Background The most abundant and potent carcinogenic tobacco-specific nitrosamines in tobacco and tobacco smoke is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In vivo, NNK is rapidly metabolized to both the (R)- and (S)-enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which possesses similar carcinogenic properties as NNK. The major detoxification pathway for both NNAL enantiomers is glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes including UGT2B10 and UGT2B17. Methods NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc and free NNAL were simultaneously and directly quantified in the urine of smokers by LC-MS analysis. Genotypes were determined by Taqman-assay using genomic DNA. Results The average percentage of total urinary NNAL that existed as NNAL-N-Gluc, (R)-NNAL-O-Gluc, (S)-NNAL-O-Gluc, and free-NNAL in 180 active smokers was 23.2%, 21.7%, 26.9% and 28.2%, respectively. The functional knock-out polymorphism in the UGT2B10 gene at codon 67 (Asp>Tyr) was significantly (P<0.0001) associated with a 93% decrease in creatinine-adjusted NNAL-N-Gluc. The polymorphic whole-gene deletion of the UGT2B17 gene was associated with significant (P=0.0048) decreases in the levels of creatinine-adjusted (R)-NNAL-O-Gluc, with a 32% decrease in the levels of urinary (R)-NNAL-O-Gluc/(S)-NNAL-O-Gluc among subjects with the UGT2B17 (*2/*2) genotype as compared to subjects with the UGT2B17 (*1/*1) genotype. Conclusions These results suggest that functional polymorphisms in UGT2B10 and UGT2B17 are associated with a reduced detoxification capacity against NNAL and may therefore affect individual cancer risk upon exposure to tobacco. Impact This is the first report to clearly demonstrate strong genotype-phenotype associations between both the UGT2B10 codon 67 Asp

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.

Tobacco companies use price discounts, including coupons and rebates, to market their products. Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) communities are targeted by these marketing strategies, contributing to inequitably high tobacco use. Some localities have adopted policies restricting tobacco price discounts; for successful implementation, community buy-in is crucial. From July–October 2018, Equality California staff conducted semi-structured interviews with seven participants in Los Angeles, CA. Themes included familiarity with tobacco price discounts, their perceived impact on tobacco use in LGBTQ+ communities, and attitudes toward potential policy restrictions. Interview notes were analyzed using a deductive approach to qualitative analysis. Awareness of tobacco price discounts varied; some interviewees were familiar, while others expressed surprise at their ubiquity. Price discounts were seen to disproportionately impact LGBTQ+ individuals, especially those who additionally identify with other vulnerable groups, including young people and communities of color. Support for policy restrictions was unanimous; however, interviewees expressed concern over political opposition and emphasized a need for culturally competent outreach to LGBTQ+ communities. Community organizations are essential in mobilizing support for policy reform. Understanding the perceptions and recommendations of community leaders provides tools for policy action, likely improving outcomes to reduce LGBTQ+ tobacco use through restricting tobacco price discounts.

Today's science is largely funded by taxpayer dollars, and because of this, scientists have a responsibility to ensure that their research is being effectively communicated back to taxpayers and to the policy makers who determine the distribution of those funds. The importance and impact of effective science communication is compounded when research is used to inform legislative action. Science impacts policy, and policy can impact science. However, the formal education of scientists does not usually include specific training on interacting with science policy. This article describes strategies for engaging with science policy—starting with simple and easy policy actions, and delving into more complex event planning and group organizing tasks. Whether advocating for evidence‐based policies or policies that impact the scientific enterprise or STEM education, practicing skills pertinent to science policy can help you gain comfort in translating your experiences and experiments into lasting change. © 2019 by John Wiley & Sons, Inc.

Menthol, which creates mint flavor and scent, is often added to tobacco in both menthol and nonmenthol cigarettes. A potent tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is extensively metabolized to its equally carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) as (R)-or (S)-NNAL enantiomers. NNAL is detoxified by UDPglucuronosyltransferase (UGT) enzymes, with glucuronidation occurring on either NNAL's pyridine ring nitrogen (NNAL-N-Gluc) or the chiral alcohol [(R)-or (S)-NNAL-O-Gluc]. To characterize a potential effect by menthol on NNAL glucuronidation, in vitro menthol glucuronidation assays and menthol inhibition of NNAL-Gluc formation assays were performed. Additionally, NNAL and menthol glucuronides (MG) were measured in the urine of smokers (n 5 100) from the Southern Community Cohort Study. UGTs 1A9, 1A10, 2A1, 2A2, 2A3, 2B4, 2B7, and 2B17 all exhibited glucuronidating activity against both L-and D-menthol. In human liver microsomes, both L-and D-menthol inhibited the formation of each NNAL-Gluc, with a stereospecific difference observed between the formation of (R)-NNAL-O-Gluc and (S)-NNAL-O-Gluc in the presence of D-menthol but not L-menthol. With the exception of three nonmenthol cigarette smokers, urinary MG was detected in all menthol and nonmenthol smokers, with L-MG comprising >98% of total urinary MG. Levels of urinary NNAL-N-Gluc were significantly (P < 0.05) lower among subjects with high levels of total urinary MG; no significant changes in free NNAL were observed. These data suggest that the presence of menthol could lead to increases in alternative, activating metabolic pathways of NNAL in tobacco target tissues, increasing the opportunity for NNAL to damage DNA and lead to the development of tobacco-related cancers. SIGNIFICANCE STATEMENTHigh levels of the major menthol metabolite, menthol-glucuronide, was observed in the urine of smokers of either menthol or nonmenthol cigarettes. The fact that a significant inverse correlation was observed between the levels of urinary menthol-glucuronide and NNAL-Nglucuronide, a major detoxification metabolite of the tobacco carcinogen, NNK, suggests that menthol may inhibit clearance of this important tobacco carcinogen.