylation of PhIP or IQ.
高温烹制的肉类含有诱变杂环胺，如2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）和2-氨基-3-甲基咪唑并[4,5-f]喹啉（IQ）。在雌性Fischer 344大鼠中，IQ是一种多器官致癌物，而PhIP可诱发乳腺腺癌。对于IQ和PhIP，微粒体细胞色素P-450 1A1和/或1A2催化的N-羟基化，然后是酯化，尤其是O-乙酰化，是导致DNA加合物形成的主要步骤。共轭亚油酸（CLA）是在各种肉类和乳制品中发现的共轭亚油酸异构体的混合物。我们研究了日粮CLA对雌性Fischer 344大鼠中PhIP和IQ诱导的DNA加合物形成的影响。四周龄动物维持在不含或含有CLA（4%重量/重量）的AIN-76A日粮上，两周后用IQ或PhIP（50mg/kg灌胃）处理。分别在1天、4天和8天后处死动物（每组4只）。通过32P后标记分析从乳腺上皮细胞、肝脏、结肠和白细胞中分离的DNA中的致癌物-DNA加合物。在第1天，日粮CLA显著抑制IQ处理的大鼠乳腺上皮细胞中的加合物形成（82.0%），但对PhIP处理的大鼠无效。在结肠中，日粮CLA在第8天显著抑制PhIP-DNA加合物形成（18.7%），但在第8天增加IQ-DNA加合物形成（30.5%）。日粮CLA对肝脏或白细胞中的加合物水平没有影响。将小牛胸腺DNA与N-羟基-PhIP或-NIQ在乙酰辅酶A存在下孵育。酶促活化由肝脏或乳腺细胞溶胶催化。用2%（重量/重量）日粮CLA进行两周预处理对O-乙酰转移酶催化的IQ-或PhIP-DNA加合物形成没有影响。得出结论，在某些条件下，日粮CLA可以降低IQ-和PhIP-DNA加合物的形成。然而，总体而言，CLA的主要作用方式可能是通过一种不同于抑制PhIP或IQ的N-羟基化及随后的O-乙酰化的机制。
