Purification and characterization of two unique forms of cytochrome P-450 from rabbit nasal microsomes

Ding, Xinxin; Coon, Minor J.

doi:10.1021/bi00422a007

Cited by 95 publications

(60 citation statements)

References 35 publications

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“…The column was washed with buffer B and eluted with a pH gradient from 6.4 (buffer B) to 7.4 (200 mM phosphate in buffer A). A nearly homogeneous preparation of CYP2A13 was recovered at about pH 6.9, dialyzed overnight against 10 mM phosphate buffer, pH 7.4, 0.2% NP-10, and 20% glycerol (buffer C), and applied to a second HTP column (3-ml) to remove NP-10, as described previously (Ding and Coon, 1988). The detergent-free CYP2A13 was eluted and dialyzed as described for the purification of CYP2A5 (Gu et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

Genetic Polymorphisms of the HumanCYP2A13Gene: Identification of Single-Nucleotide Polymorphisms and Functional Characterization of an Arg257Cys Variant

Zhang

et al. 2002

J Pharmacol Exp Ther

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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. The aim of this study was to identify any genetic polymorphisms of the CYP2A13 gene, which may alter the metabolic capacities of the enzyme. Polymerase chain reaction (PCR) single-strand conformational polymorphism analysis was used to identify single-nucleotide polymorphisms (SNPs) in all of the exons and at the exon-intron boundaries, and PCR-restriction fragment length polymorphism analysis and DNA sequencing were used to determine the frequencies of the newly identified variant alleles in the four major ethnic groups. Blood spot DNA from more than 100 individuals was used for these analyses. Seven variant alleles were found, but only one SNP was detected in the coding region, in exon 5, leading to an Arg257Cys amino acid change. The frequencies of the Arg257Cys allele in white, black, Hispanic, and Asian individuals are 1.9%, 14.4%, 5.8%, and 7.7%, respectively. Functional analysis of the variant protein was performed following its heterologous expression. The Arg257Cys variant was 37 to 56% less active than the wild-type Arg-257 protein toward all substrates tested. With NNK, Cys-257 had higher K m and lower V max values than did Arg-257, with a Ͼ2-fold decrease in catalytic efficiency. The Arg257Cys mutation could provide some protection against xenobiotic toxicity in the respiratory tract to individuals who are homozygous for the Cys-257 allele.

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Section: Methodsmentioning

confidence: 99%

Genetic Polymorphisms of the HumanCYP2A13Gene: Identification of Single-Nucleotide Polymorphisms and Functional Characterization of an Arg257Cys Variant

Zhang

et al. 2002

J Pharmacol Exp Ther

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“…Sustentacular cells are glial-like cells, which possess many glial cell functions (Farbman, 1992). For example, they structurally support ORNs (Nomura et al, 2004), electrically isolate each ORN (Farbman, 1992), and function in a neuroprotective manner through the expression of various enzymes responsible for detoxification (Ding and Coon, 1988;Chen et al, 1992). On the other hand, several layers of ORNs exist in the middle layer.…”

Section: Introductionmentioning

confidence: 99%

Six1 is indispensable for production of functional progenitor cells during olfactory epithelial development

Ikeda¹,

Kageyama²,

Suzuki³

et al. 2010

Int. J. Dev. Biol.

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The rodent olfactory epithelium (OE) is a good model system for studying the principles of stem and progenitor cell biology, because of its capacity for continuous neurogenesis throughout life and relatively well-characterized neuronal lineage. The development of mouse OE is divided into two stages, early and established neurogenesis. In established neurogenesis, which starts at embryonic day (E) 12.5, sustentacular cells and olfactory receptor neurons (ORNs) are produced from apical and basal progenitors, respectively. We previously reported that Six1 -/-shows a lack of mature ORNs throughout development and disorganization of OE after E12.5. However, the molecular bases for these defects have not been addressed. Here, we show that Six1 is expressed in both apical and basal progenitors. In Six1 -/-mice, apical proliferating cells were absent and no morphologically identifiable sustentacular cells were observed. Consistently, the expression of Notch2 and Jagged1 in the apical layer was absent in Six1 -/-mice. On the other hand, basal proliferating cells were observed in Six1 -/-animals, but the expression of Ngn1, NeuroD, Notch1, and Jagged2 in the basal layer was absent. The expression of Mash1, the determination gene for ORNs, and Hes genes was enhanced in Six1 -/-mice. The present findings suggest that Six1 regulates production of functional apical and basal progenitors during OE development, through the regulation of various genes, such as neuronal basic helix-loop-helix (bHLH), neuronal repressor bHLH, and genes involved in the Notch signaling pathway.

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“…However, no such association was detected in a similar study of a Norwegian population (9 CYP2A6 is a constitutive cytochrome P450 which is expressed in human liver at variable levels (18). This enzyme may also be expressed in other tissues, including nasal tissue (19). CYP2A6 carries out 7-hydroxylation of coumarin but also appears to activate certain procarcinogens, including hexamethylphosphoramide (19), Nnitrosodimethylamine (20), NNK (14) and aflatoxin B1 (21).…”

Section: Introductionmentioning

confidence: 99%

Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility.

Daly

Cholerton

Armstrong

et al. 1994

Environ Health Perspect

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Polymorphisms in many xenobiotic metabolizing enzymes occur leading to variation in the level of enzyme expression in vivo. Enzymes showing such polymorphisms include the cytochrome P450 enzymes CYPlAl, CYP1A2, CYP2A6, CYP2D6, and CYP2E1 and the phase two metabolism enzymes glutathione S-transferase Ml (GSTMI) and arylamine N-acetyltransferase 2 (NAT2). In the past, these polymorphisms have been studied by phenotyping using in vivo administration of probe drugs. However, the mutations which give rise to several of these polymorphisms have now been identified and genotyping assays for polymorphisms in CYPIA 1, CYP2A6, CYP2D6, CYP2E1, GSTMI, and NAT2 have been developed. Specific phenotypes for several of the polymorphic enzymes have been associated with increased susceptibility to malignancy, particularly lung and bladder cancer, and Parkinson's disease. These associations are likely to be due to altered activation or detoxication of chemicals initiating these diseases, including components of tobacco smoke and neurotoxins. The substrate specificity and tissue distribution of polymorphic enzymes implicated in disease causation discussed with particular reference to previously described disease-phenotype associations

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Purification and characterization of two unique forms of cytochrome P-450 from rabbit nasal microsomes

Cited by 95 publications

References 35 publications

Genetic Polymorphisms of the HumanCYP2A13Gene: Identification of Single-Nucleotide Polymorphisms and Functional Characterization of an Arg257Cys Variant

Genetic Polymorphisms of the HumanCYP2A13Gene: Identification of Single-Nucleotide Polymorphisms and Functional Characterization of an Arg257Cys Variant

Six1 is indispensable for production of functional progenitor cells during olfactory epithelial development

Genotyping for polymorphisms in xenobiotic metabolism as a predictor of disease susceptibility.

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