Buhler D R, Unlu F, Thakker D R, Slaga T J, Newman M S, Levin W, Conney A H, Jerina D M
Cancer Res. 1982 Nov;42(11):4779-83.
The skin tumor-initiating activities of 7-, 8-, 9-, and 10-fluorobenzo(a)pyrenes have been compared to that of benzo(a)pyrene in female Sencar mice after 16 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Single initiating doses of 200 or 400 nmol of each hydrocarbon were tested, and the mice were treated twice weekly with 3.2 nmol of the promoter. Under these conditions, benzo(a)pyrene caused an average of 2.9 and 5.7 papillomas/mouse, respectively, whereas none of the four fluorinated hydrocarbons had significant tumor-initiating activity. Examination of the hepatic metabolism of 7- and 8-fluorobenzo(a)pyrene revealed that a 7,8-dihydrodiol was not detected as a metabolite; thus, the bay-region diol-epoxide pathway known to be responsible for the tumorigenic activity of benzo(a)pyrene is blocked. Although 7,8-dihydrodiols are formed from 9- and 10-fluorobenzo(a)pyrene, these dihydrodiols with fluorine substituted on the 9,10-double bond may not be converted to diol-epoxides by the cytochrome P-450 system, or such fluorinated 7,8-diol-9,10-epoxides may not be tumorigenic.
在用12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯促进16周后，比较了7 -、8 -、9 - 和10 - 氟苯并(a)芘与苯并(a)芘在雌性Sencar小鼠中的皮肤肿瘤起始活性。测试了每种碳氢化合物200或400 nmol的单次起始剂量，并且每周两次用3.2 nmol的促进剂处理小鼠。在这些条件下，苯并(a)芘分别导致平均每只小鼠2.9个和5.7个乳头状瘤，而四种氟化碳氢化合物均没有显著的肿瘤起始活性。对7 - 和8 - 氟苯并(a)芘的肝脏代谢检查显示未检测到7,8 - 二氢二醇作为代谢产物；因此，已知负责苯并(a)芘致癌活性的湾区二醇环氧化物途径被阻断。尽管9 - 和10 - 氟苯并(a)芘形成了7,8 - 二氢二醇，但这些在9,10 - 双键上有氟取代的二氢二醇可能不会被细胞色素P - 450系统转化为二醇环氧化物，或者这种氟化的7,8 - 二醇 - 9,10 - 环氧化物可能没有致癌性。
