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Journal of Pharmaceutical Sciences Jul 2023N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework... (Review)
Review
N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of N-nitrosamines in drug products. One strategy to inhibit the formation of N-nitrosamines during the manufacture and storage of drug products involves the incorporation of nitrite scavengers in the formulation. Diverse molecules have been tested in screening studies including the antioxidant vitamins ascorbic acid and α-tocopherol, amino acids, and other antioxidants used in foods or drugs, for inclusion into drug products to mitigate N-nitrosamine formation. This review article outlines key considerations for the inclusion of nitrite scavengers in oral drug product formulations.
Topics: Humans; Nitrosamines; Nitrites; Antioxidants; Ascorbic Acid; Pharmaceutical Preparations
PubMed: 37023856
DOI: 10.1016/j.xphs.2023.03.022 -
Tobacco Control May 2014To review the available evidence evaluating the chemicals in refill solutions, cartridges, aerosols and environmental emissions of electronic cigarettes (e-cigarettes). (Review)
Review
OBJECTIVE
To review the available evidence evaluating the chemicals in refill solutions, cartridges, aerosols and environmental emissions of electronic cigarettes (e-cigarettes).
METHODS
Systematic literature searches were conducted to identify research related to e-cigarettes and chemistry using 5 reference databases and 11 search terms. The search date range was January 2007 to September 2013. The search yielded 36 articles, of which 29 were deemed relevant for analysis.
RESULTS
The levels of nicotine, tobacco-specific nitrosamines (TSNAs), aldehydes, metals, volatile organic compounds (VOCs), flavours, solvent carriers and tobacco alkaloids in e-cigarette refill solutions, cartridges, aerosols and environmental emissions vary considerably. The delivery of nicotine and the release of TSNAs, aldehydes and metals are not consistent across products. Furthermore, the nicotine level listed on the labels of e-cigarette cartridges and refill solutions is often significantly different from measured values. Phenolic compounds, polycyclic aromatic hydrocarbons and drugs have also been reported in e-cigarette refill solutions, cartridges and aerosols. Varying results in particle size distributions of particular matter emissions from e-cigarettes across studies have been observed. Methods applied for the generation and chemical analyses of aerosols differ across studies. Performance characteristics of e-cigarette devices also vary across and within brands.
CONCLUSIONS
Additional studies based on knowledge of e-cigarette user behaviours and scientifically validated aerosol generation and chemical analysis methods would be helpful in generating reliable measures of chemical quantities. This would allow comparisons of e-cigarette aerosol and traditional smoke constituent levels and would inform an evaluation of the toxicity potential of e-cigarettes.
Topics: Aerosols; Aldehydes; Chromatography, Liquid; Electronic Nicotine Delivery Systems; Metals; Nicotine; Nitrosamines; Particle Size; Tandem Mass Spectrometry
PubMed: 24732157
DOI: 10.1136/tobaccocontrol-2013-051482 -
Scientific Reports Jun 2021Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA,...
Using a validated yeast chemogenomic platform, we characterized the genome-wide effects of several pharmaceutical contaminants, including three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds (DMF and 4NQO) and several of their metabolites. A collection of 4800 non-essential homozygous diploid yeast deletion strains were screened in parallel and the strain abundance was quantified by barcode sequencing. These data were used to rank deletion strains representing genes required for resistance to the compounds to delineate affected cellular pathways and to visualize the global cellular effects of these toxins in an easy-to-use searchable database. Our analysis of the N-nitrosamine screens uncovered genes (via their corresponding homozygous deletion mutants) involved in several evolutionarily conserved pathways, including: arginine biosynthesis, mitochondrial genome integrity, vacuolar protein sorting and DNA damage repair. To investigate why NDMA, NDEA and DMF caused fitness defects in strains lacking genes of the arginine pathway, we tested several N-nitrosamine metabolites (methylamine, ethylamine and formamide), and found they also affected arginine pathway mutants. Notably, each of these metabolites has the potential to produce ammonium ions during their biotransformation. We directly tested the role of ammonium ions in N-nitrosamine toxicity by treatment with ammonium sulfate and we found that ammonium sulfate also caused a growth defect in arginine pathway deletion strains. Formaldehyde, a metabolite produced from NDMA, methylamine and formamide, and which is known to cross-link free amines, perturbed deletion strains involved in chromatin remodeling and DNA repair pathways. Finally, co-administration of N-nitrosamines with ascorbic or ferulic acid did not relieve N-nitrosamine toxicity. In conclusion, we used parallel deletion mutant analysis to characterize the genes and pathways affected by exposure to N-nitrosamines and related compounds, and provide the data in an accessible, queryable database.
