McGregor D B, Riach C G, Brown A, Edwards I, Reynolds D, West K, Willington S
Department of Mutagenic and Cellular Toxicology, Inveresk Research International Limited, Musselburgh, Scotland.
Environ Mol Mutagen. 1988;11(4):523-44. doi: 10.1002/em.2850110413.
Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of several catecholamines and related compounds were examined. No supplementary metabolic activation systems were used. In the mouse lymphoma assay, the dihydroxybenzenes catechol and hydroquinone had similar and appreciable mutagenic potentials, whereas resorcinol was less active. Derivatives of catechol, such as dopamine and epinephrine, were mutagenic, whereas the related monohydroxylated compounds tyramine and synephrine were inactive. The primary amine, arterenol, and the corresponding secondary amine, epinephrine, induced similar mutagenic responses. Carboxylation of the side chain of dopamine, giving L-dopa, reduced the maximum mutagenic response. The introduction of charged groups directly on to the aromatic ring also reduced mutagenic activity, while an intervening methylene reversed this effect. Thus, 3,4-dihydroxyhydrocinnamic acid was more active than 3,4-dihydroxybenzoic acid. The compound active at the lowest doses was 4-tert-butyl catechol. The activities of these compounds are highly dependent upon substituent groups. Experiments with superoxide dismutase gave circumstantial evidence for some of the mutagenic activity being due to superoxide anion. Active oxygen species might be responsible for some of the observed effects, but this cannot be concluded from the superoxide dismutase experiments. Mutagenic responses in Salmonella were very low but were significant for L-dopa in three strains and for epinephrine and arterenol in one strain. Limited DNA association studies of 14C-dopamine suggest interactions in L5178Y and Salmonella cells and in mouse liver. The mutagenicity of dopamine in L5178Y is reduced by high serum concentrations during the exposure period, while the apparent association with DNA is unaffected.
利用L5178Y小鼠淋巴瘤细胞胸苷激酶基因座和沙门氏菌组氨酸基因座检测方法，对几种儿茶酚胺及相关化合物的诱变潜力进行了研究。未使用辅助代谢活化系统。在小鼠淋巴瘤检测中，二羟基苯类的儿茶酚和对苯二酚具有相似且明显的诱变潜力，而间苯二酚的活性较低。儿茶酚的衍生物，如多巴胺和肾上腺素，具有诱变作用，而相关的单羟基化化合物酪胺和辛内弗林则无活性。伯胺去甲肾上腺素和相应的仲胺肾上腺素诱导出相似的诱变反应。多巴胺侧链羧化生成L-多巴，降低了最大诱变反应。直接在芳环上引入带电基团也会降低诱变活性，而插入一个亚甲基则会逆转这种效应。因此，3,4-二羟基肉桂酸比3,4-二羟基苯甲酸更具活性。在最低剂量下具有活性的化合物是4-叔丁基儿茶酚。这些化合物的活性高度依赖于取代基。超氧化物歧化酶实验提供的间接证据表明，部分诱变活性归因于超氧阴离子。活性氧可能是部分观察到的效应的原因，但这不能从超氧化物歧化酶实验中得出结论。沙门氏菌中的诱变反应非常低，但L-多巴在三个菌株中以及肾上腺素和去甲肾上腺素在一个菌株中的诱变反应显著。对14C-多巴胺的有限DNA结合研究表明，其在L5178Y细胞、沙门氏菌细胞和小鼠肝脏中存在相互作用。在暴露期间，高血清浓度会降低L5178Y细胞中多巴胺的诱变性，而其与DNA的明显结合不受影响。
