The process of chemical carcinogenesis is initiated by DNA damage. This dissertation will describe quantitative approaches to assess the detoxification and DNA damage pathways of two human carcinogens: benzene and N′-nitrosonornicotine (NNN). The aspects of carcinogenesis relevant for this work include exposure to the carcinogen, biological activation to a reactive electrophile, metabolic detoxification processes, and DNA addition product (adduct) formation upon reaction of the electrophile with DNA. This dissertation will begin by presenting a collaborative study on exposure to benzene when smoking tobacco via a hookah; a urinary biomarker of benzene exposure significantly increases after a single smoking event. Next, it will describe studies of enzyme kinetics which determined for the first time that a human enzyme, GSTP1, is a good catalyst for the detoxification of benzene oxide, the activated form of benzene. This study also provided direct biochemical confirmation that GSTT1 is an important enzyme in this detoxification process. The next chapter will present collaborative data demonstrating that sulforaphane, an active phytochemical in broccoli sprouts, can upregulate these enzymatic detoxification processes in humans exposed to benzene and other air pollutants, likely by upregulating GSTP1. The last chapter on benzene will describe data showing that the major DNA adduct arising from the reaction between benzene oxide and DNA, 7-phenylguanine, is not detectable in humans or animals exposed to benzene. Thus, 7-phenylguanine is not likely to be the etiological agent responsible for the mechanism of benzene carcinogenicity, but instead some other mechanism of carcinogenesis is more important. The final chapter of this dissertation will shift focus to the analysis of a DNA adduct arising from NNN metabolic activation. NNN can be activated via two pathways: 2′-hydroxylation and 5′-hydroxylation. 2′-Hydroxylation has been more extensively studied, as it is the major pathway in rat esophagus, a target tissue of NNN carcinogenicity. However, the work presented here demonstrates that 5′-hydroxylation of NNN by human enzymes leads to higher levels of DNA adducts than does the 2′-hydroxylation pathway, and thus, 5′-hydroxylation may be the more relevant pathway for future DNA adduct studies in humans who use tobacco products.
University of Minnesota Ph.D. dissertation. May 2016. Major: Medicinal Chemistry. Advisor: Stephen Hecht. 1 computer file (PDF); xi, 173 pages.
Analyses Of Detoxification And Dna Damage From The Human Carcinogens Benzene And N′-Nitrosonornicotine.
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