Metabolism and Pharmacokinetics of<i>N′</i>-Nitrosonornicotine in the Patas Monkey

Upadhyaya, Pramod; Zimmerman, Cheryl L.; Hecht, Stephen S.

doi:10.1124/dmd.30.10.1115

Cited by 24 publications

(39 citation statements)

References 19 publications

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“…Animal studies consistently show that low amounts, generally <1% of the dose, of unchanged NNN are excreted in urine and there was no indication of the presence of NNN-N-Gluc (13). Based on this work, we expected that NNN and NNN-N-Gluc, if present in human urine, would be found in relatively low concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…These results provide a specific biomarker of human NNN exposure, which could be important for the investigation of esophageal and oral cancer risk in people who use tobacco products. Previous studies aimed at finding urinary biomarkers of NNN uptake were unsuccessful, because the metabolites were also formed from nicotine and related tobacco alkaloids (13,24). This study also resulted in the discovery of NAT, NAB, and their pyridine-N-glucuronides in the urine of smokers and smokeless tobacco users, which presents the first opportunity to measure the uptake of these tobacco-specific nitrosamines in humans.…”

Section: Discussionmentioning

confidence: 97%

“…Whereas these comparisons provide a general index of levels of the new biomarkers compared with the more extensively studied NNAL, it is difficult to directly relate these data to dose because of differences in metabolism. For example, in patas monkeys given similar doses of NNN and NNK, levels of unchanged NNN in urine were only about 2% to 3% of NNAL-Gluc (13,34).…”

Section: Discussionmentioning

confidence: 99%

“…The NNAL biomarker has been extensively applied in studies of NNK uptake in smokers, smokeless tobacco users, and nonsmokers exposed to secondhand tobacco smoke (12). However, no biomarker was available to assess uptake of NNN in humans, because all NNN metabolites which occur in reasonable quantities in urine are also metabolites of nicotine or other tobacco alkaloids, which occur in far higher concentrations in tobacco products than does NNN (7,13). A specific biomarker of NNN uptake would be crucial in studies investigating the causes of oral and esophageal cancer in people who use tobacco products.…”

Section: Introductionmentioning

confidence: 99%

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Tobacco-Specific Nitrosamines and Their Pyridine-N-glucuronides in the Urine of Smokers and Smokeless Tobacco Users

Stepanov

Hecht

2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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112

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Tobacco-specific nitrosamines are believed to play a significant role as causes of cancer in people who use tobacco products. Whereas the uptake of one tobaccospecific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, has been shown by analysis of its metabolites in urine, there are no published studies on urinary levels of NV-nitrosonornicotine (NNN), NV-nitrosoanatabine (NAT), and NV-nitrosoanabasine (NAB) or their metabolites in human urine. We developed a method for quantitation of NNN, NAT, NAB, and their pyridine-N-glucuronides NNN-N-Gluc, NAT-N-Gluc, and NAB-N-Gluc in human urine. Total NNN (NNN plus NNN-N-Gluc) was assayed using 5-methyl-NV-nitrosonornicotine as internal standard. Urine was treated with B-glucuronidase. Following solvent partitioning and solid-phase extraction, total NNN was determined using gas chromatography with nitrosamine-selective detection. Total NAT and total NAB were quantified in the same samples. Separate quantitation of NNN and NNN-N-Gluc was accomplished by extraction of the urine with ethyl acetate before B-glucuronidase hydrolysis; NNN was analyzed in the ethyl acetate extract, and after enzyme treatment, NNN released from NNN-N-Gluc was quantified in the extracted urine. Separate analyses of NAT, NAT-N -Gluc, NAB, and NAB-N -Gluc proceeded similarly. Analyte identities were confirmed by gas chromatographytandem mass spectrometry. Mean levels of total NNN, NAT, and NAB in the urine of 14 smokers were (pmol/mg creatinine) 0.18 F 0.22, 0.19 F 0.20, and 0.040 F 0.039, respectively, whereas the corresponding amounts in the urine of 11 smokeless tobacco users were 0.64 F 0.44, 1.43 F 1.10, and 0.23 F 0.19, respectively. Pyridine-N-glucuronides accounted for 59% to 90% of total NNN, NAT, and NAB. The results of this study show the presence of NNN, NAT, NAB, and their pyridine-N-glucuronides in human urine and provide a quantitative method for application in mechanistic and epidemiologic studies of the role of tobaccospecific nitrosamines in human cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tobacco-Specific Nitrosamines and Their Pyridine-N-glucuronides in the Urine of Smokers and Smokeless Tobacco Users

Stepanov

Hecht

2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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112

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“…5′-Hydroxylation of NNN initially gives 5′-hydroxyNNN (6) which ring opens yielding diazohydroxide 8. Although the mutagenicity of 5′-acetoxyNNN (4), a stable precursor to 5′-hydroxyNNN (6), has been known for nearly 30 years (12), and the 5′-hydroxylation pathway is a prevalent one in the metabolism of NNN in monkeys and in human tissues (13,14), there are no reports in the literature on DNA adduct formation by 5′-hydroxylation of NNN. In this paper, we describe the first characterization of deoxyguanosine (dGuo) and DNA adducts resulting from this pathway of NNN metabolism.…”

Section: Introductionmentioning

confidence: 99%

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Upadhyaya

McIntee

Villalta

et al. 2006

Chem. Res. Toxicol.

