Cyp2a6 and Cyp2b6 Are Involved in Nornicotine Formation From Nicotine in Humans: Interindividual Differences in These Contributions

Yamanaka, Hidetoshi

doi:10.1124/dmd.105.006254

Cited by 46 publications

(47 citation statements)

References 25 publications

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“…221,223 There is evidence suggesting CYP2B6 is also expressed in the brain and can potentially metabolize nicotine. [224][225][226] As such, genetic variations in CYP2B6 may represent additional differences in sensitivity to nicotine with consequent effects on smoking cessation.…”

Section: Genetic Basis For Variations In Response To Smoking Cessatiomentioning

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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Section: Genetic Basis For Variations In Response To Smoking Cessatiomentioning

confidence: 99%

Overview of the pharmacogenomics of cigarette smoking

Tyndale

2007

Pharmacogenomics J

102

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“…E. coli membranes expressing human CYP2A6 and CYP2A13 were previously prepared. (13,14) The expression system of human CYP2S1 in E. coli was constructed according to the method by Wu et al (15) and E. coli membranes expressing CYP2S1 were also prepared. The P450 content and protein concentration were determined according to the method described previously.…”

Section: Methodsmentioning

confidence: 99%

Immunohistochemical analysis of CYP2A13 in various types of human lung cancers

Fukami¹,

Nakajima²,

Matsumoto³

et al. 2010

Cancer Science

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Human CYP2A13, which is expressed in the respiratory tract, is the most efficient enzyme for the metabolic activation of tobacco-specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The relevance of CYP2A13 in carcinogenicity and toxicity in the respiratory tract has been suggested, but the expression of CYP2A13 protein in lung cancer tissues remains to be determined. We first prepared a mouse monoclonal antibody against human CYP2A13. The antibody showed no cross reactivity with the other CYP isoforms including CYP2A6. Using the specific antibody, we performed immunohistochemical analysis for human lung carcinomas. In adenocarcinomas (n = 15), all specimens were positive for the staining and five samples showed strong staining. In squamous cell carcinomas (n = 15) and large cell carcinomas (n = 15), each 14 samples were positive for the staining and two and three samples showed strong staining, respectively. In small cell carcinoma samples (n = 15), eight samples were negative for the staining and five samples showed weak or moderate staining.In conclusion, we first found that the expression of CYP2A13 was markedly increased in non-small cell lung carcinomas. The high expression might be associated with the tumor development and progression in non-small cell lung carcinomas. (Cancer Sci 2010; 101: 1024-1028

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“…Escherichia coli membranes expressing recombinant human CYP1A1/NPR (Yamazaki et al, 2002), CYP1A2/NPR (Yamazaki et al, 2002), CYP2A6/NPR (Fukami et al, 2004), and CYP2A13/NPR (Yamanaka et al, 2005) were previously prepared in our laboratory. The cytochrome P450 (P450) content and protein concentration were determined according to a method described previously (Omura and Sato, 1964;Bradford, 1976).…”

Section: Methodsmentioning

confidence: 99%

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

Fukami¹,

Nakajima²,

Sakai³

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:Human cytochrome CYP2A13 shows overlapping substrate specificity with CYP2A6, catalyzing the metabolism of coumarin, nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Recently, it was found that CYP2A13 could catalyze the metabolic activations of 4-aminobiphenyl and aflatoxin B 1 , which are known to be catalyzed by human CYP1A2. In the present study, we investigated the substrate specificity of CYP2A13. It was shown that CYP2A13 could catalyze ethoxyresorufin O-deethylation, methoxyresorufin O-demethylation, and phenacetin O-deethylation, which are used as marker activities for human CYP1A2. Although the intrinsic clearances (V max /K m ) of the two former reactions by CYP2A13 were much lower than that of CYP1A2, the value of the last reaction by CYP2A13 was 2-fold higher than that of CYP1A2.Of particular interest was that CYP2A13 has higher affinity toward phenacetin than CYP1A2. In contrast, CYP2A6 hardly catalyzed these reactions, although the amino acid identity with CYP2A13 is as high as 93.5%. Furthermore, we found that CYP2A13 can catalyze theophylline 8-hydroxylation and 3-demethylation, which are known to be mainly catalyzed by human CYP1A2, although the intrinsic clearances were approximately one-tenth that of CYP1A2. CYP2A13 would not contribute to the systemic clearance of these drugs because CYP2A13 is hardly expressed in human liver. However, it may play a role in metabolism in local tissues such as lung or trachea. In conclusion, the results of the present study could extend our understanding of the substrate specificity of CYP2A13.

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Cyp2a6 and Cyp2b6 Are Involved in Nornicotine Formation From Nicotine in Humans: Interindividual Differences in These Contributions

Cited by 46 publications

References 25 publications

Overview of the pharmacogenomics of cigarette smoking

Overview of the pharmacogenomics of cigarette smoking

Immunohistochemical analysis of CYP2A13 in various types of human lung cancers

CYP2A13 Metabolizes the Substrates of Human CYP1A2, Phenacetin, and Theophylline

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