Nesnow S, Ross J, Beck S, Lasley J, Nelson G, Lambert G, Platt K L, Agarwal S C
Carcinogenesis and Metabolism Branch, US Environmental Protection Agency, Research Triangle Park, NC 27711.
Carcinogenesis. 1994 Oct;15(10):2225-31. doi: 10.1093/carcin/15.10.2225.
The major routes of metabolic activation of dibenz[a,h]-anthracene (DBA) have been studied in transformable C3H10T1/2CL8 (C3H10T1/2) mouse embryo fibroblasts in culture. The morphological transforming activities of three potential intermediates formed by metabolism of DBA by C3H10T1/2 cells, trans-3,4-dihydroxy-3,4-dihydro-DBA-(DBA-3,4-diol), trans-dihydroxy-3,4-dihydro-DBA-anti-1,2-oxide (DBA-3,4-diol-1,2-oxide) and DBA-5,6-oxide were determined. DBA-3,4-diol-1,2-oxide was a strong morphological transforming agent giving a mean of 73% dishes with Type II or III foci and 1.63 Type II and III foci per dish at 0.5 microgram/ml. DBA-3,4-diol produced a mean of 42% dishes with Type II or III foci and 0.81 Type II and III foci per dish at 2.5 micrograms/ml. DBA gave a mean of 24% dishes with Type II or III foci and 0.29 Type II and III foci per dish at 2.5 micrograms/ml. DBA-5,6-oxide was found to be inactive. DNA adducts of DBA, DBA-3,4-diol, DBA-3,4-diol-1,2-oxide, DBA-1,4/2,3-tetrol and DBA-5,6-oxide in C3H10T1/2 cells were analyzed by 32P-postlabeling method. DBA gave 11 adducts, nine of which were observed in the DNA of cells treated with DBA-3,4-diol and seven from cells treated with DBA-3,4-diol-1,2-oxide. Two of these adducts that appear in each of the treatment groups have been identified as the product of the interaction of DBA-3,4-diol-1,2-oxide with 2'-deoxyguanosine. Furthermore, there is evidence for DBA-DNA adducts in cells treated with DBA, DBA-3,4-diol and DBA-3,4-diol-1,2-oxide arising from metabolism to (+,-)-trans,trans-3,4,10,11-tetrahydroxy-3,4,10,11-tetrahydro-DBA (DBA-3,4,10,11-bis-diol). These results are based on co-migration of C3H10T1/2 DNA adducts with skin DNA adducts formed after topical treatment of mice with DBA-3,4,10,11-bis-diol. In C3H10T1/2 cells, DBA is metabolically activated through DBA-3,4-diol, which is further activated via the DBA-3,4-diol-1,2-oxide and DBA-3,4,10,11-bis-diol pathways. No evidence is provided for the metabolism of DBA by the K-region pathway.
在可转化的C3H10T1/2CL8（C3H10T1/2）小鼠胚胎成纤维细胞培养物中，研究了二苯并[a,h]蒽（DBA）的主要代谢活化途径。测定了C3H10T1/2细胞对DBA进行代谢形成的三种潜在中间体，即反式-3,4-二羟基-3,4-二氢-DBA-（DBA-3,4-二醇）、反式二羟基-3,4-二氢-DBA-反式-1,2-氧化物（DBA-3,4-二醇-1,2-氧化物）和DBA-5,6-氧化物的形态转化活性。DBA-3,4-二醇-1,2-氧化物是一种强效的形态转化剂，在0.5微克/毫升时，平均有73%的培养皿出现II型或III型病灶，每个培养皿有1.63个II型和III型病灶。DBA-3,4-二醇在2.5微克/毫升时，平均有42%的培养皿出现II型或III型病灶，每个培养皿有0.81个II型和III型病灶。DBA在2.5微克/毫升时，平均有24%的培养皿出现II型或III型病灶，每个培养皿有0.29个II型和III型病灶。发现DBA-5,6-氧化物无活性。采用32P后标记法分析了C3H10T1/2细胞中DBA、DBA-3,4-二醇、DBA-3,4-二醇-1,2-氧化物、DBA-1,4/2,3-四醇和DBA-5,6-氧化物的DNA加合物。DBA产生了11种加合物，其中9种在经DBA-3,4-二醇处理的细胞DNA中观察到，7种在经DBA-3,4-二醇-1,2-氧化物处理的细胞DNA中观察到。在每个处理组中出现的两种加合物已被鉴定为DBA-3,4-二醇-1,2-氧化物与2'-脱氧鸟苷相互作用的产物。此外，有证据表明，在用DBA、DBA-3,4-二醇和DBA-3,4-二醇-1,2-氧化物处理的细胞中，DBA-DNA加合物是由代谢生成（±）-反式，反式-3,4,10,11-四羟基-3,4,10,11-四氢-DBA（DBA-3,4,10,11-双二醇）产生的。这些结果是基于C3H10T1/2细胞DNA加合物与用DBA-3,4,10,11-双二醇局部处理小鼠后形成的皮肤DNA加合物的共迁移得出的。在C3H10T1/2细胞中，DBA通过DBA-3,4-二醇进行代谢活化，DBA-3,4-二醇再通过DBA-3,4-二醇-1,2-氧化物和DBA-3,4,10,11-双二醇途径进一步活化。没有证据表明DBA通过K区域途径进行代谢。
