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

FEBS Letters

Gullstén, Harriet²  McLellan, Roman A.³  Rautio, Arja²  Ingelman-Sundberg, Magnus³  Raunio, Hannu²  Agúndez, José A.G.¹  Pelkonen, Olavi²  Benı́tez, Julio¹  Oscarson, Mikael³ 

[1] Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain;Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland;Division of Molecular Toxicology, National Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden

关键词: Cytochrome P450;    Cytochrome P450 2A6;    Coumarin;    Nicotine;    Cotinine;    Lung cancer;    CYP or P450;    cytochrome P450;    wt;    wild type;    PM;    poor metaboliser;    PCR;    polymerase chain reaction;   

DOI  :  10.1016/S0014-5793(99)01364-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 3′ 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.

【 授权许可】

Unknown