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PubMedDate not supplied

The interrelationship between the metabolism of (S)-continine-N-oxide and (S)-cotinine.

The metabolism of (S)-cotinine-N-oxide was studied in the rabbit and the dog. The pattern of Koenig-positive substances in the urine of the animals suggested the presence of cotinine, demethylcotinine, hydroxycotinine, and allohydroxycotinine, compounds already previously identified as metabolites of (S)-cotinine and (S)-nicotine in many mammalian species. In the dog, 34% of the administered oral dose of (S)-cotinine-N-oxide was recovered from the urine, and 21% was recovered from the urine of the rabbit. Confirmation of the presence of (S)-cotinine, (S)-demethulcotinine, hydroxycotinine, and allohydroxycotinine in the urine of the rabbits was obtained by isolation of the metabolites as themselves of as derivatives. The data, although establishing the possibilities of an intermediary role for (S)-cotinine-N-oxide in the metabolism of nicotine, do not clearly indicate whether the metabolites such as demethylcotinine arise via the route (S)-cotinine-N-oxide leads to (S)-cotinine leads to (S)-demethylcotinine or via the alternate route (S)-cotinine-N-oxide leads to (S)-demethylcotinine-N-oxide leads to (S)-demethylcotinine.

Animals↗
PubMedDate not supplied

Localization of nicotine-14C, cotinine-14C, and nicotine-1'-N-oxide-14C in tissues of the mouse.

The distrubutions of nicotine-14C (2'- or methyl-labeled), cotinine-14C, and nicotine-1'-N-oxide-14C were studied by whole-body autoradiography in mice and in perfused rabbit lung. The compounds were administered either iv, sc, ip, or by inhalation. Blank sections were also incubated with nicotine-14C and cotinine-14C in vitro. The distributions were compared in a black (C57BL/6J), brown (C57L/J), and albino (A/HeJ) strain and in CD-1 germ-free mice. After administration of nicotine-14C in vivo, radioactivity was localized in all strains in bronchi, nasal mucosa, salivary gland, Harder's gland, liver, kidney, stomach, spleen, pancreas, intestine, bone, gallbladder, and adrenal medulla. In the pigmented strains, it was also localized in melanin in the eye, brain, and hair. Radioactivity did not accumulate in the bronchi of late-term fetuses or the 1-day-old newborn but was present in the 2-day-old and older. Cotinine-14C and nicotine-1'-N-oxide-14C, after iv administration, did not localize in bronchi or nasal mucosa at short time intervals after injection. Frozen sections incubated in vitro did not accumulate either nicotine-14C or cotinine-14C in the bronchi; whereas the affinity for melanin was unchanged. Incubation of fresh, nonfrozen mouse lung and perfusion of rabbit lung in vitro with nicotine-14C produced the same localization of radioactivity in bronchi as that seen after in vivo administration. Preheating the frozen sections or lungs in a microwave oven before incubation did not change the localization of radioactivity in the bronchi or other tissues. The localization of radioactivity in bronchi may be due to metabolism, active transport, or binding of nicotine; this mechanism is destroyed by freezing the tissue.

Animals↗
PubMed1979

Nicotine and cotinine in breast fluid.

Breast fluid which bathes the mammary ductal epithelium may contain tumorogenic components. In view of the number of tobacco components inhaled during smoking, it was of interest whether nicotine and its metabolites were present in this fluid. Fluid was obtained from the nipple from menstruating women who were smokers and non-smokers. In smokers, nicotine and cotinine were detectable in the fluid 30 min after smoking. Further analysis of breast fluid may give leads as to whether components present are related to breast carcinogenesis.

Body Fluids↗
PubMed1975

Nicotine absorption by workers harvesting green tobacco.

Green-tobacco sickness is an occupational illness of tobacco harvesters. Symptoms include nausea, vomiting, dizziness, and prostration. The disease is self-limited and of short duration, but recurs frequently in susceptible workers. The aetiology is not known, but nicotine has been suspected as a causative agent. Thirty-two workers on four North Carolina tobacco farms were studied during harvesting. None of these workers smoked or chewed tobacco. Urinary cotinine (the major metabolite of nicotine) levels were monitored over a 24-hour period to evaluate nicotine absorption. There was a tenfold rise in mean excretion of cotinine among workers who had greatest contact with the tobacco. Less cotinine was found in urine of workers who had less exposure. Levels of cotinine exceeded those found in novice smokers who smoked 3 cigarettes in succession. Absorption of nicotine from tobacco leaf is the likely cause of tobacco sickness.

Absorption↗
PubMedDate not supplied

Effect of dose on the pharmacokinetics of intravenous nicotine in the rat.

