Agarwal R, Coffing S L, Baird W M, Harvey R G, Dipple A
ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
Chem Res Toxicol. 1999 May;12(5):437-41. doi: 10.1021/tx980258r.
The tumor initiating activities of 4H-cyclopenta[def]chrysene (C[def]C) and its two putative reactive metabolites, trans-1, 2-dihydroxy-anti-3,3a-epoxy-1,2,3, 3a-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-3,3a-DE) and trans-6,7-dihydroxy-anti-8,9-epoxy-6,7,8, 9-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-8,9-DE), were evaluated previously in mice [Amin, S., et al. (1995) Carcinogenesis 16, 2813-2817]. C[def]C-3,3a-DE was the more active inducer of lung tumors and elicited twice as many tumors as C[def]C-8,9-DE. In this study, the route of metabolism of C[def]C to DNA-reactive metabolites in the human mammary carcinoma cell line (MCF-7) was investigated using the 32P-postlabeling assay. The results show that metabolic activation to DNA-binding species proceeds through the formation of both trans-1,2-dihydrodiol and trans-6,7-dihydrodiol metabolites of C[def]C. At a 1 microM dose, adducts from the methylene-bridged (C[def]C-3,3a-DE) and bay region (C[def]C-8,9-DE) dihydrodiol epoxides were detected in comparable amounts. In contrast, the majority of the postlabeled adducts recovered from cells exposed to a 10 microM dose were derived from the bay region dihydrodiol epoxide, C[def]C-8,9-DE. Using markers from reactions of the dihydrodiol epoxides with deoxyguanosine 3'-phosphate and deoxyadenosine 3'-phosphate, it was shown that the major radioactive spots formed with both anti-C[def]C-3,3a-DE and anti-C[def]C-8,9-DE chromatographed with deoxyguanosine adduct markers. Thus, the human cells used in these studies can activate C[def]C to carcinogenic metabolites.
4H-环戊并[def]苯并菲（C[def]C）及其两种假定的反应性代谢物，反式-1,2-二羟基-反式-3,3a-环氧-1,2,3,3a-四氢-4H-环戊并[def]苯并菲（C[def]C-3,3a-DE）和反式-6,7-二羟基-反式-8,9-环氧-6,7,8,9-四氢-4H-环戊并[def]苯并菲（C[def]C-8,9-DE）的肿瘤起始活性先前已在小鼠中进行了评估[Amin, S., 等人 (1995) 《癌变》16, 2813 - 2817]。C[def]C-3,3a-DE是更具活性的肺肿瘤诱导剂，引发的肿瘤数量是C[def]C-8,9-DE的两倍。在本研究中，使用32P后标记分析法研究了C[def]C在人乳腺癌细胞系（MCF-7）中代谢为DNA反应性代谢物的途径。结果表明，代谢活化为与DNA结合的物质是通过形成C[def]C的反式-1,2-二氢二醇和反式-6,7-二氢二醇代谢物进行的。在1微摩尔剂量下，检测到来自亚甲基桥连（C[def]C-3,3a-DE）和湾区（C[def]C-8,9-DE）二氢二醇环氧化物的加合物数量相当。相比之下，从暴露于10微摩尔剂量的细胞中回收的大多数后标记加合物来自湾区二氢二醇环氧化物C[def]C-8,9-DE。使用二氢二醇环氧化物与脱氧鸟苷3'-磷酸和脱氧腺苷3'-磷酸反应的标记物表明，与反式-C[def]C-3,3a-DE和反式-C[def]C-8,9-DE形成的主要放射性斑点与脱氧鸟苷加合物标记物一起进行色谱分析。因此，这些研究中使用的人类细胞可以将C[def]C活化为致癌代谢物。
