Chen J, Barnes W S, Maiello J, Weisburger J H
J Cancer Res Clin Oncol. 1984;108(1):135-40. doi: 10.1007/BF00390985.
The biochemical denitrosation of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in tissues from four strains of rat, inbred Buffalo, Lewis, B-N, and the random-bred Sprague-Dawley, with different sensitivities to MNNG-induced gastric carcinomas was investigated as a possible explanation for the species/strain differences in MNNG-induced carcinogenesis. An analytical HPLC method was developed to assay denitrosation of MNNG to N-methyl-N'-nitroguanidine (MNG) by cytosolic, microsomal, mitochondrial, and nuclear cell fractions. All the activity was contained in the microsomal and cytosolic fractions, with the major portion occurring in the cytosol. The activity in both fractions was NADPH-dependent, but denitrosation was not reduced by inhibitors of the cytochrome P-450 system. Denitrosation of MNNG post-mitochondrial supernatant (S9) fractions from liver, glandular stomach mucosa, and duodenal mucosa of the four rat strains was determined. In all strains, denitrosation activities were highest in liver. Comparisons between the three strains most sensitive to MNNG-induced gastric carcinogenesis indicated no large differences for any tissue. However, Buffalo, the most resistant strain, did have a higher level of denitrosating activity in all three tissues, which is consistent with the hypothesis that higher levels of detoxifying enzymes may lead to a decreased incidence of tumors. On the other hand, denitrosation accounts for less than 3% of the MNNG that disappears during the incubation period so that the relevance of denitrosation as a mechanism in strain-specific sensitivity to MNNG-induced gastric carcinoma requires additional studies.
研究了四种大鼠品系（近交系布法罗大鼠、刘易斯大鼠、B - N大鼠以及随机繁殖的斯普拉格 - 道利大鼠）对N - 甲基 - N'- 硝基 - N - 亚硝基胍（MNNG）诱导的胃癌具有不同敏感性的组织中MNNG的生化脱亚硝化作用，以此作为MNNG诱导致癌作用中物种/品系差异的一种可能解释。开发了一种分析型高效液相色谱法，用于测定胞质、微粒体、线粒体和细胞核细胞组分将MNNG脱亚硝化生成N - 甲基 - N'- 硝基胍（MNG）的情况。所有活性都存在于微粒体和胞质组分中，主要部分存在于胞质溶胶中。两个组分中的活性均依赖于NADPH，但细胞色素P - 450系统的抑制剂不会降低脱亚硝化作用。测定了四种大鼠品系肝脏、腺胃黏膜和十二指肠黏膜的线粒体后上清液（S9）组分中MNNG的脱亚硝化作用。在所有品系中，肝脏中的脱亚硝化活性最高。对三种对MNNG诱导的胃癌最敏感的品系进行比较，结果表明任何组织之间都没有很大差异。然而，最具抗性的品系布法罗大鼠在所有三种组织中的脱亚硝化活性水平确实更高，这与解毒酶水平较高可能导致肿瘤发生率降低的假设一致。另一方面，脱亚硝化作用在孵育期内消失的MNNG中所占比例不到3%，因此脱亚硝化作用作为对MNNG诱导的胃癌品系特异性敏感性的一种机制的相关性还需要进一步研究。
