Arcos J C, Valle R T, Bryant G M, Buu-Hoi N P, Argus M F
J Toxicol Environ Health. 1976 Jan;1(3):395-408. doi: 10.1080/15287397609529339.
Studies with 58 polynuclear aromatic hydrocarbons have shown that to repress demethylation of dimethylnitrosamine (DMN) in rat liver, the hydrocarbons must satisfy specific requirements of molecular geometry regarding size, shape, and coplanarity. Expressing the molecular size of these planar compounds by the two-dimensional area occupied, the size for maximal repressor activity ranges between about 85 and 150 A2. In addition to being within the correct molecular size range the hydrocarbons must have an elongated-rather than compact-molecular shape; circularly shaped and/or highly symmetrical hydrocarbons, such as coronene, triphenylene, ovalene, and tetrabenzonaphthalene, have very low activity or are inactive, in spite of being in the optimum size range. Coplanarity of the molecule is a critical requirement; thus, the potent carcinogen, 9,10-dimethyl-1,2-benzanthracene, is inactive as repressor of DMN-demethylase synthesis. Two exceptions, fluoranthene and benzol[ghi] fluoranthene, showed significant induction of DMN-demethylase. The molecular size distribution of hydrocarbons that repress the DMN-demethylase shows a mirror-image relationship with respect to the earlier reported molecular size requirement for indcution of azo dye N-demethylase. Compounds other than hydrocarbons also show the mirror-image relationship in the sense that pregnenolene-16alpha-carbonitrile, alpha- and beta-naphthoflavone, and Aroclor 1254 (known to be inducers of various mixed-function oxidases) are strong repressors of DMN-demethylase. Aminoacetonitrile, a strong inhibitor of carcinogenesis by DMN, is also a potent repressor of DMN-demethylase. The enzyme is inhibited by pretreatment of the animals with cobaltous chloride, an inhibitor of the synthesis of cytochrome P-450. Pregnenolone-16alpha-carbonitrile and 3-methylcholanthrene, despite their similarity of action on DMN-demethylase, have different effects on azo reductase, which is repressed by the former and induced by the latter compound.
对58种多环芳烃的研究表明，要抑制大鼠肝脏中二甲基亚硝胺（DMN）的去甲基化，这些烃类必须满足有关分子几何结构在大小、形状和共面性方面的特定要求。用占据的二维面积来表示这些平面化合物的分子大小，最大抑制活性的大小范围在约85至150 Ų之间。除了处于正确的分子大小范围内，这些烃类还必须具有细长而非紧凑的分子形状；圆形和/或高度对称的烃类，如晕苯、三亚苯、椭圆烯和四苯并萘，尽管处于最佳大小范围内，但活性很低或无活性。分子的共面性是一个关键要求；因此，强效致癌物9,10 - 二甲基 - 1,2 - 苯并蒽作为DMN - 去甲基酶合成的抑制剂是无活性的。两个例外，荧蒽和苯并[ghi]荧蒽，显示出对DMN - 去甲基酶有显著诱导作用。抑制DMN - 去甲基酶的烃类的分子大小分布与先前报道的诱导偶氮染料N - 去甲基酶的分子大小要求呈现出镜像关系。除烃类以外的化合物在某种意义上也呈现出镜像关系，即孕烯醇酮 - 16α - 腈、α - 和β - 萘黄酮以及多氯联苯混合物Aroclor 1254（已知是各种混合功能氧化酶的诱导剂）是DMN - 去甲基酶的强抑制剂。氨基乙腈是DMN致癌作用的强抑制剂，也是DMN - 去甲基酶的有效抑制剂。用氯化钴（细胞色素P - 450合成的抑制剂）对动物进行预处理可抑制该酶。孕烯醇酮 - 16α - 腈和3 - 甲基胆蒽，尽管它们对DMN - 去甲基酶的作用相似，但对偶氮还原酶有不同的影响，前者抑制偶氮还原酶，后者诱导偶氮还原酶。
