Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism

Abstract

The polymorphic human cytochrome P450 2A6 (CYP2A6) metabolises a number of drugs, activates a variety of precarcinogens and constitutes the major nicotine C-oxidase. A relationship between CYP2A6 genotype and smoking habits, as well as incidence of lung cancer, has been proposed. Two defective alleles have hitherto been identified, one of which is very common in Asian populations. Among Caucasians, an additional defective and frequently distributed allele (CYP2A6*3) has been suggested to play a protective role against nicotine addiction and cigarette consumption. Here, we have re-evaluated the genotyping method used for the CYP2A6*3 allele and found that a gene conversion in the 3P P flanking region of 30^40% of CYP2A6*1 alleles results in genotype misclassification. In fact, no true CYP2A6*3 alleles were found among 100 Spaniards and 96 Chinese subjects. In one Spanish poor metaboliser of the CYP2A6 probe drug coumarin, we found two novel defective alleles. One, CYP2A6*5, encoded an unstable enzyme having a G479L substitution and the other was found to carry a novel type of CYP2A6 gene deletion (CYP2A6*4D). The results imply the presence of numerous defective as well as active CYP2A6 alleles as a consequence of CYP2A6/CYP2A7 gene conversion events. We conclude that molecular epidemiological studies concerning CYP2A6 require validated genotyping methods for accurate detection of all known defective CYP2A6 alleles.z 1999 Federation of European Biochemical Societies.

CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele

“…8 In the CYP2A6*4 (CYP2A6*4A, CYP2A6*4B, and CYP2A6*4D) alleles, the entire CYP2A6 gene is deleted and the enzymatic activity is lacking. [8][9][10][11] The CYP2A6*1X2 allele has a duplication of the CYP2A6 gene as the reciprocal product of the CYP2A6*4D allele after an unequal crossover event. 12 The CYP2A6*12 is a CYP2A7/CYP2A6 hybrid allele created by an unequal crossover in intron 2.…”

Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort

“…4,5 A gene conversion of interest is CYP2A6*1B where the 3 0 -flanking region adjacent to exon 9 has been replaced by the corresponding CYP2A7 sequence (72 bp). 6 The subjects who possess the CYP2A6*1B allele appear to show higher capabilities of nicotine metabolism to cotinine. 7 The allele frequency of CYP2A6*1B ranges from 30% in Caucasian subjects 6 to nearly 40% in Japanese, Korean 7 and Chinese subjects 6 and up to 55% in Canadian native Indian.…”

“…6 The subjects who possess the CYP2A6*1B allele appear to show higher capabilities of nicotine metabolism to cotinine. 7 The allele frequency of CYP2A6*1B ranges from 30% in Caucasian subjects 6 to nearly 40% in Japanese, Korean 7 and Chinese subjects 6 and up to 55% in Canadian native Indian. 3 Genetic polymorphism in this gene may be of particular importance for an individual's need for nicotine.…”

Association of CYP2A6 Gene Deletion with Cigarette Smoking Status in Japanese Adults.

“…The principal metabolic pathway of nicotine is a conversion to inactive cotinine by cytochrome P450 (CYP) 2A6.2.3 The gene encoding this enzyme, CYP2A6, has several polymorphic variants. [4][5][6][7][8] Large inter-individual differences in nicotine metabolism, including a poor metabolism phenotype with deficient cotinine formation, have been found in humans, and previous works demonstrated that the difference in nicotine metabolism is attributable to the genetic polymorphism of CYP2A6. [9][10][11][12][13] Considerable ethnic differences exist in the frequency of the inactive alleles of CYP2A6.…”