title: Potential Metabolic Activation of a Representative C2-Alkylated Polycyclic Aromatic Hydrocarbon 6-Ethylchrysene Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells.
abstract: Exposure to polycyclic aromatic hydrocarbons (PAHs) is the major human health hazard associated with the Deepwater Horizon oil spill. C2-Chrysenes are representative PAHs present in crude oil and could contaminate the food chain. We describe the metabolism of a C2-chrysene regioisomer, 6-ethylchrysene (6-EC), in human HepG2 cells. The structures of the metabolites were identified by HPLC-UV-fluorescence detection and LC-MS/MS. 6-EC-tetraol isomers were identified as signature metabolites of the diol-epoxide pathway. O-Monomethyl-O-monosulfonated-6-EC-catechol, its monohydroxy products, and N-acetyl-l-cysteine(NAC)-6-EC-ortho-quinone were discovered as signature metabolites of the ortho-quinone pathway. Potential dual metabolic activation of 6-EC involving the formation of bis-electrophiles, i.e., a mono-diol-epoxide and a mono-ortho-quinone within the same structure, bis-diol-epoxides, and bis-ortho-quinones was observed as well. The identification of 6-EC-tetraol, O-monomethyl-O-monosulfonated-6-EC-catechol, its monohydroxy products, and NAC-6-EC-ortho-quinone supports potential metabolic activation of 6-EC by P450 and AKR enzymes followed by metabolic detoxification of the ortho-quinone through interception of its redox cycling capability by catechol-O-methyltransferase and sulfotransferase enzymes. The tetraols and catechol conjugates could be used as biomarkers of human exposure to 6-EC resulting from oil spills.
authors.affiliation: Center of Excellence in Environmental Toxicology and ‡Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Meng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Center of Excellence in Environmental Toxicology and ‡Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Clementina
authors.initials: C
authors.lastname: Mesaros
authors.affiliation: Center of Excellence in Environmental Toxicology and ‡Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Suhong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Center of Excellence in Environmental Toxicology and ‡Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: Center of Excellence in Environmental Toxicology and ‡Center for Cancer Pharmacology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D002911:Chrysenes / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D059392:Petroleum Pollution / Q000032:analysis*; D015238:Sulfotransferases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D002911:Chrysenes; C116651:ethylchrysene; D003577:Cytochrome P-450 Enzyme System; D002394:Catechol O-Methyltransferase; D015238:Sulfotransferases; D000469:Alkaline Phosphatase