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首页> 外文学位 >Human cytochrome P450-mediated metabolism of nicotine and tobacco-specific carcinogens: N-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
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Human cytochrome P450-mediated metabolism of nicotine and tobacco-specific carcinogens: N-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

机译：人类细胞色素P450介导的尼古丁和烟草特有致癌物的代谢：N-亚硝基松香碱和4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮。

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摘要

Smoking is the principal risk factor for developing lung cancer, the leading cause of cancer-related deaths in the United States. Two potent tobacco-specific carcinogens are 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N '-nitrosonornicotine (NNN). Metabolic activation of NNK and NNN is required in order to exert their carcinogenic potential. Cytochrome P450 enzymes catalyze the activation of NNK and NNN via hydroxylation of carbons positioned alpha to the N-nitroso group of the nitrosamine.;In this thesis, the role of human cytochrome P450 enzymes in the metabolism of NNK. NNN, and nicotine was investigated. Specifically, the contribution by CYP2A6 and CYP2B6 to the metabolism of NNK and nicotine in human liver microsomes was studied. CYP2B6 was determined to be an efficient catalyst of NNK metabolism but not nicotine metabolism in human liver microsomes. Although CYP2B6 is not as abundant as CYP2A6 in the liver; it expressed in the lung. Therefore, its ability to catalyze NNK alpha-hydroxylation efficiently may have important implications in the lung.;Another P450 expressed in the human lung is CYP2A13, an excellent catalyst of NNK alpha-hydroxylation. Recently several genetic polymorphisms have been identified for CYP2A13 including polymorphisms that result in single amino acid changes. Functional differences in CYP2A13-catalyzed NNK and NNN metabolism as a result of these genetic polymorphisms was investigated. No significant differences were observed for NNN metabolism. However, modest but significant decreases in NNK metabolism were determined for three variants, R257C, D158E, and V323L. This work should provide better guidelines for design and interpretation of epidemiology studies.;Lastly, a novel key active site residue of CYP2A13 was identified for NNK metabolism. Site-directed mutagenesis was used to generate a single mutation in the active site of CYP2A13. The characterization of NNK metabolism by mutant, Asn297Ala CYP2A13 confirmed the importance of this residue to the catalytic efficiency of NNK alpha-hydroxylation by CYP2A13. Computational docking of NNK into the active site of CYP2A13 indicated that residue Asn297 is also important for substrate orientation. This thesis research has contributed to the understanding of carcinogenesis by tobacco-specific carcinogens by further elucidating the cytochrome P450-catalyzed metabolic activation pathways of NNN and NNK.
机译：吸烟是发展肺癌的主要危险因素，而肺癌是美国癌症相关死亡的主要原因。两种强效的烟草特有致癌物是4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）和N'-亚硝基异烟碱（NNN）。为了发挥其致癌潜力，需要NNK和NNN的代谢活化。细胞色素P450酶通过亚硝胺N-亚硝基的α碳原子的羟基化来催化NNK和NNN的活化。本论文研究了人类细胞色素P450酶在NNK代谢中的作用。 NNN和尼古丁进行了调查。具体地，研究了CYP2A6和CYP2B6对人肝微粒体中NNK和烟碱代谢的贡献。在人肝微粒体中，CYP2B6被确定为NNK代谢的有效催化剂，而不是尼古丁代谢。尽管肝脏中CYP2B6不如CYP2A6丰富;它在肺中表达。因此，其有效催化NNKα-羟基化的能力可能在肺中具有重要意义。在人肺中表达的另一种P450是CYP2A13，它是NNKα-羟基化的优良催化剂。最近，已确定CYP2A13的几种遗传多态性，包括导致单个氨基酸变化的多态性。由于这些遗传多态性，研究了CYP2A13催化的NNK和NNN代谢的功能差异。 NNN代谢未观察到显着差异。但是，对于三种变体R257C，D158E和V323L，确定了NNK代谢的适度但显着下降。这项工作应为流行病学研究的设计和解释提供更好的指导原则。最后，CYP2A13的一个新的关键活性位点残基被确定用于NNK代谢。使用定点诱变在CYP2A13的活性位点产生单个突变。突变体Asn297Ala CYP2A13对NNK代谢的表征证实了此残基对CYP2A13对NNKα-羟基化催化效率的重要性。 NNK的计算对接到CYP2A13的活性位点表明，残基Asn297对底物取向也很重要。通过进一步阐明细胞色素P450催化的NNN和NNK代谢活化途径，本论文研究有助于理解烟草特异性致癌物的致癌作用。

著录项

  • 作者

    Schlicht, Kari Elizabeth.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 122 p.
  • 总页数 122
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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