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N′-Nitrosonornicotine (NNN) is believed to play an important role as a cause of cancer in people who use tobacco products and is considered to be a human carcinogen. NNN requires metabolism to form DNA adducts, which are absolutely critical to its carcinogenic properties. Previous studies have identified cytochrome P450-catalyzed 2′-and 5′-hydroxylation of NNN as potential DNA adduct forming metabolic pathways. 5′-Hydroxylation is the more prevalent of these in monkeys and humans, and is known to generate mutagenic intermediates, but the DNA adducts formed by this pathway have never been characterized. In this study, we used 5′-acetoxyNNN as a stable precursor to 5′-hydroxyNNN, and investigated its esterase-catalyzed reactions with deoxyguanosine (dGuo) and DNA. Adducts resulting from carbocation and oxonium ion intermediates, produced by the spontaneous decomposition of 5′-hydroxyNNN, were identified. The carbocation pathway resulted in the formation of 2-[2-hydroxy-5-(3-pyridyl)pyrrolidin-1-yl]deoxyinosine (12) which was characterized by comparison to an independently synthesized standard. Treatment of 12 with NaBH 3 CN produced two diastereomers of 2-[2-(3-pyridyl)pyrrolidin-1-yl]deoxyinosine (14), and their absolute configurations at the 2-position were determined by comparison to synthetic standards. The oxonium ion pathway produced diastereomers of N 2 [5-(3-pyridyl)tetrahydrofuran-2-yl]dGuo (16), identified by comparison to synthetic standards. The absolute configuration at the 5-position was determined by establishing the stereochemistry of the enantiomers of 5-(3-pyridyl)-2-hydroxytetrahydrofuran at the 5-position, and allowing these to react individually with dGuo. Treatment of 16 with NaBH 3 CN produced N 2 [4-hydroxy-4-(3-pyridyl)but-1-yl]dGuo (18) which was also synthesized independently. Using liquid chromatography-electrospray ionization-tandem mass spectrometry with selected reaction monitoring, adducts 12 and 16 were identified as products of the reactions of 5′-acetoxyNNN with dGuo. Similarly, adducts 14 and 18 were identified as products of the reaction of 5′-acetoxyNNN with DNA followed by NaBH 3 CN treatment and enzymatic hydrolysis. These results provide the first structural characterization of DNA adducts that can be formed by 5′-hydroxylation of NNN.

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Composition of e‐cigarette aerosols: A review and risk assessment of selected compounds

Heywood,

Abele,

Langenbach

et al. 2024

J of Applied Toxicology

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The potential harms and benefits of e‐cigarettes, or electronic nicotine delivery systems (ENDS), have received significant attention from public health and regulatory communities. Such products may provide a reduced risk means of nicotine delivery for combustible cigarette smokers while being inappropriately appealing to nicotine naive youth. Numerous authors have examined the chemical complexity of aerosols from various open‐ and closed‐system ENDS. This body of literature is reviewed here, with the risks of ENDS aerosol exposure among users evaluated with a margin of exposure (MoE) approach for two non‐carcinogens (methylglyoxal, butyraldehyde) and a cancer risk analysis for the carcinogen N‐nitrosonornicotine (NNN). We identified 96 relevant papers, including 17, 13, and 5 reporting data for methylglyoxal, butyraldehyde, and NNN, respectively. Using low‐end (minimum aerosol concentration, low ENDS use) and high‐end (maximum aerosol concentration, high ENDS use) assumptions, estimated doses for methylglyoxal (1.78 × 10−3–135 μg/kg‐bw/day) and butyraldehyde (1.9 × 10−4–66.54 μg/kg‐bw/day) corresponded to MoEs of 227–17,200,000 and 271–280,000,000, respectively, using identified points of departure (PoDs). Doses of 9.90 × 10−6–1.99 × 10−4 μg/kg‐bw/day NNN corresponded to 1.4–28 surplus cancers per 100,000 ENDS users, relative to a NNN‐attributable surplus of 7440 per 100,000 cigarette smokers. It was concluded that methylglyoxal and butyraldehyde in ENDS aerosols, while not innocuous, did not present a significant risk of irritant effects among ENDS users. The carcinogenic risks of NNN in ENDS aerosols were reduced, but not eliminated, relative to concentrations reported in combustible cigarette smoke.

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Metabolism and Pharmacokinetics ofN′-Nitrosonornicotine in the Patas Monkey

Cited by 24 publications

References 19 publications

Tobacco-Specific Nitrosamines and Their Pyridine-N-glucuronides in the Urine of Smokers and Smokeless Tobacco Users

Tobacco-Specific Nitrosamines and Their Pyridine-N-glucuronides in the Urine of Smokers and Smokeless Tobacco Users

Identification of Adducts Formed in the Reaction of 5‘-Acetoxy-N‘-Nitrosonornicotine with Deoxyguanosine and DNA

Composition of e‐cigarette aerosols: A review and risk assessment of selected compounds

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