Disease relevance of CYP2A13

• Together, these findings suggest that CYP2A13 plays important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the human respiratory tract [1].
• In this study, a CYP2A13 cDNA was prepared by RNA-PCR from human nasal mucosa and was translated using a baculovirus expression system [1].
• There was little expression of CYP2A13 protein in different types of lung cancers [2].
• Stratification analysis shows that the reduced risk of lung adenocarcinoma related to the variant CYP2A13 genotype was limited to smokers, especially light smokers (OR, 0.23; 95% CI, 0.08-0.68) but not nonsmokers or heavy smokers [3].
• The K(m) and V(max) values for ABP N-hydroxylation by recombinant CYP2A13 in E. coli were 38.5 +/- 0.6 muM and 7.8 +/- 0.0 pmol/min/pmol CYP, respectively [4].

High impact information on CYP2A13

• A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles [5].
• Three complete CYP2A genes--CYP2A6, CYP2A7, and CYP2A13--plus two pseudogenes truncated after exon 5, were identified and sequenced [5].
• Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK [3].
• In this case-control study, we genotyped 724 patients with lung cancer and 791 controls for this polymorphism to examine the hypothesis that the variant CYP2A13 may have impact on risk of lung cancer in relation to tobacco smoking [3].
• We found that, compared with the CC genotype, the variant CYP2A13 genotype (CT + TT) was associated with substantially reduced risk for lung adenocarcinoma [odds ratio (OR), 0.41; 95% confidence interval (CI), 0.23-0.71], but not squamous cell carcinoma (OR, 0.86; 95% CI, 0.57-1.29) or other types of lung cancer (OR, 0.58; 95% CI, 0.32-1.09) [3].

Chemical compound and disease context of CYP2A13

• Human cytochrome P450 2A13 (CYP2A13), which is highly efficient in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), may play important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the respiratory tract [6].
• 1. We investigated the total metabolism of coumarin by baculovirus (BV)-expressed CYP2A13 and compared it with metabolism by BV-expressed CYP2A6 [7].

Biological context of CYP2A13

• Of particular interest, CYP2A13 was highly active in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, with a catalytic efficiency much greater than that of other human cytochrome P450 isoforms examined previously [1].
• The tissue distribution of CYP2A13 was determined with isoform-specific RNA-PCR [1].
• Functional genetic polymorphisms of CYP2A13 may therefore be an important factor in human susceptibility to related lung cancers [8].
• In this study, we generated a peptide-specific antibody against human CYP2A13 and demonstrated by immunoblot analysis that this antibody does not cross-react with heterologously expressed human CYP2A6 and mouse CYP2A5 proteins, both sharing a high degree of amino acid sequence similarity with CYP2A13 [2].
• A C-->T transition in the CYP2A13 gene causes Arg257Cys amino acid substitution and, thus, results in a significantly reduced activity toward NNK and other substrates [3].

Anatomical context of CYP2A13

• Consistent with the activity data, there was an approximately 800-fold difference in LC50 values of AFB1 (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing CYP2A13 and CYP2A6 (50 nM versus 39 microM) [9].
• Using this highly specific antibody for immunohistochemical staining, we detected a high level of CYP2A13 protein expression in the epithelial cells of human bronchus and trachea, but a rare distribution in the alveolar cells [2].
• In conclusion, although the enzyme responsible for ABP N-hydroxylation in human bladder microsomes could not be determined, we found that CYP2A13 metabolically activates ABP [4].
• The prenatal expression of the CYP2A proteins in the olfactory mucosa suggests potential risks of developmental toxicity from maternally derived xenobiotics, since both CYP2A6 and CYP2A13 are known to be efficient in the metabolic activation of tobacco-specific nitrosamines and other respiratory toxicants [10].
• Since CYP2A13 is hardly expressed in human livers, the contribution of CYP2A13 to the nicotine N-demethylation in human liver microsomes would be negligible [11].

Associations of CYP2A13 with chemical compounds

• In a reconstituted system, the expressed CYP2A13 was more active than CYP2A6 in the metabolic activation of hexamethylphosphoramide, N,N-dimethylaniline, 2'-methoxyacetophenone, and N-nitrosomethylphenylamine but was much less active than CYP2A6 in coumarin 7-hydroxylation [1].
• The Missense Genetic Polymorphisms of Human CYP2A13: Functional Significance in Carcinogen Activation and Identification of A Null Allelic Variant [8].
• CYP2A13 expressed in human bladder metabolically activates 4-aminobiphenyl [4].
• CYP2A13 catalyzed this reaction as well as further metabolism of cotinine to 5'-hydroxycotinine, trans-3'-hydroxycotinine, and N-(hydroxymethyl)-norcotinine as enzyme inactivation occurred [12].
• Identification of Val117 and Arg372 as critical amino acid residues for the activity difference between human CYP2A6 and CYP2A13 in coumarin 7-hydroxylation [13].

Other interactions of CYP2A13

• All three transcripts (CYP2A6, CYP2A7, and CYP2A13) were found to be present in liver [14].
• The K(m) and V(max) values by recombinant CYP1A2 were 9.9 +/- 0.9 muM and 39.6 +/- 0.9 pmol/min/pmol CYP, respectively, showing 20-fold higher intrinsic clearance than CYP2A13 [4].
• Development of a real-time polymerase chain reaction-based method for the measurement of relative allelic expression and identification of CYP2A13 alleles with decreased expression in human lung [15].
• A functionally significant coding single nucleotide polymorphism (C3375T) in exon 5 of CYP2A13, which results in an amino acid substitution of Arg 257 to Cys, has been recently reported to exist in White, Black, Hispanic, and Asian individuals, with the variant 3375T allele frequencies being 1.9%, 14.4%, 5.8% and 7.7%, respectively [16].

Analytical, diagnostic and therapeutic context of CYP2A13

• Quantitative PCR analysis further revealed that CYP2A13 mRNA is expressed at the highest level in the nasal mucosa, followed by the lung and the trachea [1].
• Quantitative RT-PCR analysis showed that CYP2A6 and CYP2A7 mRNAs were present at roughly equal levels in the liver, while CYP2A13 was expressed at very low levels [14].
• Our results should be useful in designing and interpreting molecular epidemiological studies related to CYP2A13 genetic polymorphisms [8].
• [5-(3)H]Nicotine metabolism by CYP2A13 was monitored by radioflow high-pressure liquid chromatography during the course of enzyme inactivation; the major product was the Delta(1'(5'))iminium ion [12].
• Preliminary sequence analysis of CYP2A13 RNA-polymerase chain reaction (PCR) products suggested that a 7520C > G variation, located in the 3'-untranslated region, could be associated with low transcript abundance [15].

References