Association of Nicotine Metabolite Ratio and CYP2A6 Genotype With Smoking Cessation Treatment in African-American Light Smokers

Abstract

CYP2A6 is the main nicotine metabolizing enzyme in humans. We investigated the relationships between CYP2A6 genotype, baseline plasma 3HC/COT (a phenotypic marker of CYP2A6 activity), and smoking behaviors in African-American light smokers. Cigarette consumption, age of initiation, and dependence scores did not differ between 3HC/COT quartiles or CYP2A6 genotype groups. Slow metabolizers (both genetic and phenotypic) had significantly higher plasma nicotine levels suggesting cigarette consumption was not reduced to adjust for slower rates of nicotine metabolism. Individuals in the slowest 3HC/COT quartile had higher quit rates with both placebo and nicotine gum treatments (OR 1.85, 95% CI 1.08-3.16, p = 0.03). Similarly, the slowest CYP2A6 genotype group had higher quit rates, although this did not reach significance (OR 1.61, 95% CI 0.95-2.72, p = 0.08). 3HC/COT ratio, and possibly CYP2A6 genotype, may be useful in the future for personalizing the choice of smoking cessation treatment for African-American light smokers.

Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects

“…It involved only young smokers, who typically smoke fewer cigarettes/day than older smokers (CDC, 2016), and are slower metabolizers of nicotine because slower metabolizers typically quit smoking earlier than normal metabolizers (Ho et al, 2009). Therefore, the results may not be widely generalizable.…”

Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor

“…Therefore, because inhibition of CYP2A6 should facilitate oral low dose nicotine's entry into and persistence in the systemic circulation, as well as delaying the clearance of inhaled nicotine, it should allow gastrically tolerable doses of nicotine to reduce a smoker's intake of smoked nicotine and exposure to other constituents of tobacco smoke. Furthermore, there is substantial interethnic variation in nicotine C-oxidation primarily due to variation in the frequencies of CYP2A6 alleles; loss/reduce of function CYP2A6 alleles are more prevalent in Asians and Africans than amog Caucasians (Ho et al, 2009;Malaiyandi, Sellers, & Tyndale, 2005;). This is consistent with Asian Americans and African Americans metabolizing nicotine and cotinine more slowly than Caucasians (Benowitz et al, 2002).…”

“…Within any of these ethnic groups, reduction in CYP2A6-mediated nicotine metabolism results in an altered smoking behaviors including lower smoking levels and greater rates of cessation (reviewed in Ray et al, 2009). However most people in these ethnic groups are not full poor metabolizers, with both alleles being fully null, rather they range from slow to intermediate, to normal, to fast nicotine metabolizers (Ho et al, 2009;Malaiyandi et al, 2005;). Thus, as people with the slowest rates of nicotine metabolism have the best quit rates in both placebo and nicotine replacement therapies (Ho et al, 2009;Lerman et al, 2006Lerman et al, , 2010Patterson et al, 2008;Ray et al, 2009), it is possible that slowing nicotine metabolism using inhibitors, along with nicotine, will combine the two effects observed in placebo and NRT treatment arms to increase the smoking cessation rates (Sellers et al, 2000;Tyndale et al, 1999).…”

Nicotine Dependence, Nicotine Metabolism, and the Extent of Compensation in Response to Reduced Nicotine Content Cigarettes

“…23 As described previously prevalent CYP2A6 alleles with altered function were genotyped by 2 step allele-specific polymerase chain reactions and those individuals with 1 or 2 copies of reduced function alleles (*2, *4, *7, *9, *10, *12, *17, *20, *23-*28, *31, *34, and *35) were classified as CYP2A6 reduced metabolizers. 9,22,24 The SNP in the CHRNA5-A3-B4 gene cluster rs1051730 was genotyped using Applied Biosystem Taqman genotyping assays. 25 Urine measures of PAH exposure, including the PAH metabolites 2-napthol (2NP), 1-hydroxypyrene (1HP), and 2-hydroxyfluorene (2FL) were assayed by liquid chromatography/tandem mass spectrometry.…”

“…8 Further, faster metabolizers of nicotine are generally heavier smokers, more dependent on nicotine, and have a harder time quitting than slower metabolizers. 7,[9][10][11][12] Genetic associations with heavier smoking and a higher level of nicotine dependence include CYP2A6 variants and CHRNA5-A3-B4 gene cluster variants. CYP2A6 is the enzyme that is primarily responsible for nicotine metabolism, and normal metabolizers exhibit higher dependence than slow metabolizers.…”