Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method

Gf, Chen; Ym, Tang; B, Green; Dx, Lin; Fp, Guengerich; Daly, AK; Ne, Caporaso; Ff, Kadlubar

doi:10.1097/00008571-199906000-00007

Cited by 43 publications

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“…Also, the method they used for genotyping 20 has been found to have the potential to yield misclassification of the genotypes. 26,28,29 A case-control study conducted in Japan showed a significant association of CYP2A6 gene deletion with decreased lung cancer risk, 24 which is in contrast to our finding. The reason for this discrepancy is unknown.…”

Section: Resultscontrasting

confidence: 99%

“…These studies have reported conflicting data. 25,26 A relatively high frequency of theCYP2A6*4 but not other CYP2A6 alleles among the Chinese population was reported. 24,27 We examined the hypothesis that this gene deletion may be associated with a decreased risk of developing lung and esophageal cancer in this population.…”

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confidence: 95%

“…High frequencies of the gene deletion were reported among the Japanese 25 and Chinese. 24 In view of the important role played by CYP2A6 in the metabolic activation of certain nitrosamines, recent studies 25,26 have examined the association between genetic polymorphisms in the CYP2A6 locus and the risk of cancer. These studies have reported conflicting data.…”

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confidence: 99%

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Frequency ofCYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population

et al. 2001

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Section: Resultscontrasting

confidence: 99%

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Frequency ofCYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population

et al. 2001

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“…Further studies of other ethnic populations should be made, because marked inter-ethnic differences in the distribution of CYP2A6 polymorphisms have been reported (10,16,(25)(26)(27).…”

Section: The Cyp2a6*6 Polymorphism Inactivates Enzymatic Activitymentioning

confidence: 99%

CYP2A6*6, a Novel Polymorphism in Cytochrome P450 2A6, Has a Single Amino Acid Substitution (R128Q) That Inactivates Enzymatic Activity

Kitagawa

Kunugita

Kitagawa

et al. 2001

Journal of Biological Chemistry

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By using the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP), a novel polymorphism of CYP2A6, CYP2A6*6, was detected in 0.4% of the Japanese population. To study the enzymatic properties of the CYP2A6.6 protein with a single amino acid substitution of arginine 128 to glutamine, both this isozyme and the CYP2A6.1 protein (wild-type) were produced in insect cells using a baculovirus system. Coumarin 7-hydroxylation, which reflects CYP2A6 activity, was significantly reduced (one-eighth of normal) in cell lysate from CYP2A6*6-transfected Sf9 cells compared with that lysate from CYP2A6*1-transfected cells. To clarify the mechanism of inactivation of the CYP2A6.6 enzyme, the heme content and reduced CO difference spectrum were examined. Although CYP2A6.6 retained about onehalf the heme content of CYP2A6.1, the reduced CObound Soret peak was completely lost. These results suggest that the inactivation of CYP2A6.6 is mainly due to disordering of the holoprotein structure rather than a failure of heme incorporation.

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“…The occurrence of this allele at a high frequency has hampered an early genotyping method for the CYP2A6 n 2 and the proposed CYP2A6 n 3 alleles [Fernandez-Salguero et al, 1995;Oscarson et al, 1999a;Kitagawa et al, 1999;Chen et al, 1999] because the 3 0 primer used for amplification of the entire CYP2A6 gene will not correctly bind to this region [Oscarson et al, 1999a]. The altered sequence in the 3 0 flank is also of interest because of a regulatory 43-kDa protein which binds to this region of the CYP2A6 mRNA [Gilmore et al, 2001] and the indication of a higher expression level of CYP2A6 in subjects carrying this allele ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a novelCYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity

et al. 2002

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The human CYP2A6 enzyme metabolizes certain drugs and pre-carcinogens and appears to be the most important enzyme for nicotine metabolism. At present, more than 10 different allelic variants are known that cause abolished or decreased enzyme activity. Genetic polymorphism in this gene might be of particular importance for an individual's need for nicotine and for susceptibility to lung and/or liver cancer. We have identified a new CYP2A6 allele (CYP2A6*12) which carries an unequal crossover between the CYP2A6 and CYP2A7 genes in intron 2. This results in a hybrid allele where the 5' regulatory region and exons 1-2 are of CYP2A7 origin and exons 3-9 are of CYP2A6 origin, resulting in 10 amino acid substitutions compared to the CYP2A6(*)1 allele. Phenotyping with the CYP2A6 substrate coumarin indicates that it causes reduced CYP2A6 activity in'vivo. Furthermore, when expressed in mammalian COS-1 cells, the enzyme variant catalyzed 7-hydroxylation of coumarin at a rate approximately 60% of that of the wild-type enzyme. The CYP2A6(*)12 allele was present at an allele frequency of 2.2% among Spaniards, but was absent in Chinese.

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Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method

Cited by 43 publications

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Frequency ofCYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population

Frequency ofCYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population

CYP2A6*6, a Novel Polymorphism in Cytochrome P450 2A6, Has a Single Amino Acid Substitution (R128Q) That Inactivates Enzymatic Activity

Characterization of a novelCYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity

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