Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers.

Russell, Michael A.; Jarvis, Martin J.; Iyer, Radhika; Feyerabend, C.

doi:10.1136/bmj.280.6219.972

Cited by 447 publications

(223 citation statements)

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“…1B) are similar to those used in previous studies with cultured cells, including human hepatic cells (Fields et al 2005;Nagaraj et al 2006;Xiao et al 2015); they also up-regulated the drug metabolizing enzymes CYP1A1 and CYP1B1, that, together with other AhR targets such as CYP1A2, constitute key targets induced by smoking in humans (Chang et al 2003;Dobrinas et al 2011;Thum et al 2006) and are in the range of CSC concentrations (20 to 120 µg/mL) previously hypothesized to be relevant for human smokers (Gao et al 2005). On the other hand, 10-40 µg/mL CSC corresponds to 0.768-3.072 µg/mL (4.73-18.92 µM) nicotine, when considering that CSC contains 7.68 % (weight/weight) nicotine (Eldridge et al 2015), and such nicotine concentrations are much higher than those (25 to 444 nM) commonly described in smoker blood (Russell et al 1980). This may indirectly favor the hypothesis that 10-40 µg/mL CSC acting on transporters may not be reached in smokers, even if toxicokinetics features of nicotine and those of yet unidentified cigarette smoke chemicals targeting transporters may differ in a major way, bringing caution towards any extrapolation based on nicotine disposition.…”

Section: Discussionmentioning

confidence: 89%

“…A participation of nicotine to inhibitory effect of CSC towards OCT1 activity may therefore be considered. In this context, it is noteworthy that nicotine effects on OCT1 activity were dosedependent and the 10 µM nicotine concentration, which is much higher than blood nicotine concentrations in individual smokers, that varied from 25 to 444 nM (Russell et al 1980), was inactive on OCT1 activity. In vivo concentrations of nicotine in smokers are therefore very unlikely to contribute alone to inhibition of OCT1 activity.…”

Section: Discussionmentioning

confidence: 99%

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Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

et al. 2016

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Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummarySmoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG ce...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

et al. 2016

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“…The DSP preparations were analyzed by gas chromatography and then diluted by DMSO to standard nicotine content (0.1 mg/ml) [8,9]. It has been reported that in smokers, the plasma concentration of nicotine varies between 4 -72 ng/ml, and that the average concentration is 33 ng/ml [46]. In the present study, we used DSP 0.2 µl/ml which contains 20 ng/ml of nicotine.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

Zhang

Edvinsson

et al. 2008

Atherosclerosis

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“…The dosing of Nic was chosen to correlate well with the levels found in the blood and mucous secretions of smokers and snuffers. On smoking days, Nic concentrations in human plasma range between 4 and 72 ng/mL (Peacock et al, 1993) and are extremely high in saliva (Ͼ1300 ng/mL) (Lindell et al, 1993;Russell et al, 1980). The peak Nic plasma levels in the snuffers is similar to the peak values in heavy smokers (Russell et al, 1980(Russell et al, , 1981.…”

mentioning

confidence: 51%

“…On smoking days, Nic concentrations in human plasma range between 4 and 72 ng/mL (Peacock et al, 1993) and are extremely high in saliva (Ͼ1300 ng/mL) (Lindell et al, 1993;Russell et al, 1980). The peak Nic plasma levels in the snuffers is similar to the peak values in heavy smokers (Russell et al, 1980(Russell et al, , 1981. Past experiments in our laboratory using conditions identical to ADSS have found plasma Nic levels in rats to range from 2 to 17 ng/mL, with an average concentration of 12 ng/mL (Joad et al, 1993(Joad et al, , 1995.…”

Section: Figurementioning

confidence: 67%

A Receptor-Mediated Mechanism of Nicotine Toxicity in Oral Keratinocytes

Arredondo

Nguyen

Chernyavsky

et al. 2001

Laboratory Investigation

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SUMMARY:Smoking and smokeless tobacco cause morbidity that originates from the epithelium lining of the skin and upper digestive tract. Oral keratinocytes (OKC) express nicotinic acetylcholine receptors (nAChRs) that bind nicotine (Nic). We studied the mechanism of the receptor-mediated toxicity of tobacco products on OKC. Preincubation of normal human OKC with Nic altered the ligand-binding kinetics of their nAChRs, suggesting that the nAChRs underwent structural changes. This hypothesis was confirmed by the finding that exposure of OKC to Nic causes transcriptional and translational changes. Through RT-PCR and immunoblotting, we found a 1.5-to 2.9-fold increase in the mRNA and protein levels of ␣3, ␣5, ␣7, ␤2, and ␤4 nAChR subunits. Exposure of OKC to Nic also changed the mRNA and protein levels of the cell cycle and cell differentiation markers Ki-67, PCNA, p21, cyclin D1, p53, filaggrin, loricrin, and cytokeratins 1 and 10. The nicotinic antagonist mecamylamine prevented these changes, which indicates that the Nic-induced changes in the expression of both the nAChR and the cell cycle and cell differentiation genes resulted from pharmacologic stimulation of nAChRs with Nic. To establish the relevance of these findings to the pathobiologic effects of tobacco products in vivo, we studied the above parameters in the oral tissue of rats and mice after their exposure for 3 weeks to environmental cigarette smoke or drinking water containing equivalent concentrations of Nic that are pathophysiologically relevant. The changes of the nAChRs and the cell cycle and cell differentiation genes were similar to those found in vitro. The results of indirect immunofluorescence assay of tissue specimens validated these findings. Thus, some pathobiologic effects of tobacco products in oral tissues may stem from Nic-induced alterations of the structure and function of keratinocyte nAChRs responsible for the physiologic regulation of the cell cycle by the cytotransmitter acetylcholine. (Lab Invest 2001, 81:1653-1668.T he epithelial cells lining human attached gingiva and the upper two-thirds portion of the esophagus have recently been shown to express cholinergic enzymes and receptors that mediate acetylcholine (ACh) signaling (Nguyen et al, 2000a(Nguyen et al, , 2000b. The cholinergic system of oral epithelium includes the synthesizing enzyme choline acetyltransferase, two molecular forms of the degrading enzyme acetylcholinesterase, the asymmetric and the globular forms, and two classes of ACh receptors, the nicotinic and the muscarinic receptors. The heteromeric nicotinic ACh receptor (nAChRs) channels on the cell membrane of oral keratinocytes (OKC) can be composed of ␣3, ␣5, ␤2, and ␤4 subunits, eg, ␣3␤2(␤4) Ϯ ␣5, and the homomeric channels can be made of several ␣7 or ␣9 subunits (Conti-Tronconi et al, 1994). The diversity of nAChRs expressed by OKC in the course of their development could allow a single cytotransmitter ACh to exert different effects on these cells at various stages of their development, which helps explai...

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Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers.

Abstract: Summary and conclusionsBlood nicotine and carboxyhaemoglobin (COHb)

Cited by 447 publications

References 18 publications

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

Up-regulation of thromboxane A2 receptor expression by lipid soluble smoking particles through post-transcriptional mechanisms

A Receptor-Mediated Mechanism of Nicotine Toxicity in Oral Keratinocytes

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