Table 4 Epidemiologic studies of cytochrome P450 2A6 (CYP2A6), nicotine metabolization and tobacco use in human populations.

Xu 2002

Canada N = 14 in kinetic substudy N = 478 in allele frequency study

Wild-type CYP2A6*1/*1 vs. *4/*4, *4/*10, *4/*7, *7/*7, *1/*8

Homozygous wild-type genotypes CYP2A6*1/1 have lower plasma levels of nicotine and higher levels of the CYP2A6-mediated nicotine metabolite cotinine, compared to those with the null *4/4 genotype (6 hours after oral administration of nicotine)

*7/*7 genotypes or *7 in combination with gene deletion have intermediate levels of nicotine

One individual containing both *7 and *8 (CYP2A6*4/*10) has sharply reduced metabolism of both nicotine and cotinine

Rao 2000

Canada N = 296 smokers

CYP2A6*1/*1 vs. *1/*4, *1/2, *2/2, or *1/*1 plus duplication

Smokers with reduced activity or null alleles (*2/2, *1/2 or *1/4) use fewer cigarettes/day compared to those with wild-type (*1/*1) genotype both currently (13.5 ± 2.3 vs. 19.5 ± 0.7) and at time of heaviest smoking (19 vs. 29), and have lower cotinine Levels

Kitagawa 1999

Japan N = 11 smokers in smoking challenge sub-study N = 252 in genotype study

CYP2A6*1/1 vs. homozygous deletion

Homozygous wild-type genotypes CYP2A6*1/1 have higher cotinine concentrations in urine than homozygously deleted genotypes (average concentration 3.87 ± 1.64 vs. 0.40 ± 0.15 ③ g/ml at 1.5 hours after smoking for 1 hr.)

On average over the 24-hr period following smoking challenge, cotinine excretion in homozygously deleted genotypes was one-seventh compared to control group (p < 0.001)

Pianezza 1998

Canada N = 428

CYP2A6*1/1 vs. null alleles *2 or *3

Dependent smokers have lower frequency of null alleles, compared to the never-dependent control group (12.3% vs. 19.6%, p < 0.04, OR = 1.74, 95% CI 1.02–2.94)

Smokers heterozygous for null alleles have fewer number of cigarettes/week (129 vs. 159, t-test p < 0.02), compared to smokers with two active alleles