METABOLISM, MUTAGEN AND DNA ADDUCTION OF IQ

2-氨基-3-甲基咪唑(4，5-f)喹啉(IQ)是 在熟食中发现的杂环芳胺 在啮齿动物的生物测试中显示为有效的致癌物质。我们有 开始的工作涉及(1)合成N-羟基-IQ和N-乙酰氧基- IQ和IQ-N-硫酸盐，IQ的活性代谢物；(2)合成 和主要DNA-IQ加合物的表征；(3)检验 ~(32)P-后标记法检测猕猴体内DNA-IQ加合物 猴子的智商代谢；以及(5)特定细胞色素的作用 P-450在智商代谢激活中的作用。N-OH-IQ是一个直接的 TA98沙门氏菌的诱变剂及其与DNA的共价结合 而不需要进一步激活。N-OH-IQ也是由 哺乳动物O-乙酰基转移酶和N-乙酰氧基-磺基转移酶- IQ和IQ-N-硫酸盐。C8-鸟嘌呤-智商加合物是 合成并在体外由N-OH-IQ或 N-乙酰氧基-智商与DNA反应。使用32P-后标记分析， 发现了8种DNA-IQ加合物，其中包括C8-鸟嘌呤-IQ。 食蟹猴肝脏的智商与对照组相同 在喂食智商的大鼠的肝脏中发现。DNA修饰后的DNA分析 体外N-OH-IQ显示有7个加合物，其中包括C8-鸟嘌呤- 智商加合物，与体内发现的完全相同。因此，N- OH-IQ似乎是体内发现的所有加合物的罪魁祸首 只有一个例外。DNA-IQ加合物也在肾脏、结肠、 胃和膀胱，这些加合物在所有器官中都是相同的 检查过了。我们检测了新陈代谢激活的特异性 智商和其他一些诱变/致癌杂环 利用一种新的检测系统从熟食中提取芳香胺 将单独表达任一重组人的人类细胞 细胞色素P1-450或P3-450作为生物活化系统 鼠伤寒沙门氏菌对突变的评分。我们的结果表明， 细胞色素P3-450是细胞色素P.450超氧化物歧化酶的单一亚型 基因家族，负责细胞的生物活性 杂环芳胺食品致突变剂N-羟胺。

2-Amino-3-methyl-imidazole (4,5-f)quinoline (IQ) is among a number of heterocyclic arylamines found in cooked foods that have been shown lo be potent carcinogens in rodent bioassays. We have initiated work involving (1) synthesis of N-OH-IQ, and N-acetoxy- IQ and IQ-N-sulfate, the reactive metabolites of IQ; (2) synthesis and characterization of the major DNA-IQ adduct; (3) examination of DNA-IQ adducts in monkeys by the 32P-postlabeling method; (4) IQ metabolism in monkeys; and (5) the role of specific cytochromes P-450 in the metabolic activation of IQ. N-OH-IQ was a direct mutagen in Salmonella TA98 and capable of covalently binding to DNA without further activation. N-OH-IQ is also metabolized by mammalian O-acetyl-transferase and sulfotransferase to N-acetoxy- IQ and IQ-N-sulfate, respectively. The C8-guanine-IQ adduct was synthesized and shown to be formed in vitro from either N-OH-IQ or N-acetoxy-IQ reacting with DNA. Using the 32P-postlabeling assay, eight DNA-IQ adducts including C8-guanine-IQ, were found in the liver of Cynomolgus monkeys fed IQ that were identical to those found in the liver of rats fed IQ. Analysis of DNA modified in vitro with N-OH-IQ showed seven adducts, including the C8-guanine- IQ adduct, that were identical to those found in vivo. Thus, N- OH-IQ appears to be responsible for all adducts found in vivo except one. DNA-IQ adducts were also detected in kidney, colon, stomach and bladder, and these adducts were identical in all organs examined. We examined the specificity of metabolic activation of IQ and a number of other mutagenic/carcinogenic heterocyclic arylamines from cooked foods by employing a novel test system combining human cells individually expressing either recombinant cytochrome P1-450 or P3-450 as the bioactivation system with Salmonella typhimurium to score mutations. Our results show that cytochrome P3-450, a single isoform of the cytochrome P.450 super- gene family, is responsible for the bioactivation of the heterocyclic arylamine food mutagens to N-hydroxylamines.