Tumorigenicity of the diastereomeric benz[a]anthracene 3,4-diol-1,2-epoxides and the (+)- and (-)-enantiomers of benz[a]anthracene 3,4-dihydrodiol in newborn mice.
Tumorigenicity of the diastereomeric benz[a]anthracene 3,4-diol-1,2-epoxides and the (+)- and (-)-enantiomers of benz[a]anthracene 3,4-dihydrodiol in newborn mice.
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非对映体苯并[a]蒽3,4-二醇-1,2-环氧化物以及苯并[a]蒽3,4-二氢二醇的()-和(-)-对映体在新生小鼠中的致瘤性。
DOI：
10.1093/jnci/63.1.201
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发表时间：
1979
期刊：
影响因子：
--
通讯作者：
Allan H. Conney
中科院分区：
文献类型：
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作者：
P. Wislocki;M. Buening;Wayne Levin;R. Lehr;D. Thakker;D. Jerina;Allan H. Conney
苯并[a]蒽（BA）、反式-3，4-二羟基-3，4-二氢苯并[a]蒽（BA 3，4-二氢二醇）的（+）-和（-）-对映体以及BA 3，4-二醇-1，2-环氧化物的外消旋非对映体[即，在新生Swiss-Webster小鼠中检测衍生自BA 3，4-二氢二醇的非对映异构体1，2-环氧化物中的一种或两种，其中环氧化物氧相对于苄基4-羟基为顺式（二醇环氧化物-1）或反式（二醇环氧化物-2）。以分次剂量向小鼠ip施用总剂量为280纳摩尔的化合物，分次剂量由出生后24小时内40纳摩尔、8日龄时80纳摩尔和15日龄时160纳摩尔组成。当动物26周龄时终止实验。BA 3，4-二醇-1，2-环氧化物-2是测试的最有效的化合物。用BA 3，4-二醇-1，2-环氧化物-2治疗的所有动物均发生肺肿瘤，平均每只小鼠13.3个肿瘤。BA 3，4-二醇-1，2-环氧化物-1在42%的小鼠中产生肺肿瘤，平均每只小鼠仅产生0.56个肿瘤。具有[3R，4 R]绝对立体化学的BA 3，4-二氢二醇的（-）-对映体是测试的BA的第二大致瘤性衍生物;它在71%的小鼠中产生肺肿瘤，平均每只小鼠1.88个肿瘤。BA和BA 3，4-二氢二醇的（+）-对映体在试验剂量下几乎没有或没有致瘤活性。每只小鼠肺肿瘤平均数的比较显示，BA 3，4-二醇-1，2-环氧化物-2的致瘤性比BA 3，4-二醇-1，2-环氧化物-1高约30倍，比（-）-BA 3，4-二氢二醇高8倍，比BA高85倍以上。这些数据表明，在新生小鼠BA 3，4-二氢二醇和BA 3，4-二醇-1，2-环氧化物是BA的近端和最终致癌代谢产物。
The tumorigenic activity of benz[a]anthracene (BA), the (+)- and (-)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BA 3,4-dihydrodiol), and the racemic diastereomers of the BA 3,4-diol-1,2-epoxides [i.e., either or both of the diastereomeric 1,2-epoxides derived from BA 3,4-dihydrodiol in which the epoxide oxygen is cis (diol epoxide-1) or trans (diol epoxide-2) to the benzylic 4-hydroxyl group) was examined in newborn Swiss-Webster mice. The mice were administered ip a total dose of 280 nmoles of compound in divided doses consisting of 40 nmoles within 24 hours of birth, 80 nmoles at 8 days of age, and 160 nmoles at 15 days of age. The experiment was terminated when the animals were 26 weeks of age. BA 3,4-diol-1,2-epoxide-2 was the most potent compound tested. All animals treated with BA 3,4-diol-1,2-epoxide-2 developed pulmonary tumors with an average of 13.3 tumors per mouse. BA 3,4-diol-1,2-epoxide-1 produced pulmonary tumors in 42% of the mice with an average of only 0.56 tumors per mouse. The (-)-enantiomer of BA 3,4-dihydrodiol with [3R,4R] absolute stereochemistry was the second most tumorigenic derivative of BA tested; it produced pulmonary tumors in 71% of the mice with an average of 1.88 tumors per mouse. BA and the (+)-enantiomer of BA 3,4-dihydrodiol had little or no tumorigenic activity at the dose tested. A comparison of the average number of pulmonary tumors per mouse revealed that BA 3,4-diol-1,2-epoxide-2 was about 30-fold more tumorigenic than was BA 3,4-diol-1,2-epoxide-1, 8-fold more tumorigenic than was (-)-BA 3,4-dihydrodiol, and greater than 85-fold more tumorigenic than was BA. These data indicate that in newborn mice BA 3,4-dihydrodiol and a BA 3,4-diol-1,2-epoxide are proximate and ultimate carcinogenic metabolites of BA, respectively.