Padgett W T, Davis C, Lambert G, Nelson G B, Ross J A, Yacopucci M, Nesnow S
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, MD-68, Research Triangle Park, North Carolina 27711, USA.
Chem Res Toxicol. 2000 Nov;13(11):1125-34. doi: 10.1021/tx000111b.
The biotransformation of (+/-)-trans-4,5-dihydroxy-4, 5-dihydrobenzo[a]pyrene (trans-B[a]P-4,5-diol), the K-region dihydrodiol of B[a]P, by beta-naphthoflavone (BNF)-induced rat liver microsomes was studied. trans-B[a]P-4,5-diol was metabolized to six major products as characterized by NMR, MS, and UV spectroscopy, and all were identified as bis-diols: two diastereomers of trans,trans-4, 5:7,8-tetrahydroxy-4,5:7,8-tetrahydrobenzo[a]pyrene (trans, trans-B[a]P-4,5:7,8-bis-diol), two diastereomers of trans,trans-4, 5:9,10-tetrahydroxy-4,5:9,10-tetrahydrobenzo[a]pyrene (trans, trans-B[a]P-4,5:9,10-bis-diol), and two diastereomers of the somewhat unusual trans,trans-1,2:4,5-tetrahydroxy-1,2:4, 5-tetrahydrobenzo[a]pyrene (trans,trans-B[a]P-1,2:4,5-bis-diol). BNF-induced rat liver microsomes also metabolized B[a]P to the same trans-B[a]P-4,5-diol-derived bis-diols. The ability of trans-B[a]P-4, 5-diol to form DNA adducts was investigated using (32)P-postlabeling techniques specifically designed to detect stable polar DNA adducts. Four DNA adducts were detected after microsomal activation of trans-B[a]P-4,5-diol with calf thymus DNA. Further analyses indicated that each of these stable polar DNA adducts was derived from the further metabolic activation of the trans,trans-B[a]P-4,5:7, 8-bis-diols. We conclude that trans-B[a]P-4,5-diol can be metabolized to a series of B[a]P-bis-diols, and can also be metabolically activated to form stable polar DNA adducts. The trans, trans-B[a]P-4,5:7,8-bis-diols were shown to be metabolic intermediates in the formation of these DNA adducts.
研究了β-萘黄酮（BNF）诱导的大鼠肝微粒体对（±）-反式-4,5-二羟基-4,5-二氢苯并[a]芘（反式-B[a]P-4,5-二醇）的生物转化，反式-B[a]P-4,5-二醇是苯并[a]芘的K区域二氢二醇。反式-B[a]P-4,5-二醇代谢为六种主要产物，通过核磁共振（NMR）、质谱（MS）和紫外光谱（UV）进行表征，所有产物均被鉴定为双二醇：反式，反式-4,5:7,8-四羟基-4,5:7,8-四氢苯并[a]芘（反式，反式-B[a]P-4,5:7,8-双二醇）的两种非对映异构体、反式，反式-4,5:9,10-四羟基-4,5:9,10-四氢苯并[a]芘（反式，反式-B[a]P-4,5:9,10-双二醇）的两种非对映异构体，以及有点不寻常的反式，反式-1,2:4,5-四羟基-1,2:4,5-四氢苯并[a]芘（反式，反式-B[a]P-1,2:4,5-双二醇）的两种非对映异构体。BNF诱导的大鼠肝微粒体也将苯并[a]芘代谢为相同的源自反式-B[a]P-4,5-二醇的双二醇。使用专门设计用于检测稳定极性DNA加合物的（32）P后标记技术研究了反式-B[a]P-4,5-二醇形成DNA加合物的能力。用小牛胸腺DNA对反式-B[a]P-4,5-二醇进行微粒体活化后，检测到四种DNA加合物。进一步分析表明这些稳定极性DNA加合物中的每一种都源自反式，反式-B[a]P-4,5:7,8-双二醇的进一步代谢活化。我们得出结论，反式-B[a]P-4,5-二醇可代谢为一系列苯并[a]芘双二醇，也可经代谢活化形成稳定的极性DNA加合物。反式，反式-B[a]P-4,5:7,8-双二醇被证明是这些DNA加合物形成过程中的代谢中间体。
