Metabolic effects of CYP2A6 and CYP2A13 on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced gene mutation-A mammalian cell-based mutagenesis approach

Journal Article · Wed Jun 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.022· OSTI ID:21535307

Chiang, Huai-chih ^[1]; Wang, Chin-Ying ^[2]; Lee, Hui-Ling ^[2]; Tsou, Tsui-Chun ^[1]

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1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan (China)
2. Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan (China)

Both cytochrome P450 2A6 (CYP2A6) and cytochrome P450 2A13 (CYP2A13) are involved in metabolic activation of tobacco-specific nitrosamines and may play important roles in cigarette smoking-induced lung cancer. Unlike CYP2A6, effects of CYP2A13 on the tobacco-specific nitrosamine-induced mutagenesis in lung cells remain unclear. This study uses a supF mutagenesis assay to examine the relative effects of CYP2A6 and CYP2A13 on metabolic activation of a tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and its resulting mutagenesis in human lung cells. A recombinant adenovirus-mediated CYP2A6/CYP2A13 expression system was established to specifically address the relative effects of these two CYPs. Mutagenesis results revealed that both CYP2A6 and CYP2A13 significantly enhanced the NNK-induced supF mutation and that the mutagenic effect of CYP2A13 was markedly higher than that of CYP2A6. Analysis of NNK metabolism indicated that {>=} 70% of NNK was detoxified to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), either with or without CYP2A6/CYP2A13 expression. Both CYP2A6 and CYP2A13 significantly enhanced the {alpha}-hydroxylation of NNK; and the {alpha}-hydroxylation activity of CYP2A13 was significantly higher than that of CYP2A6. Analysis of the NNK-related DNA adduct formation indicated that, in the presence of CYP2A13, NNK treatments caused marked increases in O{sup 6}-methylguanine (O{sup 6}-MeG). The present results provide the first direct in vitro evidence demonstrating the predominant roles of CYP2A13 in NNK-induced mutagenesis, possibly via metabolic activation of NNK {alpha}-hydroxylation.

• OSTI ID: 21535307
• Journal Information: Toxicology and Applied Pharmacology, Vol. 253, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.03.022; PII: S0041-008X(11)00116-5; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADENOVIRUS
DNA ADDUCTS
GENE MUTATIONS
IN VITRO
LUNGS
METABOLIC ACTIVATION
MUTAGENESIS
NEOPLASMS
NITROSAMINES
RESPIRATORY TRACT CELLS
TOBACCO
ADDUCTS
AMINES
ANIMAL CELLS
BODY
DISEASES
METABOLISM
MICROORGANISMS
MUTATIONS
NITROSO COMPOUNDS
ONCOGENIC VIRUSES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PARASITES
RESPIRATORY SYSTEM
SOMATIC CELLS
VIRUSES