Fu P P, Heflich R H, Von Tungeln L S, Miranda H Z, Evans F E
National Center for Toxicological Research, Jefferson, AR 72079.
Carcinogenesis. 1988 Jun;9(6):951-8. doi: 10.1093/carcin/9.6.951.
Aerobic metabolism of 1-nitrobenzo[e]pyrene (1-nitro-BeP) by rat liver microsomes produced 1-nitro-BeP trans-4,5-dihydrodiol, 6-hydroxy-1-nitro-BeP, and 8-hydroxy-1-nitro-BeP. When 3,3,3-trichloropropylene 1,2-oxide was incorporated into the metabolism, 1-nitro-BeP 4,5-oxide was the predominant metabolite, and 1-nitro-BeP trans-4,5-dihydrodiol was not detected. All of the metabolites were purified by both reversed- and normal-phase HPLC and characterized by analysis of their mass and 500 MHz proton NMR spectral data. 1-Nitro-BeP was not metabolized under hypoxic conditions. 1-Nitro-BeP and its four metabolites were assayed in Salmonella typhimurium tester strains TA98, TA98NR and TA98/1,8-DNP6, both in the presence and absence of S9 activation. As predicted, 1-nitro-BeP was a weak mutagen without S9 (2 revertants/micrograms in TA98); the addition of S9 resulted in approximately 18, 17 and 4 revertants/micrograms in TA98, TA98NR and TA98/1,8-DNP6 respectively. The two phenolic metabolites were mutagenic both in the presence and absence of S9, producing moderate responses (19-84 revertants/micrograms). In addition, while the 1-nitro-BeP 4,5-oxide was only weakly mutagenic in TA98 (6-14 revertants/micrograms), 1-nitro-BeP trans-4,5-dihydrodiol was unexpectedly potent (approximately 300 revertants/micrograms both with and without S9). These results indicate that microsomal epoxidation of 1-nitro-BeP followed by epoxide hydrolase-catalyzed hydrolysis of the resulting epoxide to the 1-nitro-BeP trans-4,5-dihydrodiol results in the most potent mutagenic derivatives. The weak mutagenicity of 1-nitro-BeP 4,5-oxide demonstrates that not all epoxides of nitrated polycyclic aromatic hydrocarbons (PAHs) are more mutagenic than the corresponding parent nitro-PAHs. Also, the lower S9-mediated mutagenicity of 1-nitro-BeP in TA98/1,8-DNP6 compared with TA98 indicates that the mutagenicity of 1-nitro-BeP is dependent upon nitroreduction and transesterification. Finally, we previously hypothesized that nitrated PAHs with their nitro substituents perpendicular or nearly perpendicular to the aromatic rings are very weak or nondirect-acting mutagens in Salmonella typhimurium tester strains. The results reported in this communication demonstrate that ring-oxidized derivatives of nitro-PAHs do not always follow this structure--mutagenicity correlation.
大鼠肝微粒体对1-硝基苯并[e]芘（1-nitro-BeP）的需氧代谢产生了1-nitro-BeP反式-4,5-二氢二醇、6-羟基-1-nitro-BeP和8-羟基-1-nitro-BeP。当将3,3,3-三氯丙烯1,2-氧化物引入代谢过程时，1-nitro-BeP 4,5-氧化物是主要代谢产物，未检测到1-nitro-BeP反式-4,5-二氢二醇。所有代谢产物均通过反相和正相高效液相色谱法进行纯化，并通过分析其质谱和500兆赫质子核磁共振光谱数据进行表征。1-nitro-BeP在缺氧条件下未发生代谢。在有和没有S9激活的情况下，对鼠伤寒沙门氏菌测试菌株TA98、TA98NR和TA98/1,8-DNP6中的1-nitro-BeP及其四种代谢产物进行了检测。正如所预测 的，1-nitro-BeP在没有S9时是一种弱诱变剂（在TA98中为2个回复突变体/微克）；添加S9后，TA98、TA9NR和TA98/1,8-DNP6中分别产生约18、17和4个回复突变体/微克。这两种酚类代谢产物在有和没有S9的情况下均具有诱变性，产生中等反应（19 - 84个回复突变体/微克）。此外，虽然1-nitro-BeP 4,5-氧化物在TA98中仅具有弱诱变性（6 - 14个回复突变体/微克），但1-nitro-BeP反式-4,5-二氢二醇却出乎意料地具有强效诱变性（无论有无S9均约为300个回复突变体/微克）。这些结果表明，1-nitro-BeP的微粒体环氧化作用，随后环氧化物水解酶将生成的环氧化物催化水解为1-nitro-BeP反式-4,5-二氢二醇，会产生最具强效的诱变衍生物。1-nitro-BeP 4,5-氧化物的弱诱变性表明，并非所有硝化多环芳烃（PAHs）的环氧化物都比相应的母体硝基-PAHs更具诱变性。此外，与TA98相比，1-nitro-BeP在TA98/1,8-DNP6中较低的S9介导诱变性表明，1-nitro-BeP的诱变性取决于硝基还原和转酯作用。最后，我们之前假设，其硝基取代基垂直或几乎垂直于芳环的硝化PAHs在鼠伤寒沙门氏菌测试菌株中是非常弱 的或非直接作用的诱变剂。本通讯报道的结果表明，硝基-PAHs的环氧化衍生物并不总是遵循这种结构-诱变性相关性。
