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Title: Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6

Journal Article · · Chemical Research in Toxicology
 [1];  [1];  [2];  [3];  [4];  [4];  [5];  [3];  [6];  [1]
  1. Osaka Prefecture University, Osaka (Japan). Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences
  2. Osaka Prefectural Institute of Public Health, Osaka (Japan)
  3. Showa Pharmaceutical University, Machida, Tokyo (Japan). Laboratory of Drug Metabolism and Pharmacokinetics
  4. Konkuk University, Seoul (Republic of Korea). Department of Biological Sciences
  5. Xavier University of Louisiana, New Orleans, LA (United States). Department of Chemistry
  6. Vanderbilt University School of Medicine, Nashville, TN (United States). Department of Biochemistry
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In this study, naphthalene, phenanthrene, biphenyl, and their derivatives having different ethynyl, propynyl, butynyl, and propargyl ether substitutions were examined for their interaction with and oxidation by cytochromes P450 (P450) 2A13 and 2A6. Spectral interaction studies suggested that most of these chemicals interacted with P450 2A13 to induce Type I binding spectra more readily than with P450 2A6. Among the various substituted derivatives examined, 2-ethynylnaphthalene, 2-naphthalene propargyl ether, 3-ethynylphenanthrene, and 4-biphenyl propargyl ether had larger ΔAmax/Ks values in inducing Type I binding spectra with P450 2A13 than their parent compounds. P450 2A13 was found to oxidize naphthalene, phenanthrene, and biphenyl to 1-naphthol, 9-hydroxyphenanthrene, and 2- and/or 4-hydroxybiphenyl, respectively, at much higher rates than P450 2A6. Other human P450 enzymes including P450s 1A1, 1A2, 1B1, 2C9, and 3A4 had lower rates of oxidation of naphthalene, phenanthrene, and biphenyl than P450s 2A13 and 2A6. Additionally, those alkynylated derivatives that strongly induced Type I binding spectra with P450s 2A13 and 2A6 were extensively oxidized by these enzymes upon analysis with HPLC. Molecular docking studies supported the hypothesis that ligand-interaction energies (U values) obtained with reported crystal structures of P450 2A13 and 2A6 bound to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, indole, pilocarpine, nicotine, and coumarin are of use in understanding the basis of possible molecular interactions of these xenobiotic chemicals with the active sites of P450 2A13 and 2A6 enzymes. In fact, the ligand-interaction energies with P450 2A13 4EJG bound to these chemicals were found to relate to their induction of Type I binding spectra.

Research Organization:
Tulane Univ., New Orleans, LA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
FC26-00NT40843
OSTI ID:
1466774
Journal Information:
Chemical Research in Toxicology, Vol. 29, Issue 6; ISSN 0893-228X
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 15 works
Citation information provided by
Web of Science

References (45)