The pharmacokinetics of [methyl-14C]nicotine were evaluated in male Fischer-344 rats following the iv injection of 0.08-, 0.4-, or 0.8-mg/kg doses. Independent of dose, the concentration of nicotine declined biexponentially with a mean half-life ranging from 0.92 to 1.10 hr. However, the total plasma clearance of nicotine increased (p less than 0.05) from a mean value of 2.53 liter/hr-kg at the 0.08 mg/kg dose to mean values of 3.88 and 4.04 at the 0.4- and 0.8-mg/kg doses, respectively. There were no dose-related differences in the half-life of formation of the major metabolite, cotinine (range 0.33-0.46 hr) or the half-life of its elimination (range 5.39-6.63 hr). However, the areas under the cotinine plasma concentration-time curves did not increase proportionately with the dose of nicotine, indicating that the dose-related increase in the total plasma clearance of nicotine is not due to an increase in its biotransformation to cotinine. Similar conclusions were obtained with regard to the disposition kinetics of other polar metabolites of nicotine. The urinary excretions of nicotine and its metabolites were dose-independent.

Animals↗
PubMed1978

In vivo and in vitro alteration of nicotine metabolism by the major metabolite of phenytoin.

The influence of hydroxyphentoin (HPPH), the major metabolite of phenytoin, on the in vitro and in vivo metabolism of nicotine was examined. In rat liver 9,000 g supernatant HPPH decreased the appearance of cotinine from nicotine by 65% while not influencing the disappearance of nicotine or the appearance of nicotine-l'-N-oxide. In vivo, HPPH inhibited both nicotine elimination and cotinine formation but did not affect nicotin-l'-N-oxide formation.

Animals↗
PubMed2025

DNA methylation age deviation and cognitive status among older adults in the US, NHANES 1999-2002.

Biological aging, measured using DNA methylation, is a potential biomarker for cognitive health outcomes. We evaluated associations between DNA methylation measures of aging and cognition in a nationally representative sample of adults aged 60+ in the National Health and Nutrition Examination Survey (NHANES), 1999-2002. Genome-wide DNA methylation data were used to create 13 measures of biological aging trained on different aging phenotypes. Cognition was assessed with the Digit Symbol Substitution Test (DSST). To evaluate associations between each DNA methylation measure and DSST score, survey-weighted linear regression models adjusted for age, sex, race/ethnicity, education, smoking, serum cotinine, and BMI were run. We assessed effect modification by sex, education, and race and ethnicity. Included participants (N=1,463) were an average of 70.5 years old and 82.7% non-Hispanic White. The average DSST score was 46.9 (SD 17.6). Ten of 13 DNA methylation measures were associated with DSST (adjusted p<0.05). One year of GrimAge2 accelerated aging was associated with -0.41 points lower DSST score (95% CI: -0.61, -0.21; adjusted p=5&#xd7;10-4). In stratified analyses, higher magnitudes of association were observed among male and non-Hispanic White participants across multiple aging measures. DNA methylation may be a useful biomarker of cognitive status among older adults.

DNA methylation↗
PubMed2024

Tobacco, nicotine, and cannabis use and exposure in an Australian Indigenous population during pregnancy: A protocol to measure parental and foetal exposure and outcomes.

BACKGROUND: The Australian National Perinatal Data Collection collates all live and stillbirths from States and Territories in Australia. In that database, maternal cigarette smoking is noted twice (smoking <20 weeks gestation; smoking >20 weeks gestation). Cannabis use and other forms of nicotine use, for example vaping and nicotine replacement therapy, are nor reported. The 2021 report shows the rate of smoking for Australian Indigenous mothers was 42% compared with 11% for Australian non-Indigenous mothers. Evidence shows that Indigenous babies exposed to maternal smoking have a higher rate of adverse outcomes compared to non-Indigenous babies exposed to maternal smoking (S1 File). OBJECTIVES: The reasons for the differences in health outcome between Indigenous and non-Indigenous pregnancies exposed to tobacco and nicotine is unknown but will be explored in this project through a number of activities. Firstly, the patterns of parental and household tobacco, nicotine and cannabis use and exposure will be mapped during pregnancy. Secondly, a range of biological samples will be collected to enable the first determination of Australian Indigenous people's nicotine and cannabis metabolism during pregnancy; this assessment will be informed by pharmacogenomic analysis. Thirdly, the pharmacokinetic and pharmacogenomic findings will be considered against maternal, placental, foetal and neonatal outcomes. Lastly, an assessment of population health literacy and risk perception related to tobacco, nicotine and cannabis products peri-pregnancy will be undertaken. METHODS: This is a community-driven, co-designed, prospective, mixed-method observational study with regional Queensland parents expecting an Australian Indigenous baby and their close house-hold contacts during the peri-gestational period. The research utilises a multi-pronged and multi-disciplinary approach to explore interlinked objectives. RESULTS: A sample of 80 mothers expecting an Australian Indigenous baby will be recruited. This sample size will allow estimation of at least 90% sensitivity and specificity for the screening tool which maps the patterns of tobacco and nicotine use and exposure versus urinary cotinine with 95% CI within &#xb1;7% of the point estimate. The sample size required for other aspects of the research is less (pharmacokinetic and genomic n = 50, and the placental aspects n = 40), however from all 80 mothers, all samples will be collected. CONCLUSIONS: Results will be reported using the STROBE guidelines for observational studies. FORWARD: We acknowledge the Traditional Custodians, the Butchulla people, of the lands and waters upon which this research is conducted. We acknowledge their continuing connections to country and pay our respects to Elders past, present and emerging. Notation: In this document, the terms Aboriginal and Torres Strait Islander and Indigenous are used interchangeably for Australia's First Nations People. No disrespect is intended, and we acknowledge the rich cultural diversity of the groups of peoples that are the Traditional Custodians of the land with which they identify and with whom they share a connection and ancestry.

