Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
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发表时间：
2000-09
期刊：
影响因子：
11.2
通讯作者：
T. Su;Z. Bao;Qing-Yu Zhang;Theresa J. Smith;Jun-yan Hong;X. Ding
中科院分区：
文献类型：
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作者：
T. Su;Z. Bao;Qing-Yu Zhang;Theresa J. Smith;Jun-yan Hong;X. Ding
人类 CYP2A 亚家族包含三个基因：CYP2A6、CYP2A7 和 CYP2A13。 CYP2A6 对许多致癌物具有活性，并且是肝脏中主要的香豆素 7-羟化酶和尼古丁 C-氧化酶，而 CYP2A7 则无功能。 CYP2A13 的功能尚未被表征。在本研究中，通过 RNA-PCR 从人鼻粘膜制备 CYP2A13 cDNA，并使用杆状病毒表达系统进行翻译。在重组系统中，表达的 CYP2A13 在六甲基磷酰胺、N,N-二甲基苯胺、2'-甲氧基苯乙酮和 N-亚硝基甲基苯胺的代谢活化中比 CYP2A6 更活跃，但在香豆素 7-羟基化中比 CYP2A6 活性低得多。特别令人感兴趣的是，CYP2A13 在主要烟草特异性致癌物 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮的代谢激活中高度活跃，其催化效率远高于之前检测的其他人类细胞色素 P450 亚型。通过异构体特异性 RNA-PCR 确定 CYP2A13 的组织分布。在肝脏和许多肝外组织中检测到 CYP2A13 mRNA，包括鼻粘膜、肺、气管、脑、乳腺、前列腺、睾丸和子宫，但在心脏、肾、骨髓、结肠、小肠、脾、胃、胸腺或骨骼肌中未检测到。定量PCR分析进一步显示，CYP2A13 mRNA在鼻粘膜中表达量最高，其次是肺和气管。总之，这些发现表明 CYP2A13 在人类呼吸道外源性毒性和烟草相关肿瘤发生中发挥重要作用。
The human CYP2A subfamily comprises three genes, CYP2A6, CYP2A7, and CYP2A13. CYP2A6 is active toward many carcinogens and is the major coumarin 7-hydroxylase and nicotine C-oxidase in the liver, whereas CYP2A7 is not functional. The function of CYP2A13 has not been characterized. In this study, a CYP2A13 cDNA was prepared by RNA-PCR from human nasal mucosa and was translated using a baculovirus expression system. In a reconstituted system, the expressed CYP2A13 was more active than CYP2A6 in the metabolic activation of hexamethylphosphoramide, N,N-dimethylaniline, 2'-methoxyacetophenone, and N-nitrosomethylphenylamine but was much less active than CYP2A6 in coumarin 7-hydroxylation. Of particular interest, CYP2A13 was highly active in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, with a catalytic efficiency much greater than that of other human cytochrome P450 isoforms examined previously. The tissue distribution of CYP2A13 was determined with isoform-specific RNA-PCR. CYP2A13 mRNA was detected in liver and a number of extrahepatic tissues, including nasal mucosa, lung, trachea, brain, mammary gland, prostate, testis, and uterus, but not in heart, kidney, bone marrow, colon, small intestine, spleen, stomach, thymus, or skeletal muscle. Quantitative PCR analysis further revealed that CYP2A13 mRNA is expressed at the highest level in the nasal mucosa, followed by the lung and the trachea. Together, these findings suggest that CYP2A13 plays important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the human respiratory tract.