Evidence Supporting Product Standards for Carcinogens in Smokeless Tobacco Products

Hatsukami, Dorothy K.; Stepanov, Irina; Severson, Herb; Jensen, Joni; Lindgren, Bruce R.; Horn, Kimberly; Khariwala, Samir S.; Martin, Julia; Carmella, Steven G.; Murphy, Sharon E.; Hecht, Stephen S.

doi:10.1158/1940-6207.capr-14-0250

Cited by 36 publications

(47 citation statements)

References 37 publications

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“…Specifically, it has been reported that NNK and NNN nitrosamine biomarkers in the urine of smokeless tobacco users increased 32 and 12%, respectively, for every one-unit (μg/g wet wt) increase in NNK and NNN levels within their smokeless tobacco products (Hatsukami et al, 2015). In tobacco, bacteria have been identified that are capable of reducing nitrate to nitrite for the formation of TSNAs, including species of Bacillus , Staphylococcus , and Corynebacterium (Di Giacomo et al, 2007; Fisher et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Temporal Variations in Cigarette Tobacco Bacterial Community Composition and Tobacco-Specific Nitrosamine Content Are Influenced by Brand and Storage Conditions

et al. 2017

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Tobacco products, specifically cigarettes, are home to microbial ecosystems that may play an important role in the generation of carcinogenic tobacco-specific nitrosamines (TSNAs), as well as the onset of multiple adverse human health effects associated with the use of these products. Therefore, we conducted time-series experiments with five commercially available brands of cigarettes that were either commercially mentholated, custom-mentholated, user-mentholated, or non-mentholated. To mimic user storage conditions, the cigarettes were incubated for 14 days under three different temperatures and relative humidities (i.e., pocket, refrigerator, and room). Overall, 360 samples were collected over the course of 2 weeks and total DNA was extracted, PCR amplified for the V3V4 hypervariable region of the 16S rRNA gene and sequenced using Illumina MiSeq. A subset of samples (n = 32) was also analyzed via liquid chromatography with tandem mass spectrometry for two TSNAs: N’-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Comparative analyses of the five tobacco brands revealed bacterial communities dominated by Pseudomonas, Pantoea, and Bacillus, with Pseudomonas relatively stable in abundance regardless of storage condition. In addition, core bacterial operational taxonomic units (OTUs) were identified in all samples and included Bacillus pumilus, Rhizobium sp., Sphingomonas sp., unknown Enterobacteriaceae, Pantoea sp., Pseudomonas sp., Pseudomonas oryzihabitans, and P. putida. Additional OTUs were identified that significantly changed in relative abundance between day 0 and day 14, influenced by brand and storage condition. In addition, small but statistically significant increases in NNN levels were observed in user- and commercially mentholated brands between day 0 and day 14 at pocket conditions. These data suggest that manufacturing and user manipulations, such as mentholation and storage conditions, may directly impact the microbiome of cigarette tobacco as well as the levels of carcinogens.

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Section: Discussionmentioning

confidence: 99%

Temporal Variations in Cigarette Tobacco Bacterial Community Composition and Tobacco-Specific Nitrosamine Content Are Influenced by Brand and Storage Conditions

et al. 2017

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“…13 Hatsukami et al recently reported the levels of TSNAs in U.S. moist snuff and snus products and demonstrated that exposure to TSNAs is dependent on TSNA levels and independent of pattern of use. 13,14 …”

Section: Introductionmentioning

confidence: 99%

A Survey of N′-Nitrosonornicotine (NNN) and Total Water Content in Select Smokeless Tobacco Products Purchased in the United States in 2015