Cytochrome P450–Mediated Pulmonary Metabolism of Carcinogens: Regulation and Cross-Talk in Lung Carcinogenesis journal May 2011
Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer journal March 2004
Metabolic Activation of Benzo[ c ]phenanthrene by Cytochrome P450 Enzymes in Human Liver and Lung journal June 2001
Contributions of Human Enzymes in Carcinogen Metabolism journal May 2012
Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and1B1 journal January 2004
Xenobiotic-Metabolizing Enzymes Involved in Activation and Detoxification of Carcinogenic Polycyclic Aromatic Hydrocarbons journal January 2006
Generation and Characterization of a Cyp2f2 -Null Mouse and Studies on the Role of CYP2F2 in Naphthalene-Induced Toxicity in the Lung and Nasal Olfactory Mucosa journal July 2011
Essential Role of the Cytochrome P450 Enzyme CYP2A5 in Olfactory Mucosal Toxicity of Naphthalene journal October 2013
In Vitro Metabolism of Naphthalene by Human Liver Microsomal Cytochrome p450 Enzymes journal October 2005
Human Cytochrome P450 2A13 Efficiently Metabolizes Chemicals in Air Pollutants: Naphthalene, Styrene, and Toluene journal February 2008
Kinetics of naphthalene metabolism in target and non-target tissues of rodents and in nasal and airway microsomes from the Rhesus monkey journal July 2013
Metabolism of polycyclic compounds. 20. The metabolism of phenanthrene in rabbits and rats: mercapturic acids and related compounds journal September 1962
Metabolism of polycyclic compounds. 21. The metabolism of phenanthrene in rabbits and rats: dihydrodihydroxy compounds and related glucosiduronic acids journal September 1962
Studies on the hepatic microsomal metabolism of [14C]phenanthrene journal January 1978
Regio- and stereo-selective metabolism of phenanthrene by twelve cDNA-expressed human, rodent, and rabbit cytochromes P-450 journal August 1994
A fluorimetric study of the hydroxylation of biphenyl in vitro by liver preparations of various species journal September 1965
Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition journal March 2013
Structure−Function Relationships of Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 Flavonoid Derivatives journal December 2010
Spectral Modification and Catalytic Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2A6, and 2A13 by Four Chemopreventive Organoselenium Compounds journal August 2011
Reverse Type I Binding Spectra of Human Cytochrome P450 1B1 Induced by Flavonoid, Stilbene, Pyrene, Naphthalene, Phenanthrene, and Biphenyl Derivatives That Inhibit Catalytic Activity: A Structure−Function Relationship Study journal July 2009
Aryl Acetylenes as Mechanism-Based Inhibitors of Cytochrome P450-Dependent Monooxygenase Enzymes journal January 1997
Naphthoflavone propargyl ether inhibitors of cytochrome P450 journal February 2006
Recombinant Human Cytochrome P450 1B1 Expression inEscherichia coli journal September 1998
Roles of NADPH-P450 Reductase and Apo- and Holo-Cytochrome b5 on Xenobiotic Oxidations Catalyzed by 12 Recombinant Human Cytochrome P450s Expressed in Membranes of Escherichia coli journal April 2002
Nicotine and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Binding and Access Channel in Human Cytochrome P450 2A6 and 2A13 Enzymes journal August 2012
Structure of the Human Lung Cytochrome P450 2A13 journal June 2007
Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine: Cytochrome P450 2A6, 2A13 and 2E1 structural comparison journal November 2011
Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen journal August 2005
Selectivity of Polycyclic Inhibitors for Human Cytochrome P450s 1A1, 1A2, and 1B1 journal August 1998
A Role for Threonine 302 in the Mechanism-Based Inactivation of P450 2B4 by 2-Ethynylnaphthalene journal July 1996
Inhibition of CYP2B4 by 2-ethynylnaphthalene: Evidence for the co-binding of substrate and inhibitor within the active site journal December 2007
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 June 2011
Cytochrome P450 2A-Catalyzed Metabolic Activation of Structurally Similar Carcinogenic Nitrosamines:  N‘ -Nitrosonornicotine Enantiomers, N -Nitrosopiperidine, and N- Nitrosopyrrolidine journal January 2005
Metabolic Activation of the Tobacco Carcinogen 4-(Methylnitrosamino)-(3-pyridyl)-1-butanone by Cytochrome P450 2A13 in Human Fetal Nasal Microsomes journal May 2005
Key Residues Controlling Binding of Diverse Ligands to Human Cytochrome P450 2A Enzymes journal February 2009
Key Residues Controlling Phenacetin Metabolism by Human Cytochrome P450 2A Enzymes journal September 2008
Differential Distribution of CYP2A6 and CYP2A13 in the Human Respiratory Tract journal January 2012
CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody journal June 2006
Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13 journal July 2015
Oxidation of Acenaphthene and Acenaphthylene by Human Cytochrome P450 Enzymes journal January 2015
Directed Evolution Reveals Requisite Sequence Elements in the Functional Expression of P450 2F1 in Escherichia coli journal August 2012
Coupled-column high-performance liquid chromatographic method for the determination of four metabolites of polycyclic aromatic hydrocarbons, 1-, 4- and 9-hydroxyphenanthrene and 1-hydroxypyrene, in urine journal October 1994
Urinary hydroxy-metabolites of naphthalene, phenanthrene and pyrene as markers of exposure to diesel exhaust journal January 2004
Phenanthrene Metabolism in Smokers: Use of a Two-Step Diagnostic Plot Approach to Identify Subjects with Extensive Metabolic Activation journal June 2012
Metabolic activation of phenanthrene by human and mouse cytochromes P450 and pharmacokinetics in CYP1A2 knockout mice journal January 2010

Cited By (10)

Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants text January 2018
Ruthenium-Catalyzed Cycloisomerization of 2-Alkynylstyrenes via 1,2-Carbon Migration That Leads to Substituted Naphthalenes journal July 2018
Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity journal April 2017
Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone text January 2018
Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone journal January 2018
Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity journal April 2017
Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants text January 2017
Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants text January 2018
Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone text January 2018
Oxidation of 1-chloropyrene by human CYP1 family and CYP2A subfamily cytochrome P450 enzymes: catalytic roles of two CYP1B1 and five CYP2A13 allelic variants journal July 2017

Figures / Tables (12)

Figure 1(p. 17)figure Figure 1
Figure 2(p. 18)figure Figure 2
Figure 3(p. 19)figure Figure 3
Figure 4(p. 20)figure Figure 4
Figure 5(p. 21)figure Figure 5
Figure 6(p. 22)figure Figure 6
Figure 7(p. 23)figure Figure 7
Figure 8(p. 24)figure Figure 8
Figure 9(p. 25)figure Figure 9
Figure 10(p. 26)figure Figure 10
Table 1(p. 27)table Table 1
Table 2(p. 28)table Table 2

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