Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans

Nakajima, Miki; Kwon, Jun-Tack; Tanaka, Nobushige; Zenta, Takahiro; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Yamazaki, Hiroshi; Yamamoto, Toshinori; Kuroiwa, Yukio; Yokoi, Tsuyoshi

doi:10.1067/mcp.2001.112688

Cited by 148 publications

(168 citation statements)

References 21 publications

(51 reference statements)

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“…Table I shows the CYP2A6 genotype frequencies of our control group and the reported ethnic population. 5,9,13,15,20,21 Electrophoretic patterns of CYP2A6 *1/*1 and *1/*4 by polymerase chain reaction were the same pattern in our analysis method and did not discriminate CYP2A6 *1/*1 from *1/*4. There were significant interethnic differences in certain CYP2A6 genotype frequencies.…”

Section: Discussionmentioning

confidence: 63%

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Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Tsukino

Kuroda

Qiu

et al. 2002

Intl Journal of Cancer

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Cytochrome P450 (CYP) 2A6 and CYP2E1 are enzymes with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogens. The polymorphic CYP2A6 and CYP2E1 have been implicated in increased susceptibility to certain malignancies. In our study, 120 Japanese patients with gastric adenocarcinoma and 158 healthy controls were compared for frequencies of CYP2A6 and CYP2E1 genotypes. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion allele, which causes lack of the enzyme activity, was significantly higher in the gastric cancer patients than in the healthy control subjects (OR ‫؍‬ 3.14, 95% confidence interval (95% CI) ‫؍‬ 1.05-9.41). Subdividing gastric adenocarcinoma according to tumor differentiation, patients with the well-differentiated type were 4. Although gastric cancer incidence has fallen markedly over the past 50 years in industrialized nations, it remains the second leading cause of cancer death in Japan. Epidemiological and experimental evidence have indicated that excess salt intake, which promotes cell replication, increases gastric cancer risk. 1,2 There is considerable evidence to support the view that carcinogenic N-nitrosamine derivatives are important factors in human cancer, including gastric cancer. The chemical mechanisms of carcinogenesis by these nitrosamines in humans are therefore of considerable interest. 3,4 Numerous studies have shown that several cytochrome P450 (CYP) enzymes, particularly cytochrome P4502A6 (CYP2A6) and cytochrome P4502E1 (CYP2E1), catalyze metabolic activation of nitrosamine derivatives, including N-nitroso-dialkyiamines and tobacco-smoke-related nitrosamine. [5][6][7][8] Genetic polymorphisms for CYP2A6 have been described and 2 variant alleles associated with reduced activity have been identified. Variant 1 (CYP2A6*2) and Variant 2 (CYP2A6*3) are the results of amino acid exchanged for wildtype (CYP2A6*1). Recently, Kitagawa et al. 9 revealed that a novel deletion genotype variant of the CYP2A6 gene was one of the major polymorphic genes in Japanese lacking CYP2A6 activity.In addition, CYP2E1 represents a major CYP isoform in the human liver and is also expressed in extrahepatic tissue. This enzyme can be induced by certain chemicals, such as ethanol and large interindividual variations have been observed, suggesting that the variation may be due to genetic polymorphism. It was reported that RsaI polymorphism, which is located in the 5Ј-flanking region of CYP2E1 gene, has been shown to be associated with the transcriptional regulation of gene expression, resulting in different expression levels of the CYP2E1 mRNA. 6 CYP2E1 participated in the metabolic activation of various N-nitrosamines, including a potent tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 8,10 Several recent reports have investigated the role of CYP2A6 genetic polymorphisms in tobacco dependence and lung cancer risk, with conflicting results. [11][12][13][14][15] Less ...

