Friesen M, O'Neill I K, Malaveille C, Garren L, Hautefeuille A, Cabral J R, Galendo D, Lasne C, Sala M, Chouroulinkov I
Mutat Res. 1985 Jun-Jul;150(1-2):177-91. doi: 10.1016/0027-5107(85)90114-9.
Previous epidemiological studies have indicated an association between the ingestion of opium pyrolysates, dietary deficiencies, and a high incidence of oesophageal cancer in subjects in north-east Iran. Laboratory studies have shown that pyrolysates of opium and particularly of morphine, a major opium alkaloid, are highly mutagenic in bacteria and induce sister-chromatid exchanges in mammalian cells after metabolic activation. We now report the ability of these pyrolysates to transform Syrian hamster embryo cells in culture and present some evidence for their carcinogenicity in mice and hamsters following topical, subcutaneous, intratracheal and intragastric administration. 6 of the most abundant mutagenic compounds present in morphine pyrolysate were isolated and purified by high-performance liquid chromatography and characterized by gas chromatography/mass spectrometry and 1H-Fourier transform nuclear magnetic resonance spectroscopy. These hitherto unknown compounds, all containing a hydroxy-phenanthrene moiety, were identified as: 3-methyl-3H-naphth[1,2-e]indol-10-ol; 1,2-dihydro-3-methyl-3H-naphth[1,2-e]indol-10-ol; 6-methylaminophenanthren-3-ol; 2-methylphenanthro[3,4-d] [1,3]oxazol-10-ol; 2,3-dimethyl-3H-phenanthro[3,4-d]imidazol-10-ol and 2-methyl-3H-phenanthro[3,4-d]imidazol-10-ol. Mutagenicity in Salmonella typhimurium TA98 of these compounds increased in the order listed, the last compound being 35 times more active than benzo[a]pyrene. The mechanisms, by which these mutagens are formed and metabolically activated are discussed.
以往的流行病学研究表明，在伊朗东北部地区，摄入鸦片热解产物、饮食缺乏与食管癌高发之间存在关联。实验室研究表明，鸦片尤其是主要鸦片生物碱吗啡的热解产物在细菌中具有高度致突变性，并在代谢激活后诱导哺乳动物细胞发生姐妹染色单体交换。我们现在报告这些热解产物在培养中转化叙利亚仓鼠胚胎细胞的能力，并提供一些证据证明它们在局部、皮下、气管内和胃内给药后对小鼠和仓鼠具有致癌性。通过高效液相色谱法分离并纯化了吗啡热解产物中6种最丰富的致突变化合物，并通过气相色谱/质谱法和1H-傅里叶变换核磁共振光谱法对其进行了表征。这些迄今未知的化合物均含有一个羟基菲部分，分别被鉴定为：3-甲基-3H-萘并[1,2-e]吲哚-10-醇；1,2-二氢-3-甲基-3H-萘并[1,2-e]吲哚-10-醇；6-甲基氨基菲-3-醇；2-甲基菲并[3,4-d][1,3]恶唑-10-醇；2,3-二甲基-3H-菲并[3,4-d]咪唑-10-醇和2-甲基-3H-菲并[3,4-d]咪唑-10-醇。这些化合物在鼠伤寒沙门氏菌TA98中的致突变性按所列顺序增加，最后一种化合物的活性比苯并[a]芘高35倍。本文讨论了这些诱变剂的形成和代谢激活机制。