Ammann

Lovejoy

Walters

et al. 2016

J. Agric. Food Chem.

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This investigation provides an updated survey measuring the levels of N′-nitrosonornicotine (NNN) and water content of a select number of smokeless tobacco products sold in the United States in 2015. A total of 34 smokeless tobacco products were collected and analyzed for NNN and water content using LC-MS/MS and GC-TCD, respectively. Smokeless tobacco products were chosen to obtain a representative sample of the different types of products on the U.S. market. These smokeless products represent 12 of the 25 top-selling smokeless tobacco products according to 2013 Nielsen net sales data while five of the smokeless tobacco products are of lower selling smokeless tobacco products. The NNN levels and the water content of the smokeless tobacco products were determined and compared to previous studies. Although the range of NNN levels found was broad for the examined smokeless tobacco products (0.64–12.0 µg/g dry weight), dry snuff had the highest levels of NNN observed (>5 µg/g dry weight). We observed a general decrease in NNN levels for the same six moist snuff products that were analyzed in 2004 compared to our current 2015 study. The water content of the smokeless tobacco products surveyed ranged from 3.92 to 54.8%.

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“…1–6 The most abundant and potent TSNA is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). 7–11 The major metabolic pathway for NNK (Scheme 1) is carbonyl reduction to both the ( R )- and ( S )- enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), 12, 13 which, like NNK, are very potent carcinogens in rodents.…”

Section: Introductionmentioning

confidence: 99%

Stereospecific Metabolism of the Tobacco-Specific Nitrosamine, NNAL

Kozlovich

Chen

Lazarus

2015

Chem. Res. Toxicol.

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Among the most potent carcinogens in tobacco are the tobacco-specific nitrosamines (TSNAs), with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) the most abundant as well as the most potent. NNK is extensively metabolized to the equally carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Of the two NNAL enantiomers, (S)-NNAL appears to be preferentially glucuronidated and excreted in humans, but also exhibits higher stereoselective tissue retention in mice and humans and has been shown to be more carcinogenic in mice than its (R)- counterpart. Due to the differential carcinogenic potential of the two NNAL enantiomers, it is increasingly important to know which UGT enzyme targets the specific NNAL enantiomers for glucuronidation. To examine this, a chiral separation method was developed to isolate entiomerically pure (S)- and (R)-NNAL. Comparison of NNAL glucuronide (Gluc) peaks formed in reactions of UGT2B7-, UGT2B17-, UGT1A9-, and UGT2B10-over-expressing cell microsomes with pure NNAL enantiomers showed large differences in kinetics for (S)- versus (R)-NNAL, indicating varying levels of enantiomeric preference for each enzyme. UGT2B17 preferentially formed (R)-NNAL-O-Gluc and UGT2B7 preferentially formed (S)-NNAL-O-Gluc. When human liver microsomes (HLM) were independently incubated with each NNAL enantiomer, the ratio of (R)-NNAL-O-Gluc to (S)-NNAL-O-Gluc formation in HLM from subjects exhibiting the homozygous deletion UGT2B17 (*2/*2) genotype was significantly lower (p=0.012) than HLM from wild-type (*1/*1) subjects. There was a significant trend (p=0.015) towards decreased (R)-NNAL-O-Gluc:(S)-NNAL-O-Gluc ratio with increasing numbers of the UGT2B17*2 deletion allele. These data demonstrate that variations in the expression or activity of specific UGTs may affect individual susceptibility to cancers induced by specific NNAL enantiomers.

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Evidence Supporting Product Standards for Carcinogens in Smokeless Tobacco Products

Cited by 36 publications

References 37 publications

Temporal Variations in Cigarette Tobacco Bacterial Community Composition and Tobacco-Specific Nitrosamine Content Are Influenced by Brand and Storage Conditions

Temporal Variations in Cigarette Tobacco Bacterial Community Composition and Tobacco-Specific Nitrosamine Content Are Influenced by Brand and Storage Conditions

A Survey of N′-Nitrosonornicotine (NNN) and Total Water Content in Select Smokeless Tobacco Products Purchased in the United States in 2015

Stereospecific Metabolism of the Tobacco-Specific Nitrosamine, NNAL

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