PMID- 10544257
OWN - NLM
STAT- MEDLINE
DCOM- 19991210
LR  - 20220607
IS  - 0014-5793 (Print)
IS  - 0014-5793 (Linking)
VI  - 460
IP  - 2
DP  - 1999 Oct 29
TI  - Identification and characterisation of novel polymorphisms in the CYP2A locus:
      implications for nicotine metabolism.
PG  - 321-7
AB  - 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.
FAU - Oscarson, M
AU  - Oscarson M
AD  - Division of Molecular Toxicology, National Institute of Environmental Medicine,
      Karolinska Institutet, Box 210, 171 77, Stockholm, Sweden.
      mikael.oscarson@imm.ki.se
FAU - McLellan, R A
AU  - McLellan RA
FAU - Gullsten, H
AU  - Gullsten H
FAU - Agundez, J A
AU  - Agundez JA
FAU - Benitez, J
AU  - Benitez J
FAU - Rautio, A
AU  - Rautio A
FAU - Raunio, H
AU  - Raunio H
FAU - Pelkonen, O
AU  - Pelkonen O
FAU - Ingelman-Sundberg, M
AU  - Ingelman-Sundberg M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - FEBS Lett
JT  - FEBS letters
JID - 0155157
RN  - 0 (Apoproteins)
RN  - 6M3C89ZY6R (Nicotine)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.- (Steroid Hydroxylases)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP2A6 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2A6)
RN  - EC 1.14.14.1 (steroid hormone 6-beta-hydroxylase)
SB  - IM
MH  - Apoproteins/metabolism
MH  - *Aryl Hydrocarbon Hydroxylases
MH  - Base Sequence
MH  - Blotting, Southern
MH  - China
MH  - Cytochrome P-450 CYP2A6
MH  - Cytochrome P-450 Enzyme System/*genetics/metabolism
MH  - Genotype
MH  - Humans
MH  - Male
MH  - Mixed Function Oxygenases/metabolism
MH  - Models, Genetic
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Nicotine/*metabolism
MH  - Phenotype
MH  - Polymorphism, Genetic
MH  - Saccharomyces cerevisiae/metabolism
MH  - Sequence Homology, Nucleic Acid
MH  - Smoking/genetics
MH  - Spain
MH  - Steroid Hydroxylases/*genetics
MH  - Transfection
EDAT- 1999/11/02 00:00
MHDA- 1999/11/02 00:01
CRDT- 1999/11/02 00:00
PHST- 1999/11/02 00:00 [pubmed]
PHST- 1999/11/02 00:01 [medline]
PHST- 1999/11/02 00:00 [entrez]
AID - S0014-5793(99)01364-2 [pii]
AID - 10.1016/s0014-5793(99)01364-2 [doi]
PST - ppublish
SO  - FEBS Lett. 1999 Oct 29;460(2):321-7. doi: 10.1016/s0014-5793(99)01364-2.