Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450.
Metabolic activation of the potent carcinogen dibenzo[a,h]anthracene by cDNA-expressed human cytochromes P450.
复制标题
cDNA 表达的人细胞色素 P450 对强效致癌物二苯并[a,h]蒽的代谢激活。
DOI：
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发表时间：
1996
影响因子：
3.9
通讯作者：
H. Gelboin
中科院分区：
文献类型：
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作者：
M. Shou;K. Krausz;F. J. Gonzalez;H. Gelboin
用在肝癌G2细胞中表达的重组人细胞色素P450酶1A 2、2B 6、2C 8、2C 9、2 E1、3A 3、3A 4和3A 5以及14种不同的人肝微粒体研究了强致癌物二苯并[a，h]蒽（DB[a，h]A）的代谢活化。三个二氢二醇，三个酚，和一个二酚形成和分离的高效液相色谱法和紫外吸收光谱和质谱鉴定。在所有检测的P450中，1A 2和2C 9在总DB[a，h]A代谢速率方面最具活性，2B 6具有中等活性（活性是其他P450的2.5- 12倍）。反式-3，4-二氢二醇通常被认为是最终致癌的3，4-二醇-1，2-环氧化物的前体，由2C 9产生最活跃，然后是1A 2和2B 6。酶促动力学（K（m）和V（max））的值表明2C 9在3，4-二氢二醇的形成中具有最高的催化效率（V（max）/K（m）= 9.7），而1A 2（5.9）和2B 6（4.4）相反。1A 2对1，2-二氢二醇的产生具有最高活性，1，2-二氢二醇被认为是弱致癌代谢物。虽然DB[a，h]A总体代谢中人肝微粒体的比活性在个体之间存在显著差异，但观察到的代谢模式与1A 2产生的代谢模式相似。由于人1A 1（多环芳烃代谢的主要酶）在肝脏中未显著表达，因此肝微粒体2C 9、1A 2和2B 6均可能参与DB[a，h]A的代谢活化。
The metabolic activation of the potent carcinogen dibenzo[a,h]anthracene (DB[a,h]A) was investigated with recombinant human cytochrome P450 enzymes 1A2, 2B6, 2C8, 2C9, 2E1, 3A3, 3A4, and 3A5 expressed in hepatoma G2 cells and with 14 different human liver microsomes. Three dihydrodiols, three phenols, and one diphenol were formed and separated by high-performance liquid chromatography and identified by UV absorption and mass spectra. Of all P450s tested, 1A2 and 2C9 were the most active and 2B6 was moderately active in the rate of total DB[a,h]A metabolism (2.5- to 12-fold greater activity than that for other P450s). The trans-3,4-dihydrodiol, generally recognized as a precursor of the ultimate carcinogenic 3,4-diol-1,2-epoxides, was produced most actively by 2C9, then 1A2 and 2B6. The values of enzymatic kinetics (K(m) and V(max)) indicated that 2C9 had the highest catalytic efficiency (V(max)/K(m) = 9.7) in the formation of 3,4-dihydrodiol, in contrast to 1A2 (5.9) and 2B6 (4.4). 1A2 had the highest activity toward production of the 1,2-dihydrodiol, which is considered to be a weakly carcinogenic metabolite. Although specific activities of human liver microsomes in overall metabolism of DB[a,h]A markedly differed between individuals, metabolic patterns were observed similar to that generated from 1A2. Since human 1A1, a predominant enzyme for metabolism of polycyclic aromatic hydrocarbons, is not significantly expressed in the liver, hepatic microsomal 2C9, 1A2, and 2B6 all probably contribute to the metabolic activation of DB[a,h]A.