Adult↗
PubMed2024

Fine-mapping the CYP2A6 regional association with nicotine metabolism among African American smokers.

The nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine) is a stable biomarker for CYP2A6 enzyme activity and nicotine clearance, with demonstrated clinical utility in personalizing smoking cessation treatment. Common genetic variation in the CYP2A6 region is strongly associated with NMR in smokers. Here, we investigated this regional association in more detail. We evaluated the association of CYP2A6 single-nucleotide polymorphisms (SNPs) and * alleles with NMR among African American smokers (N&#x2009;=&#x2009;953) from two clinical trials of smoking cessation. Stepwise conditional analysis and Bayesian fine-mapping were undertaken. Putative causal variants were incorporated into an existing African ancestry-specific genetic risk score (GRS) for NMR, and the performance of the updated GRS was evaluated in both African American (n&#x2009;=&#x2009;953) and European ancestry smokers (n&#x2009;=&#x2009;933) from these clinical trials. Five independent associations with NMR in the CYP2A6 region were identified using stepwise conditional analysis, including the deletion variant CYP2A6*4 (beta&#x2009;=&#x2009;-0.90, p&#x2009;=&#x2009;1.55&#x2009;&#xd7;&#x2009;10-11). Six putative causal variants were identified using Bayesian fine-mapping (posterior probability, PP&#x2009;=&#x2009;0.67), with the top causal configuration including CYP2A6*4, rs116670633, CYP2A6*9, rs28399451, rs8192720, and rs10853742 (PP&#x2009;=&#x2009;0.09). Incorporating these putative causal variants into an existing ancestry-specific GRS resulted in comparable prediction of NMR within African American smokers, and improved trans-ancestry portability of the GRS to European smokers. Our findings suggest that both * alleles and SNPs underlie the association of the CYP2A6 region with NMR among African American smokers, identify a shortlist of variants that may causally influence nicotine clearance, and suggest that portability of GRSs across populations can be improved through inclusion of putative causal variants.

Adult↗
PubMedDate not supplied

Protective clothing as a means of reducing nicotine absorption in tobacco harvesters.

Green tobacco sickness is an occupational illness of tobacco illness of tobacco harvesters that is thought to be caused by dermal absorption of nicotine from contact with green tobacco leaf. Wearing of rubberized nylon rainsuits effectively prevented nicotine absorption in volunteers who picked wet tobacco. Nicotine absorption was demonstrated in workers who wore clothing that was not waterproof.

Adult↗
PubMed1976

Accumulation of nicotine in the uterine fluid of the six-day pregnant rabbit.

In 6-day pregnant New Zealand White rabbits dosed intravenously with 3H-nicotine, the 3H-activity in the uterine fluid was approximately 5 to 11 times greater than that in the plasma at the corresponding times; 3H-nicotine itself accounted for most of this radioactivity. Dichlorodiphenyltrichloroethane (DDT) also accumulated in the uterine luminal fluid of 6-day pregnant rabbits, but to a lesser extent. However, nicotine or DDT accumulation did not occur in similarly treated, nonpregnant rabbits. The radioactivity in the uterine fluid of rabbits treated with 14C-isoniazid, salicylic acid, barbital, antipyrine, and caffeine was not different from that in the plasma (uterine fluid to plasma radioactivity ratios ranged between 0.67 and 1.85) in both 6-day pregnant and nonpregnant rabbits. No differences in regard to nicotine metabolism, volume of distribution, plasma disappearance, plasma protein binding, or urinary excretion were found between 6-day pregnant and nonpregnant rabbits. Accumulation of nicotine took place in the uterine luminal fluid of nonpregnant does pretreated with either progesterone or human chorionic gonadotropin, but did not occur in does pretreated with estrogen. It is possible that the accumulation of nicotine in uterine fluid of pregnant does and in human chorionic gonadotropin- or progesterone-pretreated nonpregnant does is due to the binding of nicotine to specific uterine fluid proteins.

Animals↗