Human cytochrome P450 2A13 efficiently metabolizes chemicals in air pollutants: naphthalene, styrene, and toluene.
Human P450 2A13 is the most efficient enzyme for catalyzing the metabolism of nicotine and metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). It is conceivable that P450 2A13 also metabolizes chemicals in air pollutants because this enzyme is highly expressed in the respiratory tract. In this study, we investigated the possibility that P450 2A13 can metabolize naphthalene, styrene, and toluene, which are included in air pollutants as well as tobacco smoke, although they were known to be metabolized by P450 1A2 or 2E1. We found that P450 2A13 catalyzed 1- and 2-naphthol formations from naphthalene with higher intrinsic clearances ( kcat/ Km) (3.1- and 2.2-fold, respectively) than P450 1A2 and also more efficiently catalyzed the styrene 7,8-oxide formation from styrene and the benzylalcohol formation from toluene than P450 2E1. The overlapping substrate specificity of P450 2A13 with P450 2E1 was supported by the finding that P450 2A13 catalyzed chlorzoxazone 6-hydroxylation (8-fold higher value of kcat/ Km) and p-nitrophenol 2-hydroxylation (19-fold higher value of kcat/ Km), which are marker activities of P450 2E1. Thus, we found that P450 2A13 metabolizes diverse environmental chemicals and has overlapping substrate specificities of P450 1A2 and 2E1, suggesting that P450 2A13 plays important roles in the local metabolism of environmental chemicals in the respiratory tract related to toxicity or carcinogenicity.
Fukami
Tatsuki
T
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Katoh
Miki
M
Yamazaki
Hiroshi
H
Yokoi
Tsuyoshi
T
Nakajima
Miki
M
D000393:Air Pollutants / Q000378:metabolism*; D002384:Catalysis; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism*; D009281:Naphthalenes / Q000378:metabolism*; D009284:Naphthols / Q000378:metabolism; D013343:Styrenes / Q000378:metabolism*; D014050:Toluene / Q000378:metabolism*
D000393:Air Pollutants; D008565:Membrane Proteins; D009281:Naphthalenes; D009284:Naphthols; D013343:Styrenes; C029350:1-naphthol; D014050:Toluene; C496509:Cyp3a13 protein, mouse; D051544:Cytochrome P-450 CYP3A