Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

doi:10.2133/dmpk.20.227

Drug Metabolism and Pharmacokinetics

Volume 20, Issue 4, 2005, Pages 227-235

https://doi.org/10.2133/dmpk.20.227 Get rights and content

Summary:

Nicotine has roles in the addiction to smoking, replacement therapy for smoking cessation, as a potential medication for several diseases such as Parkinson's disease, Alzheimer's disease, and ulcerative colitis. The absorbed nicotine is rapidly and extensively metabolized and eliminated to urine. A major pathway of nicotine metabolism is C-oxidation to cotinine, which is catalyzed by CYP2A6 in human livers. Cotinine is subsequently metabolized to trans-3'-hydroxycotinine by CYP2A6. Nicotine and cotinine are glucuronidated to N-glucuronides mainly by UGT1A4 and partly by UGT1A9. Trans-3'- hydroxycotinine is glucuronidated to O-glucuronide mainly by UGT2B7 and partly by UGT1A9. Approximately 90% of the total nicotine uptake is eliminated as these metabolites and nicotine itself. The nicotine metabolism is an important determinant of the clearance of nicotine. Recently, advances in the understanding of the interindividual variability in nicotine metabolism have been made. There are substantial data suggesting that the large interindividual differences in cotinine formation are associated with genetic polymorphisms of the CYP2A6 gene. Interethnic differences have also been observed in the cotinine formation and the allele frequencies of the CYP2A6 alleles. Since the genetic polymorphisms of the CYP2A6 gene have a major impact on nicotine clearance, its relationships with smoking behavior or the risk of lung cancer have been suggested. The metabolic pathways of the glucuronidation of nicotine, cotinine, and trans-3'-hydroxycotinine in humans would be one of the causal factors for the interindividual differences in nicotine metabolism. This review mainly summarizes recent results from our studies.

References (57)

S. Cholerton et al.
Poor metabolisers of nicotine and CYP2D6 polymorphism
Lancet
(1994)
K. Kitagawa et al.
CYP2A6*6, a novel polymorphism in cytochrome P450 2A6, has a single amino acid substitution (R128Q) that inactivates enzymatic activity
J. Biol. Chem.
(2001)
C. Xu et al.
An in vivo pilot study characterizing the new CYP2A6*7, *8, and *10 alleles
Biochem. Biophys. Res. Commun.
(2002)
M. Oscarson et al.
Characterization and PCR-based detection of CYP2A6 gene deletion found at a high frequency in a Chinese population
FEBS Lett.
(1999)
M. Oscarson et al.
Identification and characterization of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism
FEBS Lett.
(1999)
N. Ariyoshi et al.
A novel single nucleotide polymorphism altering stability and activity of CYP2A6
Biochem. Biophys. Res. Commun.
(2001)
M. Pitarque et al.
Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity
Biochem. Biophys. Res. Commun.
(2001)
H. Yamanaka et al.
Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted
Eur. J. Pharm. Sci.
(2004)
A.R. Tricker
Nicotine metabolism, human drug metabolism polymorphisms, and smoking behavior
Toxicology
(2003)
M. Saeki et al.
Genetic variations and haplotypes of UGT1A4 in a Japanese population
Drug Metab. Pharmacokinet.
(2005)

B.T. Ethell et al.

The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases

Biochem. Pharmacol.

(2003)

W.C. Vial

Cigarette smoking and lung disease

Am. J. Med. Sci.

(1986)

N.L. Benowitz

Drug therapy

Pharmacologic aspects of cigarette smoking and nicotine addiction. N. Engl. J. Med.

(1988)

E.W. Lee et al.

Cigarette smoking, nicotine addiction, and its pharmacologic treatment

Arch. Intern. Med.

(1993)

M.A.H. Russell et al.

Cigarette smoking: A dependence on high-nicotine boli

Drug Metab. Rev.

(1978)

M. Nakajima et al.

Role of human cytochrome P4502A6 in C-oxidation of nicotine

Drug Metab. Dispos.

(1996)

M. Nakajima et al.

Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes

J. Pharmacol. Exp. Ther.

(1996)

N.L. Benowitz et al.

Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine

J. Pharmacol. Exp. Ther.

(1994)

G.D. Byrd et al.

Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans- 3'-hydroxycotinine in smokers

Drug Metab. Dispos.

(1992)

J.R. Cashman et al.

Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N' -oxide

Chem. Res. Toxicol.

(1992)

S.E. Murphy et al.

