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Metabolic Activation and DNA-Damaging Properties of Carcinogenic N-Nitrosamines
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | Metabolic Activation and DNA-Damaging Properties of Carcinogenic N-Nitrosamines. |
| 개인저자 | Carlson, Erik. |
| 단체저자명 | University of Minnesota. Pharmacology. |
| 발행사항 | [S.l.]: University of Minnesota., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 182 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-02B. Dissertation Abstract International |
| ISBN | 9781085598767 |
| 학위논문주기 | Thesis (Ph.D.)--University of Minnesota, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Advisor: Hecht, Stephen S. |
| 이용제한사항 | This item must not be sold to any third party vendors.This item must not be sold to any third party vendors. |
| 요약 | Upon entry into a host, carcinogens are subjected to a variety of Phase I and Phase II metabolic pathways that result in bioactivation or detoxification. The bioactivation pathways are of particular importance because they often generate DNA-damaging compounds. It would stand to reason that fully understanding these activation pathways, their outcomes, and their differences amongst individuals would aid in combating cancer. This dissertation focuses on the metabolic activation of two tobacco carcinogens: 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). Concepts pertinent to this work such as tobacco carcinogenesis, chemistry of N-nitroso compounds, cytochrome P450 metabolism, and tobacco-specific nitrosamines are reviewed.The first study of this dissertation evaluates a hypothesized metabolic pathway for N-nitrosamines: processive P450 oxidation of NNK and NNN to N-nitrosamides. In this study, the three corresponding N-nitrosamides were synthesized, tested for stability, and monitored for formation in vitro. This study shows for the first time that N-nitrosamides are direct products of N-nitrosamine metabolism by cytochrome P450s. While these compounds were minor metabolites, their relative stability and DNA-damaging properties could impart biological relevance. Determining the generality of this metabolic pathway requires future work.The second study sought after the structures and abundance of stable 2'- deoxyadenosine (dAdo) damage (DNA adducts) induced by NNK bioactivation. This was accomplished by synthesizing hypothetical dAdo-adduct structures based on known reactivity and applying them to in vitro and in vivo assays. In vitro data indicates that N6- and N1-adducts are formed, however, in vivo data only shows N6-adduct formation, indicating extensive repair of N1-adducts. The relative abundance of these adducts were determined in rat liver and lung for three different treatment groups. The biological activity of these adducts requires future study.The last study measured direct biomarkers for human NNN metabolic activation for the first time by using [pyridine-D4]NNN-enriched tobacco. The deuterium-labelling allows NNN metabolites to be selectively measured by mass spectrometry and removes all interference by competing nicotine metabolites. This study is ongoing but current data suggests metabolic activation of NNN varies among individuals and is at least partially due to the activity of P450 2A6, the dominant enzyme for NNN bioactivation. |
| 일반주제명 | Toxicology. Organic chemistry. Analytical chemistry. |
| 언어 | 영어 |
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