Erdinger L, Schmezer P, Razdan R, Kumar R, Spiegelhalder B, Preussmann R, Siddiqi M
Hygiene Institute, University of Heidelberg, Germany.
Mutat Res. 1993 Aug;292(1):41-9. doi: 10.1016/0165-1161(93)90006-l.
Mutagenesis in S. typhimurium and in vitro induction of DNA single-strand breaks in primary rat hepatocytes (DNA-SSB) have been investigated for two new N-nitroso compounds, mononitrosocaffeidine (MNC) and dinitrosocaffeidine (DNC). Mononitrosamidocaffeidine (MNAC) and tert.-(butyloxy)carbonyl-mononitrosamidocaffeidine (t-BOC-MNAC), both nitrosated derivatives of caffeidine with nitrosation at methylcarboxamide-N only, were also similarly studied. MNC, an asymmetric nitrosamine, failed to show mutagenicity in any of the tester strains used, and also did not induce DNA-SSB in rat hepatocytes. DNC, having both N-nitrosamide and N-nitrosamine groups in the molecule, showed direct mutagenicity in TA100, TA1535 and TA102. The mutagenic potential of the compound was found to increase on S9 activation. However, it was non-mutagenic in TA98 and TA1537. DNC also exhibited a high potential for inducing alkali-labile DNA-SSB in rat hepatocytes (70-78% C-T value) and was cytotoxic at concentrations over 0.1 mumole/ml. Both MNC and DNC were found to produce formaldehyde on S9 activation. MNAC was not mutagenic directly but showed weak mutagenicity on metabolic activation, whereas t-BOC-MNAC was mutagenic both with and without S9 activation in TA100, TA1535 and TA102. t-BOC-MNAC was more cytotoxic to hepatocytes than MNAC, though both caused DNA-SSB to the same extent (62% C-T value). On the basis of the presented data it is inferred that while DNC is a direct-acting mutagen in TA100, TA1535 and TA102 due to the presence of a reactive N-methylnitrosamido group, its mutagenic potential is greatly enhanced in the presence of S9 possibly due to the synergistic influence of an activated N-methylnitrosamino group in the molecule. Additionally, the study shows a qualitative consistency between Salmonella mutagenicity, genotoxicity in hepatocytes and the reactivity of the methyl group at the nitrosamido-N in nitrosated caffeidine compounds.
已针对两种新型N-亚硝基化合物单亚硝基咖啡定（MNC）和二亚硝基咖啡定（DNC），研究了它们在鼠伤寒沙门氏菌中的诱变作用以及对原代大鼠肝细胞DNA单链断裂（DNA-SSB）的体外诱导作用。还对仅在甲基甲酰胺-N处发生亚硝化的咖啡定的两种亚硝化衍生物单亚硝基酰胺基咖啡定（MNAC）和叔丁氧羰基-单亚硝基酰胺基咖啡定（t-BOC-MNAC）进行了类似研究。MNC是一种不对称亚硝胺，在所使用的任何测试菌株中均未显示出诱变性，在大鼠肝细胞中也未诱导DNA-SSB。DNC分子中同时含有N-亚硝酰胺基和N-亚硝胺基，在TA100、TA1535和TA102中表现出直接诱变性。发现该化合物经S9活化后诱变潜力增加。然而，它在TA98和TA1537中无诱变性。DNC在大鼠肝细胞中也具有诱导碱不稳定DNA-SSB的高潜力（C-T值为70-78%），并且在浓度超过0.1微摩尔/毫升时具有细胞毒性。发现MNC和DNC经S9活化后均产生甲醛。MNAC本身无诱变性，但在代谢活化时表现出弱诱变性，而t-BOC-MNAC在TA100、TA1535和TA102中无论有无S9活化均具有诱变性。t-BOC-MNAC对肝细胞的细胞毒性比MNAC更强，尽管二者导致DNA-SSB的程度相同（C-T值为62%）。根据所呈现的数据推断，由于存在反应性N-甲基亚硝酰胺基，DNC在TA100、TA1535和TA102中是直接作用的诱变剂，其诱变潜力在S9存在时可能由于分子中活化的N-甲基亚硝胺基的协同作用而大大增强。此外，该研究表明沙门氏菌诱变性、肝细胞中的遗传毒性与亚硝化咖啡定化合物中亚硝酰胺-N处甲基的反应性之间存在定性一致性。