Characterization of multiple products of cytochrome P450 2A6-catalyzed cotinine metabolism

Chem. Res. Toxicol.

(1999)

N.L. Benowitz et al.

Deficient C-oxidation of nicotine

Clin. Pharmacol. Ther.

(1995)

Y. Rao et al.

Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking

Mol. Pharmacol.

(2000)

G. Scherer et al.

Pharmacokinetics of nicotine, cotinine, and 3?-hydroxycotinine in cigarette smokers

Klin. Wochenschr.

(1988)

M. Nakajima et al.

Deficient cotinine formation from nicotine is attributed to the whole deletion of the CYP2A6 gene in humans

Clin. Pharmacol. Ther

(2000)

M. Nakajima et al.

Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans

Clin. Pharmacol. Ther.

(2001)

J.-T. Kwon et al.

Nicotine metabolism and CYP2A6 allele frequencies in Koreans

Pharmacogenetics

(2001)

K. Nunoya et al.

A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans

J. Pharmacol. Exp. Ther.

(1999)

Cited by (83)

Simultaneous quantification of urinary tobacco and marijuana metabolites using solid-supported liquid-liquid extraction coupled with liquid chromatography tandem mass spectrometry
2022, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Citation Excerpt :
Despite low extraction recovery of 3OH-COT, the method demonstrated sufficient sensitivity during MS analysis and the use of isotope dilution allows for the automatic correction for recovery thus preserving the integrity of the quantitative value. Although assessing tobacco exposure can be adequately done using the concentrations of COT alone, concentrations of 3OH-COT will permit the evaluation of the associated toxicity of tobacco modified by the individual genetic polymorphisms [3,35]. Thus, inclusion of 3OH-COT as one of the target analytes in the method has advantages for epidemiological studies.
Co-exposure to tobacco and marijuana has become common in areas where recreational marijuana use is legal. To assist in the determination of the combined health risks of this co-exposure, an analytical method capable of simultaneously measuring tobacco and marijuana metabolites is needed to reduce laboratory costs and the required sample volume. So far, no such analytical method exists. Thus, we developed and validated a method to simultaneously quantify urinary levels of trans-3′-hydroxycotinine (3OH-COT), cotinine (COT), and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC) to assess co-exposure to tobacco and marijuana. Urine (200 µL) was spiked with labelled internal standards and enzymatically hydrolyzed to liberate the conjugated analytes before extraction using solid-supported liquid-liquid extraction (SLE) with ethyl acetate serving as an eluent. The target analytes were separated on a C18 (4.6 × 100 mm, 5 μm) analytical column with a gradient mobile phase elution and analyzed using tandem mass spectrometry with multiple reaction monitoring of target ion transitions. Positive electrospray ionization (ESI) was used for 3OH-COT and COT, while negative ESI was used for COOH-THC. The total run time was 13 min. The extraction recoveries were 18.4–23.9 % (3OH-COT), 65.1–96.8 % (COT), and 80.6–95.4 % (COOH-THC). The method limits of quantification were 5.0 ng/mL (3OH-COT) and 2.5 ng/mL (COT and COOH-THC). The method showed good accuracy (82.5–98.5 %) and precision (1.22–6.21 % within-day precision and 1.42–6.26 % between-day precision). The target analytes were stable for at least 144 h inside the autosampler (10 °C). The analyses of reference materials and 146 urine samples demonstrated good method performance. The use of a 96-well plate for preparation makes the method useful for the analysis of large numbers of samples.
Complex interactions between nicotine and resveratrol in the Drosophila melanogaster wing spot test
2022, Heliyon
Citation Excerpt :
Results from the HB cross, in which the Cyp450s are over-expressed [62,78] showed no genotoxic damage in the surviving flies, at any of the concentrations tested. This supports the idea that increasing the XM and clearance of NIC [79,80,81] was sufficient to counteract the genotoxic damage NIC could have induced. We infer that NIC induced genotoxicity or aneuploidy at a low concentration because several studies of the effects of NIC in vitro have shown that NIC induces damage at low concentrations.
Nicotine (NIC) and resveratrol (RES) are chemicals in tobacco and wine, respectively, that are widely consumed concurrently worldwide. NIC is an alkaloid known to be toxic, addictive and to produce oxidative stress, while RES is thought of as an antioxidant with putative health benefits. Oxidative stress can induce genotoxic damage, yet few studies have examined whether NIC is genotoxic in vivo. In vitro studies have shown that RES can ameliorate deleterious effects of NIC. However, RES has been reported to have both antioxidant and pro-oxidant effects, and an in vivo study reported that 0.011 mM RES was genotoxic. We used the Drosophila melanogaster wing spot test to determine whether NIC and RES, first individually and then in combination, were genotoxic and/or altered the cell division. We hypothesized that RES would modulate NIC’s effects. NIC was genotoxic in the standard (ST) cross in a concentration-independent manner, but not genotoxic in the high bioactivation (HB) cross. RES was not genotoxic in either the ST or HB cross at the concentrations tested. We discovered a complex interaction between NIC and RES. Depending on concentration, RES was protective of NIC’s genotoxic damage, RES had no interaction with NIC, or RES had an additive or synergistic effect, increasing NIC’s genotoxic damage. Most NIC, RES, and NIC/RES combinations tested altered the cell division in the ST and HB crosses. Because we used the ST and HB crosses, we demonstrated that genotoxicity and cell division alterations were modulated by the xenobiotic metabolism. These results provide evidence of NIC’s genotoxicity in vivo at specific concentrations. Moreover, NIC’s genotoxicity can be modulated by its interaction with RES in a complex manner, in which their interaction can lead to either increasing NIC’s damage or protecting against it.