Topics: Arginine; Biosynthetic Pathways; DNA Damage; DNA Repair; DNA, Fungal; Drug Contamination; Genetic Fitness; Genome, Fungal; Mitochondria; Nitrosamines; Saccharomyces cerevisiae; Sequence Deletion; Toxicity Tests, Acute
PubMed: 34127714
DOI: 10.1038/s41598-021-91792-1 -
Cancer Epidemiology, Biomarkers &... Jan 2015Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and...
BACKGROUND
Identifying sources of variation in the nicotine and nitrosamine metabolic inactivation pathways is important to understanding the relationship between smoking and cancer risk. Numerous UGT1A and UGT2B enzymes are implicated in nicotine and nitrosamine metabolism in vitro; however, little is known about their roles in vivo.
METHODS
Within UGT1A1, UGT1A4, UGT1A9, UGT2B7, UGT2B10, and UGT2B17, 47 variants were genotyped, including UGT2B10*2 and UGT2B17*2. The association between variation in these UGTs and glucuronidation activity within European and African American current smokers (n = 128), quantified as urinary ratios of the glucuronide over unconjugated compound for nicotine, cotinine, trans-3'-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), was investigated in regression models assuming a dominant effect of variant alleles.
RESULTS
Correcting for multiple testing, three UGT2B10 variants were associated with cotinine glucuronidation, rs2331559 and rs11726322 in European Americans and rs835309 in African Americans (P ≤ 0.0002). Additional variants predominantly in UGT2B10 were nominally associated with nicotine (P = 0.008-0.04) and cotinine (P = <0.001-0.02) glucuronidation in both ethnicities in addition to UGT2B10*2 in European Americans (P = 0.01, P < 0.001). UGT2B17*2 (P = 0.03) in European Americans and UGT2B7 variants (P = 0.02-0.04) in African Americans were nominally associated with 3HC glucuronidation. UGT1A (P = 0.007-0.01), UGT2B10 (P = 0.02), and UGT2B7 (P = 0.02-0.03) variants in African Americans were nominally associated with NNAL glucuronidation.
CONCLUSIONS
Findings from this initial in vivo study support a role for multiple UGTs in the glucuronidation of tobacco-related compounds in vivo, in particular UGT2B10 and cotinine glucuronidation.
IMPACT
Findings also provide insight into ethnic differences in glucuronidation activity, which could be contributing to ethnic disparities in the risk for smoking-related cancers. Cancer Epidemiol Biomarkers Prev; 24(1); 94-104. ©2014 AACR.
Topics: Adult; Black or African American; Aged; Genetic Variation; Genotyping Techniques; Glucuronosyltransferase; Humans; Middle Aged; Nicotine; Nitrosamines; Smoking; White People
PubMed: 25277794
DOI: 10.1158/1055-9965.EPI-14-0804 -
Nicotine & Tobacco Research : Official... Jun 2023Cigarette smoke contains highly reactive free radicals thought to play an important role in tobacco smoke-induced harm. Previously, large variations in free radical and...
INTRODUCTION
Cigarette smoke contains highly reactive free radicals thought to play an important role in tobacco smoke-induced harm. Previously, large variations in free radical and toxicant output have been observed in commercial cigarettes. These variations are likely because of cigarette design features (paper, filter, and additives), tobacco variety (burley, bright, oriental, etc.), and tobacco curing methods (air, sun, flue, and fire). Previous reports show that tobacco varieties and curing methods influence the production of tobacco smoke constituents like the tobacco-specific carcinogen nicotine-derived nitrosamine ketone (NNK).
AIMS AND METHODS
We evaluated free radical, nicotine, and NNK production in cigarette smoke from cigarettes produced with 15 different types of tobacco. Gas-phase free radicals were captured by spin trapping with N-tert-butyl-α-phenylnitrone and particulate-phase radicals were captured on a Cambridge Filter pad (CFP). Both types of radicals were analyzed using electron paramagnetic resonance spectroscopy. Nicotine and NNK were extracted from the CFP and analyzed by gas chromatography flame ionization detection and liquid chromatography-mass spectrometry, respectively.
