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Titolo:
Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism
Autore:
Oscarson, M; McLellan, RA; Gullsten, H; Agundez, JAG; Benitez, J; Rautio, A; Raunio, H; Pelkonen, O; Ingelman-Sundberg, M;
Indirizzi:
Karolinska Inst, Natl Inst Environm Med, Div Mol Toxicol, S-17177 Stockholm, Sweden Karolinska Inst Stockholm Sweden S-17177 icol, S-17177 Stockholm, Sweden Univ Oulu, Dept Pharmacol & Toxicol, Oulu, Finland Univ Oulu Oulu Finland iv Oulu, Dept Pharmacol & Toxicol, Oulu, Finland Univ Extremadura, Sch Med, Dept Pharmacol, Badajoz, Spain Univ Extremadura Badajoz Spain Sch Med, Dept Pharmacol, Badajoz, Spain
Titolo Testata:
FEBS LETTERS
fascicolo: 2, volume: 460, anno: 1999,
pagine: 321 - 327
SICI:
0014-5793(19991029)460:2<321:IACONP>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; COUMARIN 7-HYDROXYLATION; YEAST-CELLS; INTERINDIVIDUAL VARIABILITY; MONOOXYGENASE ACTIVITIES; CYTOCHROME-P450 CYP2A6; C-OXIDATION; AMINO-ACID; EXPRESSION; 3-HYDROXYLATION;
Keywords:
cytochrome P450; cytochrome P450 2A6; coumarin; nicotine; cotinine; lung cancer;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Oscarson, M Karolinska Inst, Natl Inst Environm Med, Div Mol Toxicol, Box 210, S-17177Stockholm, Sweden Karolinska Inst Box 210 Stockholm Sweden S-17177 holm, Sweden
Citazione:
M. Oscarson et al., "Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism", FEBS LETTER, 460(2), 1999, pp. 321-327

Abstract

The polymorphic human cytochrome p450 2A6 (CYP2A6) metabolises a number ofdrugs, 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. Tn 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, (C) 1999 Federation of European Biochemical Societies.

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Documento generato il 03/07/20 alle ore 01:32:09