Slower nicotine metabolism among postmenopausal Polish smokers
2018, Pharmacological Reports
A non-invasive phenotypic indicator of the rate of nicotine metabolism is nicotine metabolite ratio (NMR) defined as a ratio of two major metabolites of nicotine – trans-3′-hydroxycotinine/cotinine. The rate of nicotine metabolism has important clinical implications for the likelihood of successful quitting with nicotine replacement therapy (NRT). We conducted a study to measure NMR among Polish smokers.
In a cross-sectional study of 180 daily cigarette smokers (42% men; average age 34.6 ± 13.0), we collected spot urine samples and measured trans-3′-hydroxycotinine (3-HC) and cotinine levels with LC–MS/MS method. We calculated NMR (molar ratio) and analyzed variations in NMR among groups of smokers.
In the whole study group, an average NMR was 4.8 (IQR 3.4–7.3). The group of women below 51 years had significantly greater NMR compared to the rest of the population (6.4; IQR 4.1–8.8 vs. 4.3; IQR 2.8–6.4). No differences were found among group ages of male smokers.
This is a first study to describe variations in nicotine metabolism among Polish smokers. Our findings indicate that young women metabolize nicotine faster than the rest of population. This finding is consistent with the known effects of estrogen to induce CYP2A6 activity. Young women may require higher doses of NRT or non-nicotine medications for most effective smoking cessation treatment.
Nicotine pharmacokinetic profiles of the Tobacco Heating System 2.2, cigarettes and nicotine gum in Japanese smokers
2017, Regulatory Toxicology and Pharmacology
Citation Excerpt :
However, a study conducted by Gries et al. in 1996 estimated a t1/2 of 11 h, calculated using urinary excretion of nicotine, which is more sensitive in detecting lower levels than plasma measurements (Gries et al., 1996). One possible reason of this longer half-life might have been that Japanese more often exhibit cytochrome P450 2A6 (CYP2A6) polymorphism resulting in a lower metabolic rate of nicotine; in this case the 24-h wash-out period prior to single product use was not sufficient to completely eliminate nicotine (Nakajima et al., 2006; Nakajima and Yokoi, 2005). Also, with the analytical method used in this study, the LLOQ was 0.2 ng/mL, whereas LLOQ values typically reported in the literature are approximately 0.5–1 ng/mL (Gries et al., 1996; Lerman et al., 2015).
Two open-label randomized cross-over studies in Japanese smokers investigated the single-use nicotine pharmacokinetic profile of the Tobacco Heating System (THS) 2.2, cigarettes (CC) and nicotine replacement therapy (Gum).
In each study, one on the regular and one on the menthol variants of the THS and CC, both using Gum as reference, 62 subjects were randomized to four sequences: Sequence 1: THS - CC (n = 22); Sequence 2: CC – THS (n = 22); Sequence 3: THS – Gum (n = 9); Sequence 4: Gum – THS (n = 9). Plasma nicotine concentrations were measured in 16 blood samples collected over 24 h after single use.
Maximal nicotine concentration (C_max) and area under the curve from start of product use to time of last quantifiable concentration (AUC_0-last) were similar between THS and CC in both studies, with ratios varying from 88 to 104% for C_max and from 96 to 98% for AUC_0-last. Urge-to-smoke total scores were comparable between THS and CC.
The THS nicotine pharmacokinetic profile was close to CC, with similar levels of urge-to-smoke. This suggests that THS can satisfy smokers and be a viable alternative to cigarettes for adult smokers who want to continue using tobacco.
Safety of long-term nicotine use: An ongoing debate
2016, Revue des Maladies Respiratoires
La nicotine au long cours a été proposée dans le cadre de la réduction des risques des fumeurs ne parvenant ou ne souhaitant pas arrêter de fumer. Sa sécurité d’emploi reste cependant débattue.
Analyse des publications identifiées dans PubMed, Toxibase, Google Scholar et sur les sites de la Food and Drug Administration et de la Haute Autorité de santé.
La nicotine semble impliquée dans la genèse de l’athérosclérose. Elle pourrait être un précurseur de néoplasies, être impliquée dans la prolifération des cancers, dans leur angiogenèse, dans la réduction de l’apoptose et avoir un effet génotoxique. Une évaluation plus complète du rapport bénéfice–risque de la nicotine au long cours nécessite des nouvelles données.
Il semble difficile d’affirmer l’innocuité de la nicotine au long cours. Son utilisation doit être pensée en termes de réduction des risques, comme les autres stratégies mises en œuvre, notamment dans le domaine des drogues illicites.
Long-term nicotine use has been proposed as a risk-reduction strategy in smokers unwilling or unable to quit. However, its safety remains debated.
Analysis of publications identified in PubMed, Toxibase, Google Scholar and in the Food and Drug Administration, and French National Authority for Health websites.
Nicotine seems to be implicated in the genesis of atherosclerosis. It could be a cancer precursor, could be implicated in cancer proliferation and angiogenesis, in apoptosis reduction, and may be genotoxic. New studies are warranted for more complete assessment of the risk–benefit balance.
It is difficult to affirm the safety of long term nicotine use. The risk–benefit balance should be assessed in terms of a risk-reduction strategy, as in other domains, notably illicit drug use.
Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8
2015, Drug Metabolism and Pharmacokinetics
While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug–drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the k_inact and K′_app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min⁻¹ and 57.3 μM, respectively. In this study, the k_{obs, in vivo} value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The k_{obs, in vivo} values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min⁻¹ and 0.0051 min⁻¹, respectively. The k_{obs, in vivo} value of gemfibrozil was 0.0060 min⁻¹, which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo.

