Carmichael P L, Platt K L, Shé M N, Lecoq S, Oesch F, Phillips D H, Grover P L
Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom.
Cancer Res. 1993 Mar 1;53(5):944-8.
Dibenz[a,h]anthracene (DB[a,h]A) and its microsomal metabolites, trans-3,4-dihydro-3,4-dihydroxydibenz[a,h]anthracene (DBA-3,4-diol), trans,trans-3,4:8,9-tetrahydro-3,4:8,9-tetrahydroxydibenz[a,h]anth racene, trans,trans-3,4:10,11-tetrahydro-3,4:10,11-tetrahydroxydibenz[a,h] - anthracene (DBA-3,4,10,11-bis-diol) and trans,trans-3,4:12,13-tetrahydro-3,4:12,13- tetrahydroxydibenz[a,h]anthracene were each applied topically to mouse skin and the epidermal DNA isolated 24 h later. 32P-postlabeling analysis of each of the DNA samples was performed. DNA from mice treated with DB[a,h]A produced an adduct map on TLC consisting of one major and three minor adduct spots. A similar pattern of spots was produced by DBA-3,4-diol. No detectable DNA adducts were produced by trans,trans-3,4:12,13-tetrahydro-3,4:12,13-tetrahydroxy- dibenz[a,h]anthracene, although a single, minor adduct spot was produced by trans,trans-3,4:8,9-tetrahydro-3,4:8,9-tetrahydroxydibenz[a,h]- anthracene. However, DBA-3,4,10,11-bis-diol was found to produce a major single adduct that comigrated on thin layer chromatography with the major adduct produced by both DB[a,h]A and DBA-3,4-diol. In addition, this adduct was present at a level 10 times higher than the corresponding adduct produced by treatment with the parent hydrocarbon. Coelution of the major adducts formed from DB[a,h]A and DBA-3,4-diol with that formed from DBA-3,4,10,11-bis-diol was also demonstrated on reverse-phase high performance liquid chromatography. Thus, we propose that, in mouse skin, the major pathway of DB[a,h]A activation to DNA binding products is via a 3,4-diol to the 3,4,10,11-bis-diol and ultimately to a bis-diol-epoxide (potentially the 3,4,10,11-bis-dihydrodiol-1,2-oxide).
将二苯并[a,h]蒽（DB[a,h]A）及其微粒体代谢产物反式-3,4-二氢-3,4-二羟基二苯并[a,h]蒽（DBA-3,4-二醇）、反式,反式-3,4:8,9-四氢-3,4:8,9-四羟基二苯并[a,h]蒽、反式,反式-3,4:10,11-四氢-3,4:10,11-四羟基二苯并[a,h]蒽（DBA-3,4,10,11-双二醇）和反式,反式-3,4:12,13-四氢-3,4:12,13-四羟基二苯并[a,h]蒽分别局部涂抹于小鼠皮肤，24小时后分离表皮DNA。对每个DNA样本进行32P后标记分析。用DB[a,h]A处理的小鼠的DNA在薄层层析上产生了一个加合物图谱，由一个主要加合物斑点和三个次要加合物斑点组成。DBA-3,4-二醇产生了类似的斑点模式。反式,反式-3,4:12,13-四氢-3,4:12,13-四羟基二苯并[a,h]蒽未产生可检测到的DNA加合物，尽管反式,反式-3,4:8,9-四氢-3,4:8,9-四羟基二苯并[a,h]蒽产生了一个单一的次要加合物斑点。然而，发现DBA-3,4,10,11-双二醇产生了一个主要的单一加合物，该加合物在薄层层析上与DB[a,h]A和DBA-3,4-二醇产生的主要加合物共迁移。此外，该加合物的水平比用母体烃处理产生的相应加合物高10倍。在反相高效液相色谱上也证明了由DB[a,h]A和DBA-3,4-二醇形成的主要加合物与由DBA-3,4,10,11-双二醇形成的主要加合物的共洗脱。因此，我们提出，在小鼠皮肤中，DB[a,h]A激活生成DNA结合产物的主要途径是通过3,4-二醇生成3,4,10,11-双二醇，并最终生成双二醇环氧化物（可能是3,4,10,11-双氢二醇-1,2-氧化物）。
