Carcinogen-DNA adduct formation in the lungs and livers of preweanling CD-1 male mice following administration of [3H]-6-nitrochrysene, [3H]-6-aminochrysene, and [3H]-1,6-dinitropyrene.
Carcinogen-DNA adduct formation in the lungs and livers of preweanling CD-1 male mice following administration of [3H]-6-nitrochrysene, [3H]-6-aminochrysene, and [3H]-1,6-dinitropyrene.
复制标题
断奶前CD-1雄性小鼠给予[3H]-6-硝基、[3H]-6-氨基和[3H]-1,6-二硝基芘后，其肺和肝脏中致癌物-DNA加合物的形成。
作者：
Delclos Kb;R. Walker;Dooley Kl;P. Fu;F. Kadlubar
6-硝基菊烯(NC)和6-氨基菊烯(AC)经多次腹腔注射后，具有较强的肺、肝等致癌作用。对断奶前小鼠的剂量。在同一生物测定中，1，6-二硝基并[1，6-二硝基]芘已被证明是一种强的肝癌致癌物，而弱的肺癌致癌物。我们检测了单剂量或多次注射这些化合物后，断奶前雄性CD-1小鼠目标组织中致癌物-DNA加合物的分布。根据组织和给药程序的不同，服用[~3H]NC的动物的DNA修饰总水平比服用[~3H]AC的动物高2-9倍。无论给药程序如何，从[~3H]NC和[~H]AC处理的断奶前雄性小鼠的肺和肝脏中提取的DNA都含有单一的主要和层析相同的加合物。这一主要加合物占处理动物酶解物中致癌DNA加合物总量的90%，与N-羟基-AC与小牛胸腺DNA反应生成的主要C8-嘌呤取代加合物在层析上是不同的。与NC和AC的结果相反，经[~3H]-1，6-二硝基芘处理的小鼠肝脏中形成的主要致癌物-DNA加合物与N-羟基-1-氨基-6-硝基芘的产物1-N-(脱氧鸟苷-8-基)氨基-6-硝基吡喃形成了共层析。由于NC及其硝基还原衍生物AC在体内产生了相同的致癌物-DNA加合物，而该加合物不是来自N-羟基-AC，因此我们得出结论，NC在新生小鼠体内的代谢激活肯定涉及到以前未描述的环氧化和硝基还原途径的组合。这一激活途径可能是决定NC和AC在该生物检测系统中作为致癌物的效力的重要因素。
6-Nitrochrysene (NC) and 6-aminochrysene (AC) have been shown to be potent lung and liver carcinogens when administered in multiple i.p. doses to preweanling mice. 1,6-Dinitropyrene has been shown to be a strong hepatocarcinogen but a weak lung carcinogen in this same bioassay. We have examined carcinogen-DNA adduct profiles in the target tissues of preweanling male CD-1 mice following administration of single or multiple doses of these compounds. Depending on the tissue and the dosing schedule, the total level of DNA modification in animals dosed with [3H]NC was 2- to 9-fold higher than in animals dosed with [3H]AC. Regardless of the dosing schedule, DNA isolated from the lungs and livers of both [3H]NC- and [3H]AC-treated preweanling male mice contained a single major and chromatographically identical adduct. This major adduct, which accounted for as much as 90% of the total carcinogen-DNA adducts in enzymatic hydrolysates from treated animals, was chromatographically distinct from the major C8-purine-substituted adducts formed from the reaction of N-hydroxy-AC with calf thymus DNA. In contrast to the results obtained with NC and AC, the major carcinogen-DNA adduct formed in the livers of mice treated with [3H]-1,6-dinitropyrene was found to cochromatograph with 1-N-(deoxyguanosin-8-yl)amino-6-nitropyrene, a product derived from N-hydroxy-1-amino-6-nitropyrene. Since NC and its nitro-reduced derivative, AC, yielded an identical carcinogen-DNA adduct in vivo and this adduct was not derived from N-hydroxy-AC, we conclude that the metabolic activation of NC in the neonatal mouse must involve some previously undescribed combination of ring-oxidation and nitro-reduction pathways. This activation pathway could be an important factor in determining the potency of NC and AC as carcinogens in this bioassay system.