Expression of Biotransformation Enzymes in Human Fetal Olfactory Mucosa: Potential Roles in Developmental Toxicity

Gu, Jun; Su, Ting; Ying, Chen; Zhang, Qing Yu; Ding, Xinxin

doi:10.1006/taap.2000.8923

Cited by 62 publications

(38 citation statements)

References 21 publications

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“…CYP2A6 is mainly expressed in the liver, whereas CYP2A13 is predominantly expressed in the respiratory tract, with the highest level in the nasal mucosa, followed by the lung and trachea (Koskela et al, 1999;Gu et al, 2000;Su et al, 2000). Both CYP2A6 and CYP2A13 are composed of 494 amino acids with a high degree of identity (93.5%).…”

mentioning

confidence: 99%

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

Fukami¹,

Nakajima²,

Sakai³

et al. 2006

Drug Metab Dispos

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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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mentioning

confidence: 99%

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

Fukami¹,

Nakajima²,

Sakai³

et al. 2006

Drug Metab Dispos

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“…25 The physiology of fetal OE is worth mentioning here. Gu et al 26 found high levels of cytochrome P450 enzymes in the olfactory mucosa of developing human fetal tissue. High expression of these enzymes suggests that the olfactory mucosa may be deeply and intricately involved in the metabolism of maternally derived compounds; specifically, the olfactory mucosa may be a preferred target of certain toxic compounds.…”

Section: Developmental Anatomymentioning

confidence: 99%

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2014

J Neurol Surg B Skull Base

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“…The two SNPs in the 3Ј-untranslated region are not expected to alter RNA folding, according to an analysis using mfold, version 3.1 (http:// www.bioinfo.rpi.edu/applications/mfold) Zuker et al, 1999). Further studies on the impact of these mutations on the expression of the CYP2A13 gene are warranted, since significant interindividual differences in the level of CYP2A proteins have been found in microsomes from fetal nasal mucosa (Gu et al, 2000). …”

Section: Discussionmentioning

confidence: 99%

SINGLE NUCLEOTIDE POLYMORPHISMS OF THE HUMANCYP2A13GENE: EVIDENCE FOR A NULL ALLELE

Zhang¹,

Chen²,

Liu³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Human CYP2A13 is believed to be important in the metabolic activation of tobacco-specific nitrosamines in the respiratory tract; therefore, genetic polymorphisms of the CYP2A13 gene may be associated with interindividual differences in the risks of tobaccorelated tumorigenesis. Our earlier studies identified a frequent single nucleotide polymorphism in CYP2A13 exon 5, Arg257Cys, which led to an approximate 50% decrease in metabolic activities. In the present study, three additional coding region mutations (Arg25Gln, Arg101Stop, and Asp158Glu) and several mutations in the introns and flanking regions were identified in a Chinese patient population. Of particular interest is the Arg101Stop mutation, which was due to a C > T change in exon 2. Thus, individuals homozygous for this nonsense mutation would not have a functional CYP2A13 protein and, therefore, might have reduced sensitivity to xenobiotic toxicity resulting from CYP2A13-mediated metabolic activation in the respiratory tract. The frequencies of the coding region mutations were further examined using random samples of white, black, Hispanic, and Asian newborns from New York. The frequency of the Arg25Gln mutation in Asian newborns (9.6%) was very similar to that found in the Chinese population (10.9%). On the other hand, the Arg101Stop mutation was not detected in 136 newborn samples examined (23 white, 21 black, 19 Hispanic, and 73 Asian), suggesting that this mutation may be unique for the Chinese patient population. Haplotype analysis indicated that the Arg25Gln and Arg257Cys mutations are parts of a common haplotype. However, an additional haplotype that consists of the 25Gln but not the 257Cys allele was also identified.

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Expression of Biotransformation Enzymes in Human Fetal Olfactory Mucosa: Potential Roles in Developmental Toxicity

Cited by 62 publications

References 21 publications

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

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

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SINGLE NUCLEOTIDE POLYMORPHISMS OF THE HUMANCYP2A13GENE: EVIDENCE FOR A NULL ALLELE

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