The influence of CYP2A6 polymorphisms and cadmium on nicotine metabolism in Thai population.

ABSTRACT

We investigated the influence of genetic, cadmium exposure and smoking status, on cytochrome P450-mediated nicotine metabolism (CYP2A6) in 182 Thai subjects after receiving 2mg of nicotine gum chewing for 30min. The urinary excretion of cotinine was normally distributed over a 2h period (logarithmically transformed). Individuals with urinary cotinine levels in the ranges of 0.01-0.21, and 0.52-94.99µg/2h were categorized as poor metabolizes (PMs 6.5%), and extensive metabolizers (EMs 93.5%), respectively. The majority of EMs (45%) carried homozygous wild-type genotypes (CYP2A6*1A/*1A, CYP2A6*1A/*1B and CYP2A6*1B/*1B), whereas only 1% of PMs carried these genotypes. Markedly higher frequencies of EMs were also observed in all heterozygous defective genotypes including the null genotype (*4C/*4C; 1 subject). A weak but significant positive correlation was observed between total amounts of urinary cadmium excretion and total cotinine excretion over 2h. Our study shows generally good agreement between CYP2A6 genotypes and phenotypes. Smokers accumulated about 3-4-fold higher mean total amounts of 2-h urinary cadmium excretion (127.5±218.2ng/2h) than that of non-smokers (40.5±78.4ng/2h). Among the smokers (n=16), homologous wild-type genotype *1/*1 was significantly the predominant genotype (6/16) compared with other defective allele including *4C/*4C. In addition, 2h urinary excretion of cotinine in smokers of all genotypes was significantly higher than non-smokers. The proportion of smokers who smoked more than 5 cigarettes/day was significantly higher in EMs in all CYP2A6 genotypes (n=14) than in PMs (n=0).