RESULTS
Gas-phase radicals varied nearly 8-fold among tobacco types with Saint James Perique tobacco producing the highest levels (42 ± 7 nmol/g) and Canadian Virginia tobacco-producing the lowest levels (5 ± 2 nmol/g). Nicotine and NNK levels in smoke varied 14-fold and 192-fold, respectively, by type. Gas-phase free radicals were highly correlated with NNK levels (r = 0.92, p < .0001) and appeared to be most impacted by tobacco curing method.
CONCLUSIONS
Altogether, these data suggest that tobacco types used in cigarette production may serve as a target for regulation to reduce harm from cigarette smoking.
IMPLICATIONS
Variations in cigarette free radical and NNK levels vary based on the tobacco variety and curing method. Reducing the ratio of high-producing free radical and NNK tobacco types offer a potential tool for regulators and producers looking to reduce toxicant output from cigarettes.
Topics: Humans; Nicotiana; Nicotine; Tobacco Smoke Pollution; Cigarette Smoking; Canada; Gas Chromatography-Mass Spectrometry; Tobacco Products; Free Radicals; Nitrosamines
PubMed: 36967618
DOI: 10.1093/ntr/ntad049 -
Basic & Clinical Pharmacology &... Sep 2017Human beings are exposed to many reactive electrophiles, both formed endogenously and from exogenous exposures. Such compounds could react with cellular biomolecules and... (Review)
Review
Human beings are exposed to many reactive electrophiles, both formed endogenously and from exogenous exposures. Such compounds could react with cellular biomolecules and form stable reaction products, adducts, at nucleophilic sites in proteins and DNA, constituting a risk for toxic effects. Adductomic approaches aim to study the totality of adducts, to specific biomolecules, by mass spectrometric screening. This Mini-Review focuses on the development and application of an adductomic approach for the screening of unknown adducts to N-terminal valine (Val) in haemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC-MS/MS). The approach is based on the FIRE procedure, a modified Edman procedure for the analysis of adducts to N-terminal Val in Hb by LC-MS/MS. In the first application of the approach, samples from 12 smokers/non-smokers were screened for Hb adducts, and six previously identified adducts and 20 unknown adducts were detected. To confirm the observation of the detected unknown adducts, targeted screenings were performed in larger sets of blood samples (n = 50-120) from human cohorts. The majority of the previously detected unknown adducts was found in all analysed samples, with large interindividual variations in adduct levels. For structural identification of unknown adducts, a strategy using adductome LC-MS/MS data was formulated and applied. Six identified adducts correspond to ethylation and the precursor electrophiles ethyl vinyl ketone, glyoxal, methylglyoxal, acrylic acid and 1-octen-3-one. The observation of these adducts in human blood motivate further studies to evaluate possible contributions to health risks, as well as their potential as biomarkers of exposure.
Topics: Aldehydes; Biomarkers; Chromatography, Liquid; DNA Adducts; Environmental Exposure; Epoxy Compounds; Hemoglobins; Humans; Nitrosamines; Tandem Mass Spectrometry; Valine
PubMed: 27889941
DOI: 10.1111/bcpt.12715 -
International Journal of Molecular... Apr 2022Carcinogenic -nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens-widely detectable... (Review)
Review
Carcinogenic -nitrosamine contamination in certain drugs has recently caused great concern and the attention of regulatory agencies. These carcinogens-widely detectable in relatively low levels in food, water, cosmetics, and drugs-are well-established and powerful animal carcinogens. The electrophiles resulting from the cytochrome P450-mediated metabolism of -nitrosamines can readily react with DNA and form covalent addition products (DNA adducts) that play a central role in carcinogenesis if not repaired. In this review, we aim to provide a comprehensive and updated review of progress on the metabolic activation and DNA interactions of 10 carcinogenic -nitrosamines to which humans are commonly exposed. Certain DNA adducts such as -methylguanine with established miscoding properties play central roles in the cancer induction process, whereas others have been linked to the high incidence of certain types of cancers. We hope the data summarized here will help researchers gain a better understanding of the bioactivation and DNA interactions of these 10 carcinogenic -nitrosamines and facilitate further research on their toxicologic and carcinogenic properties.
