Tumorigenicity of enantiomers of chrysene 1,2-dihydrodiol and of the diastereomeric bay-region chrysene 1,2-diol-3,4-epoxides on mouse skin and in newborn mice.
Tumorigenicity of enantiomers of chrysene 1,2-dihydrodiol and of the diastereomeric bay-region chrysene 1,2-diol-3,4-epoxides on mouse skin and in newborn mice.
复制标题
1,2-二氢二醇对映体和湾区非对映体 1,2-二醇-3,4-环氧化物对小鼠皮肤和新生小鼠的致瘤性。
作者：
R. Chang;W. Levin;A. Wood;H. Yagi;M. Tada;K. Vyas;D. Jerina;A. Conney
摘要在两种肿瘤模型中评估了(+)-和(-)-反式-1,2-二羟基-1,2-二氢chrysene （chrysene 1,2-二氢二醇）以及(+)-和(-)-非对映异构体海湾区chrysene 1,2-二醇-3,4-环氧化物的致瘤性。在小鼠皮肤上单次局部应用0.4或1.2µmol的chrysene衍生物，然后用12- o - tetradecanoylphorbol13 -acetate促进25周，结果显示(-)-chrysene 1,2-二氢二醇的肿瘤启动活性大约是chrysene的两倍，而(+)-对映体没有明显的致瘤活性。在蒽-1,2 -二醇-3,4-环氧化合物的四个异构体中，只有(+)-1β，2α-二羟基-3α，4α-环氧-1,2,3,4-四氢蒽[(+)-二环氧化合物2]具有显著的致瘤活性，其中苯基羟基和环氧氧是反式的。（+）-二醇环氧化物2异构体具有与母体烃相同的肿瘤启动活性。在新生小鼠中，总剂量为0.7或1.4 μ mol的化合物分三次在出生后第1天、第8天和第15天进行腹腔注射，并在小鼠37至41周龄时测定其致瘤活性。对照动物平均每只小鼠产生0.13个肺肿瘤，而用(+)-环氧二醇2、(-)-蒽1,2-二氢二醇或外消旋蒽1,2-二氢二醇处理的动物平均每只小鼠每µmol化合物分别产生7.8、6.5和2.5个肺肿瘤。母体烃和所有其他被测试的衍生物在产生肺肿瘤方面基本上是无活性的。对于雄性小鼠的肝脏肿瘤，(-)-chrysene 1,2-二氢二醇是所测试的最活跃的化合物，每μ mol化合物比(+)-环氧二醇2，外消旋chrysene 1,2-二氢二醇，chrysene和(+)-chrysene 1,2-二氢二醇产生的肝脏肿瘤分别多3-，4-，6-和10倍。其他衍生物在试验剂量下没有显著的肝致瘤活性。（-）-chrysene 1,2-二氢二醇和(+)-环氧二醇2在小鼠皮肤和新生小鼠中的高致瘤活性表明，这些化合物分别是chrysene的近似和最终致癌代谢物。（+）-二醇环氧化物2异构体具有绝对构型，使其与苯并(a)芘的(+)-二醇环氧化物2异构体[(+)-7β，8α-二羟基-9α，10α-环氧-7,8,9,10-四氢苯并(a)芘]重叠，后者是苯并(a)芘的最终致癌代谢物。
Abstract The tumorigenicity of chrysene, (+)- and (-)-trans-1,2-dihydroxy-1,2-dihydrochrysene (chrysene 1,2-dihydrodiol), and the (+)- and (-)-enantiomers of the diastereomeric bay-region chrysene 1,2-diol-3,4-epoxides was assessed in two tumor models. A single topical application of 0.4 or 1.2 µmol of the chrysene derivatives on mouse skin followed by 25 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate revealed that (-)-chrysene 1,2-dihydrodiol had approximately twice the tumor-initiating activity of chrysene, while the (+)-enantiomer had no significant tumorigenic activity. Of the four isomers of chrysene 1,2-diol-3,4-epoxide, only (+)-1β,2α-dihydroxy-3α,4α-epoxy-1,2,3,4-tetrahydrochrysene [(+)-diolepoxide 2], in which the benzylic hydroxyl group and epoxide oxygen are trans, had significant tumorigenic activity. The (+)-diol-epoxide 2 isomer had tumor-initiating activity that was equivalent to the activity of the parent hydrocarbon. In newborn mice, a total dose of 0.7 or 1.4 µmol of compound divided into three i.p. injections was administered on the first, eighth, and 15 days of life, and tumorigenic activity was determined when the mice were 37 to 41 weeks old. Control animals developed an average of 0.13 lung tumor/mouse, whereas animals treated with (+)-diol-epoxide 2, (-)-chrysene 1,2-dihydrodiol, or racemic chrysene 1,2-dihydrodiol had an average of 7.8, 6.5, and 2.5 lung tumors per mouse per µmol of compound administered, respectively. The parent hydrocarbon and all other derivatives tested were essentially inactive in producing lung tumors. With respect to hepatic tumors in male mice, (-)-chrysene 1,2-dihydrodiol was the most active compound tested, and produced 3-, 4-, 6-, and 10-fold more hepatic tumors per mouse per µmol of compound administered than did (+)-diol-epoxide 2, racemic chrysene 1,2-dihydrodiol, chrysene, and (+)-chrysene 1,2-dihydrodiol, respectively. Other derivatives had no significant hepatotumorigenic activity at the doses tested. The high tumorigenic activity of (-)-chrysene 1,2-dihydrodiol and (+)-diol-epoxide 2 on mouse skin and in newborn mice indicate that these compounds are, respectively, proximate and ultimate carcinogenic metabolites of chrysene. The (+)-diol-epoxide 2 isomer of chrysene has absolute configuration such that it is superimposable on the (+)-diol-epoxide 2 isomer of benzo(a)pyrene [(+)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene], the ultimate carcinogenic metabolite of benzo(a)pyrene.