title: The effects of CYP1A inhibition on alkyl-phenanthrene metabolism and embryotoxicity in marine medaka (Oryzias melastigma).
abstract: Alkylated polycyclic aromatic hydrocarbons (alkyl-PAHs) are the predominant form of PAHs in crude oils, of which, 3-5 ring alkyl-PAH may cause dioxin-like toxicity to early life stages of fish. Retene (7-isopropyl-1-methylphenanthrene), a typical alkyl-phenanthrene compound, can be more toxic than phenanthrene, and the mechanism of retene toxicity is likely related to its rapid biotransformation by cytochrome P450 (CYP) enzymes to metabolites with a wide array of structures and potential toxicities. Here, we investigated how α-naphthoflavone (ANF), a cytochrome P450 1A (CYP1A) inhibitor, affected the embryotoxicity of retene and the role that CYP1A inhibition may play in the interactions. Marine medaka (Oryzias melastigma) embryos were exposed, separately or together, to 200 μg/L retene with 0, 5, 10, 100, and 200 μg/L ANF for 14 days. The results showed that ANF significantly inhibited the induction of CYP1A activity by retene; however, ANF interacted with retene to induce significant developmental toxicity and genotoxicity at 10, 100, and 200 μg/L (p < 0.01). Tissue concentrations of retene and its metabolites and lipid hydroperoxide (LPO) activity also increased, whereas the inhibition of the glutathione S-transferase (GST) activity and the alteration in metabolic profiles of retene were observed. The interactions of retene with ANF indicate that CYP1A inhibition was possibly act through different mechanisms to produce similar developmental effects and genotoxicity. Retene metabolites and altered metabolic profile were likely responsible for retene embryotoxicity to marine medaka. Therefore, elevated toxicity of alkyl-phenanthrene under CYP1A inhibitor suggested that the ecotoxicity of PAHs in coastal water may have underestimated the threat of PAHs to fish or ecosystem.
authors.affiliation: Key Laboratory for Ecological Environment in Coastal Areas (State Oceanic Administration, SOA), National Marine Environmental Monitoring Center, Dalian, 116023, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Mu
authors.affiliation: Key Laboratory for Ecological Environment in Coastal Areas (State Oceanic Administration, SOA), National Marine Environmental Monitoring Center, Dalian, 116023, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jin
authors.affiliation: Key Laboratory for Ecological Environment in Coastal Areas (State Oceanic Administration, SOA), National Marine Environmental Monitoring Center, Dalian, 116023, China. jywang@nmemc.org.cn.
authors.forename: Juying
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory for Ecological Environment in Coastal Areas (State Oceanic Administration, SOA), National Marine Environmental Monitoring Center, Dalian, 116023, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory for Ecological Environment in Coastal Areas (State Oceanic Administration, SOA), National Marine Environmental Monitoring Center, Dalian, 116023, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cong
mesh_terms: D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects* / Q000201:enzymology; D005982:Glutathione Transferase / Q000378:metabolism; D009990:Oryzias / Q000196:embryology / Q000378:metabolism*; D010578:Petroleum / Q000032:analysis / Q000378:metabolism; D010616:Phenanthrenes / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D001571:Benzoflavones; D010578:Petroleum; D010616:Phenanthrenes; D014874:Water Pollutants, Chemical; C447880:retene; C011512:alpha-naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase
keywords: Alkylated polycyclic aromatic hydrocarbons; CYP1A activity; Marine medaka; Metabolism; Synergistic toxicity