AIM: Plasma values of nicotine and its metabolites are highly variable, and this variability has a strong genetic influence. In our study, we analysed the impact of common polymorphisms associated with smoking on the plasma values of nicotine, nicotine metabolites and their ratios and investigated the potential effect of these polymorphisms and nicotine metabolite ratios on the successful treatment of tobacco dependence. METHODS: Five variants (rs16969968, rs6474412, rs578776, rs4105144 and rs3733829) were genotyped in a group of highly dependent adult smokers (n=103). All smokers underwent intensive treatment for tobacco dependence; 33 smokers were still abstinent at the 12-month follow-up. RESULTS: The rs4105144 (CYP2A6, P<0.005) and rs3733829 (EGLN2, P<0.05) variants were significantly associated with plasma concentrations of 3OH-cotinine and with 3OH-cotinine: cotinine ratios. Similarly, the unweighted gene score was a significant (P<0.05) predictor of both cotinine:nicotine and 3OH-cotinine:cotinine ratios. No associations between the analysed polymorphisms or nicotine metabolite ratios and nicotine abstinence rate were observed. CONCLUSION: Although CYP2A6 and EGLN2 polymorphisms were associated with nicotine metabolism ratios, neither these polymorphisms nor the ratios were associated with abstinence rates.
- MeSH
- cytochrom P450 CYP2A6 genetika MeSH
- cytochrom P450 CYP2B6 genetika MeSH
- dospělí MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nikotin krev metabolismus MeSH
- nikotinové receptory genetika MeSH
- poruchy vyvolané užíváním tabáku krev genetika metabolismus terapie MeSH
- proteiny nervové tkáně genetika MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Tobacco/nicotine dependence has a significant heritable component. Genome-wide association studies have associated the single nucleotide polymorphisms (SNPs) rs578776, rs16969968, rs6474412, rs3733829 and rs4105144 with nicotine dependence in Western European populations. We examined whether these SNPs influence nicotine dependence and successful treatment of tobacco dependence in the Czech middle-European population. MATERIALS AND METHODS: Variants were analysed by PCR-RFLP or by TaqMan assay in 807 adult heavy tobacco-dependent smokers - patients of the Centre for Treatment of Tobacco Dependence (Prague) as well as 1,362 self-reported non-smokers. RESULTS AND DISCUSSION: Except for rs3733829, association with tobacco dependence was confirmed for all other genetic variants. In agreement with previous studies, the strongest determinant of tobacco dependence was rs16969968 with OR (95%CI) 1.32 (1.08-1.62) for A allele carriers vs. GG comparison (P=0.003). In contrast, none of the analysed variants reached significance with respect to a 1-year course of successful tobacco dependence treatment (all P over 0.18) in a subset of 525 patients. CONCLUSION: We confirmed the association between variants within genes that code nicotinic-acetylcholine receptors (-A3, -A5 and -B3), CYP2A6/B6 and tobacco dependence development in the Czech population. The success of the tobacco dependence treatment was not influenced by the analysed SNPs.
- MeSH
- celogenomová asociační studie MeSH
- cytochrom P450 CYP2A6 MeSH
- cytochrom P450 CYP2B6 genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- nikotinové receptory genetika MeSH
- poruchy vyvolané užíváním tabáku genetika terapie MeSH
- proteiny nervové tkáně MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Československo MeSH
- MeSH
- alkoholdehydrogenasa genetika MeSH
- alkoholismus * genetika MeSH
- dopamin genetika MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- nikotinové receptory genetika MeSH
- polymorfismus genetický MeSH
- poruchy spojené s užíváním psychoaktivních látek * genetika MeSH
- poruchy vyvolané užíváním tabáku * genetika MeSH
- receptory dopaminové genetika MeSH
- závislost (psychologie) MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
While the parasympathetic nervous system appears to be involved in the regulation of tumor progression, its exact role is still unclear. Therefore, using a rat BP6-TU2 fibrosarcoma tumor model, we investigated the effect of (1) reduction of vagal activity produced by subdiaphragmatic vagotomy; and (2) enhancement of vagal activity produced by continuous delivery of electric impulses to the cervical part of the vagus nerve on tumor development and survival of tumor-bearing rats. We also evaluated the expression of cholinergic receptors within in vitro cultivated BP6-TU2 cells. Interestingly, we found that both, vagal stimulation and subdiaphragmatic vagotomy slightly reduced tumor incidence. However, survival of tumor-bearing rats was not affected by any of the experimental approaches. Additionally, we detected mRNA expression of the α1, α2, α5, α7, and α10 subunits of nicotinic receptors and the M1, M3, M4, and M5 subtypes of muscarinic receptors within in vitro cultivated BP6-TU2 cells. Our data indicate that the role of the vagus nerve in modulation of fibrosarcoma development is ambiguous and uncertain and requires further investigation.
- MeSH
- elektrická stimulace MeSH
- fibrosarkom mortalita patologie patofyziologie MeSH
- messenger RNA metabolismus MeSH
- míra přežití MeSH
- nádorové buněčné linie MeSH
- nervus vagus patofyziologie MeSH
- nikotinové receptory genetika metabolismus MeSH
- potkani Wistar MeSH
- receptory muskarinové genetika metabolismus MeSH
- vagotomie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Physostigmine (Phy), a reversible inhibitor of acetylcholine (ACh) esterase (AChE), may also act as a low potency agonist and a modulator of the nicotinic receptor. The actions of Phy on mouse muscle nicotinic receptors in the COS-7 cell line were studied by the patch-clamp technique. Currents were recorded in the whole-cell mode 3-7 days after cell transfection by plasmids coding alphabetagammadelta combination of receptor subunits. The application of ACh to cells clamped at -10 mV produced inward currents which displayed desensitization. The application of Phy in concentrations up to 1 x 10(-3) M did not give reliable specific whole-cell membrane responses. The application of Phy in concentrations of 10(-6)-10(-4) M together with ACh modulated the amplitude; accelerated desensitization of currents induced by ACh and increased the final extent of desensitization in a concentration-dependent manner. This finding is in contrast to the suppression and slowing down of desensitization by Phy and 1-methyl-galanthamine observed in Torpedo receptors.
- MeSH
- acetylcholin farmakologie metabolismus MeSH
- buněčná membrána genetika metabolismus účinky léků MeSH
- Cercopithecus aethiops MeSH
- cholinesterasové inhibitory farmakologie MeSH
- COS buňky MeSH
- financování organizované MeSH
- fysostigmin farmakologie MeSH
- genetické vektory chemická syntéza MeSH
- iontové kanály chemická syntéza metabolismus účinky záření MeSH
- kosterní svaly inervace metabolismus MeSH
- membránové potenciály genetika účinky léků MeSH
- metoda terčíkového zámku MeSH
- myši MeSH
- nervosvalové spojení mikrobiologie účinky léků MeSH
- nervový přenos imunologie účinky záření MeSH
- nikotinové receptory genetika nedostatek účinky léků MeSH
- synergismus léků MeSH
- transfekce MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