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Section: Discussionmentioning

confidence: 63%

“…In the control cases, the frequency of the CYP2A6 homozygote deletion was found in 3.2% and that was consistent with the results of previous studies of Japanese people. 9,20 The frequencies of CYP2A6 and CYP2E1 genotypes associated with gastric adenocarcinoma are shown in Table II. In our samples, we found no CYP2A6*2, CYP2A6*3 alleles.…”

Section: Discussionmentioning

confidence: 99%

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Tsukino

Kuroda

Qiu

et al. 2002

Intl Journal of Cancer

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“…39 Large interindividual and interethnic variations in CYP2A6 activity have been reported; [170][171][172][174][175][176][177] this variability is mainly attributed to the large genetic variations in CYP2A6. 178,179 A brief summary of how genetic variations in CYP2A6 affect smoking behaviors will be provided here as a detailed review was recently published. 10 Several studies have associated genetic variations leading to reduced or absent CYP2A6 activity with lower risk of smoking, 175,180,181 decreased cigarette consumption in adults and even in adolescents despite their low smoking rates, 175,[180][181][182][183][184][185][186] decreased smoking intensity, 187 shorter smoking duration, 175 decreased withdrawal symptoms during abstinence 188 and increased cessation.…”

Section: Other Likely Candidates Involved In Neurotransmitter Systemsmentioning

confidence: 99%

Overview of the pharmacogenomics of cigarette smoking

Tyndale

2007

Pharmacogenomics J

102

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Cigarette smoking increases the risk of numerous health problems, including cancer, cardiovascular and pulmonary disorders, making smoking the leading cause of preventable death in the world. Nicotine is primarily responsible for the highly addictive properties of cigarettes. Although the majority of smokers express a desire to quit, few are successful in doing so. Twin and family studies have indicated substantial genetic contributions to smoking behaviors. One major research focus has been to elucidate the specific genes involved; this has been accomplished primarily through genome-wide linkage analyses and candidate gene association studies. Much attention has focused on genes involved in the neurotransmitter pathways for the brain reward system and genes altering nicotine metabolism. This paper reviews the current state of knowledge for genetic factors implicated in smoking behaviors, and examines how genetic variations may affect therapeutic outcomes for drugs used to assist smoking cessation.

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“…1 Subjects genotyped as CYP2A6*4/CYP2A6*4 are completely deficient in cotinine formation. 2 The allele frequency of CYP2A6*4 is low in European and particularly French subjects (4%) compared to Japanese (18%). 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).…”

Section: Introductionmentioning

confidence: 98%

“…There are large ethnic differences in the frequencies of CYP2A6 alleles that might affect the potency of nicotine metabolism in each population. 2,3 The 'wild type' of the CYP2A6 gene is termed CYP2A6*1A. There are three gene deletion alleles, namely CYP2A6*4A (also termed CYP2A6*4C), CYP2A6*4B and CYP2A6*4D.…”

Section: Introductionmentioning

confidence: 99%

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

Gambier

Marie

et al. 2005

Pharmacogenomics J

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This study was designed in order to investigate the influence of the genetic polymorphism of CYP2A6 on the amount of smoking. In all, 463 French adults included in the Stanislas cohort were studied and underwent two examinations at 5 years distance (t 0 and t þ 5 years). Information on their smoking habits was collected. They were genotyped by RFLP for the CYP2A6*1A, CYP2A6*1B and CYP2A6*4 alleles. CYP2A6*1B and CYP2A6*4 allele frequencies were 32 and 4%, respectively. The subjects carrying the CYP2A6*1B allele oxidize nicotine to cotinine faster than subjects with the CYP2A6*1A allele. The number of cigarettes smoked per day was significantly higher in the CYP2A6*1B/*1B group as compared to the CYP2A6*1A/*1A group (P ¼ 0.01 at t 0 ; P ¼ 0.001 t þ 5 years), with a larger increase in their daily cigarettes consumption over the 5-year period (P ¼ 0.006). No significant difference in the smoking status was observed according to the CYP2A6 genotype. These data suggest that the CYP2A6*1B is associated with the number of cigarettes smoked per day.

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Relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans

Abstract: The relationship between interindividual differences in nicotine metabolism and CYP2A6 genetic polymorphism in humans was proved.

Cited by 148 publications

References 21 publications

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

Overview of the pharmacogenomics of cigarette smoking

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

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