CENTRAL ROLE OF RADICAL CATIONS IN METABOLIC-ACTIVATION OF POLYCYCLIC AROMATIC-HYDROCARBONS
CENTRAL ROLE OF RADICAL CATIONS IN METABOLIC-ACTIVATION OF POLYCYCLIC AROMATIC-HYDROCARBONS
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DOI：
10.3109/00498259509061885
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发表时间：
1995-07-01
期刊：
影响因子：
1.8
通讯作者：
ROGAN, EG
中科院分区：
文献类型：
--
作者：
CAVALIERI, EL;ROGAN, EG
1.多环芳烃（PAH）自由基阳离子化学的发展提供了证据，表明这些中间体在P450代谢多环芳烃及其与DNA的结合中起着重要作用.苯并[a]芘（BP）的氟取代反应是研究P450催化BP生成醌类和酚类反应中氧转移机理的合适探针。由6-氟BP（6-FBP）代谢形成BP-1，6-、-3，6-和-6，12-二酮由中间体6-FBP+介导。类似地，1-FBP和3-FBP通过大鼠肝微粒体的代谢分别产生BP-1，6-二酮和BP-3，6-二酮。这些结果表明，醌类和酚类的形成是通过从BP到P450的初始电子转移和随后从P450的铁矿石络合物到BP的氧转移而发生的。自由基阳离子也在强致癌物7，12-二甲基苯并[a]蒽（DMBA）、BP和二苯并[a，l]芘（DB[a，l]P）形成DNA加合物中起主要作用。在BP的体内外结合中，80%的加合物是通过单电子氧化形成的，即8-（BP-B-yl）guanine（BP-6-C8 Gua），BP-6-N7 Gua和BP-6-N7 adenine（Ade），并通过脱嘌呤作用从DNA中丢失。对于DB[a，l]P，由自由基阳离子形成的脱嘌呤加合物DB[a，l]P-10-C8 Gua、DB[a，l]P-10-N7 Gua、DB[a，l]P-10-N7 Ade和DB[a，l]P-10-N3 Ade占总DNA加合物的50%。对于DMBA，99%的加合物是由自由基阳离子7-CH（3）BA-12-CH 2-N7 Gua和7-CH（3）BA-12-CH 2-N7 Ad形成的脱嘌呤加合物。总之，多环芳烃的自由基阳离子在代谢和代谢活化中起着重要作用，导致形成DNA加合物，这在肿瘤起始机制中至关重要。
1. Development of the chemistry of polycyclic aromatic hydrocarbon (PAH) radical cations has provided evidence that these intermediates play a major role in the metabolism of PAHs by P450 and in their binding to DNA.2. Fluoro substitution of benzo[a]pyrene (BP) represents a suitable probe for studying mechanisms of oxygen transfer in the P450-catalysed formation of quinones and phenols from BP. Formation of BP-1,6-, -3,6- and -6,12-dione from the metabolism of 6-fluoroBP (6-FBP) is mediated by the intermediate 6-FBP.+. Similarly, metabolism of 1-FBP and 3-FBP by rat liver microsomes produces BP-1,6-dione and BP-3,6-dione respectively. These results demonstrate that formation of quinones and phenols occurs via an initial electron transfer from BP to P450 and subsequent transfer of oxygen from the iron-ore complex of P450 to BP.3. Radical cations also play a major role in the formation of DNA adducts by the potent carcinogens 7,12-dimethylbenz[a]anthracene (DMBA), BP and dibenzo[a,l]pyrene (DB[a,l]P). In the binding of BP both in vitro and in vivo, 80% of the adducts are formed by one-electron oxidation, namely, 8-(BP-B-yl)guanine (BP-6-C8Gua), BP-6-N7Gua and BP-6-N7adenine (Ade), and are lost from the DNA by depurination. For DB[a,l]P, depurinating adducts formed from the radical cation, DB[a,l]P-10-C8Gua, DB[a,l]P-10-N7Gua, DB[a,l]P-10-N7Ade, and DB[a,l]P-10-N3Ade comprise 50% of the total DNA adducts. For DMBA, 99% of the adducts are depurinating adducts formed from the radical cation, 7-CH(3)BA-12-CH2-N7Gua and 7-CH(3)BA-12-CH2-N7Ade.4. In summary, radical cations of PAHs play a major role in both the metabolism and metabolic activation leading to formation of DNA adducts that are critical in the mechanism of tumour initiation.