Topics: Activation, Metabolic; Animals; Carcinogens; Cytochrome P-450 Enzyme System; DNA; DNA Adducts; Humans; Nitrosamines
PubMed: 35562949
DOI: 10.3390/ijms23094559 -
Journal of Mammary Gland Biology and... Sep 2017Smoking cigarettes is one of the most concerning issues that leads to tobacco-related cancers and can even result in death. Therefore, these issues should be addressed... (Review)
Review
Smoking cigarettes is one of the most concerning issues that leads to tobacco-related cancers and can even result in death. Therefore, these issues should be addressed with a great sense of urgency with low-cost and simple approaches. Over the past several years, the scientific community has attempted to find solutions to overcome this issue. Thus, a large number of excellent studies have been reported in this field, and summarizing these results and providing important roadmaps for future studies is currently of great importance. Finding an outstanding solution to address aforementioned issue would be of great value to the community and to the social. Tobacco contains thousands of chemicals, and sixty-nine compounds have been established as human carcinogens; specifically, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the strongest carcinogen among the tobacco-specific nitrosamines. Tobacco carcinogens are also linked to mammary gland pathogenesis and increased risk of developing many cancers, including breast cancer, the most common cancer in women worldwide. This mini-review summarizes the role of NNK and the mechanisms of its receptor, nicotine acetylcholine receptor (nAChR), signaling in breast cancer based on publications identified using the keywords "secondhand smoke (SHS)", "Nitrosamines" and "breast cancer". Furthermore, this review considers the risk of NNK to the public in an effort to reduce exposure to SHS in women and their chances of developing breast cancer.
Topics: Animals; Breast Neoplasms; Carcinogenesis; Carcinogens; Female; Humans; Nitrosamines; Receptors, Nicotinic; Signal Transduction
PubMed: 28664511
DOI: 10.1007/s10911-017-9381-z -
Current Neuropharmacology 2015The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative... (Review)
Review
The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.
Topics: Animals; Antioxidant Response Elements; Biosensing Techniques; Cysteine; Humans; Nitric Oxide; Nitrosamines; Transient Receptor Potential Channels
PubMed: 26411770
DOI: 10.2174/1570159x1302150525122020 -
Journal of the American Society For... May 2022Carcinogenic -nitrosamines were recently found in the sartan family of drugs and caused many drug recalls. Both of their detection and quantification are therefore...
Carcinogenic -nitrosamines were recently found in the sartan family of drugs and caused many drug recalls. Both of their detection and quantification are therefore important. Methods reported for -nitrosamine quantitation rely on the use of standards and are just applicable to simple -nitrosamines. There is an urgent need to quantify -nitrosamines derived from drugs with a complicated structure that lack standards. To tackle the issue, this study describes a novel absolute quantitation strategy for -nitrosamines using coulometric mass spectrometry (CMS) without standards. In our approach, -nitrosamine is first converted into electrochemically active hydrazine via zinc reduction under acidic condition and the resulting hydrazine can then be easily quantified using CMS. To validate our method, six simple -nitrosamines, -nitrosodiethylamine (NDEA), -nitroso-4-phenylpiperidine (NPhPIP), -nitrosodiphenylamine (NDPhA), -nitrosodibutylamine (NDBA), -nitrosodipropylamine (NDPA), and -nitrosopiperidine (NPIP), were chosen as test samples, and they all were quantified with excellent measurement accuracy (quantitation error ≤1.1%). Taking this one step further, as a demonstration of the method utility, a drug-like -nitrosamine, ()--(2-(6-chloro-5-methyl-1'-nitroso-2,3-dihydrospiro[indene-1,4'-piperidin]-3-yl)propan-2-yl)acetamide (), was also synthesized and successfully quantified using our method at 15 ppb level in a complex formulation matrix, following solvent extraction, -nitrosamine isolation, and reductive conversion. Because of the feature of requiring no standards, CMS provides a simple and powerful approach for -nitrosamine absolute quantitation and has great potential for analysis of other drug impurities or metabolites.
Topics: Gas Chromatography-Mass Spectrometry; Hydrazines; Nitrosamines; Tandem Mass Spectrometry
PubMed: 35446584
DOI: 10.1021/jasms.2c00064