QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.106.011064v1 35/3/335    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fukami, T. Articles by Yokoi, T. Search for Related Content PubMed PubMed Citation Articles by Fukami, T. Articles by Yokoi, T.

SHORT COMMUNICATION

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

Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

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 B₁, 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.

This article has been cited by other articles:

				N. M. DeVore, B. D. Smith, J. L. Wang, G. H. Lushington, and E. E. Scott Key Residues Controlling Binding of Diverse Ligands to Human Cytochrome P450 2A Enzymes Drug Metab. Dispos., June 1, 2009; 37(6): 1319 - 1327. [Abstract] [Full Text] [PDF]

				N. M. DeVore, B. D. Smith, M. J. Urban, and E. E. Scott Key Residues Controlling Phenacetin Metabolism by Human Cytochrome P450 2A Enzymes Drug Metab. Dispos., December 1, 2008; 36(12): 2582 - 2590. [Abstract] [Full Text] [PDF]

				P. J. Brown, L. L. Bedard, K. R. Reid, D. Petsikas, and T. E. Massey Analysis of CYP2A Contributions to Metabolism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone in Human Peripheral Lung Microsomes Drug Metab. Dispos., November 1, 2007; 35(11): 2086 - 2094. [Abstract] [Full Text] [PDF]

				B. D. Smith, J. L. Sanders, P. R. Porubsky, G. H. Lushington, C. D. Stout, and E. E. Scott Structure of the Human Lung Cytochrome P450 2A13 J. Biol. Chem., June 8, 2007; 282(23): 17306 - 17313. [Abstract] [Full Text] [PDF]