View all citing articles on Scopus

View full text

ReviewInterindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation

Summary:

Lancet

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

FEBS Lett.

FEBS Lett.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Eur. J. Pharm. Sci.

Toxicology

Drug Metab. Pharmacokinet.

Biochem. Pharmacol.

Cigarette smoking and lung disease

Am. J. Med. Sci.

Drug therapy

Pharmacologic aspects of cigarette smoking and nicotine addiction. N. Engl. J. Med.

Cigarette smoking, nicotine addiction, and its pharmacologic treatment

Arch. Intern. Med.

Cigarette smoking: A dependence on high-nicotine boli

Drug Metab. Rev.

Role of human cytochrome P4502A6 in C-oxidation of nicotine

Drug Metab. Dispos.

Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes

J. Pharmacol. Exp. Ther.

Nicotine metabolic profile in man: comparison of cigarette smoking and transdermal nicotine

J. Pharmacol. Exp. Ther.

Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans- 3'-hydroxycotinine in smokers

Drug Metab. Dispos.

Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N' -oxide

Chem. Res. Toxicol.

Characterization of multiple products of cytochrome P450 2A6-catalyzed cotinine metabolism

Chem. Res. Toxicol.

Deficient C-oxidation of nicotine

Clin. Pharmacol. Ther.

Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking

Mol. Pharmacol.

Pharmacokinetics of nicotine, cotinine, and 3?-hydroxycotinine in cigarette smokers

Klin. Wochenschr.

Deficient cotinine formation from nicotine is attributed to the whole deletion of the CYP2A6 gene in humans

Clin. Pharmacol. Ther

Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans

Clin. Pharmacol. Ther.

Nicotine metabolism and CYP2A6 allele frequencies in Koreans

Pharmacogenetics

A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans

J. Pharmacol. Exp. Ther.

Review
Interindividual Variability in Nicotine Metabolism: C-Oxidation and Glucuronidation