title: Selenoneine, a novel selenium-containing compound, mediates detoxification mechanisms against methylmercury accumulation and toxicity in zebrafish embryo.
abstract: The selenium (Se)-containing antioxidant selenoneine (2-selenyl-N α,N α,N α-trimethyl-L-histidine) has recently been discovered to be the predominant form of organic Se in tuna blood. Although dietary intake of fish Se has been suggested to reduce methylmercury (MeHg) toxicity, the molecular mechanism of MeHg detoxification by Se has not yet been determined. Here, we report evidence that selenoneine accelerates the excretion and demethylation of MeHg, mediated by a selenoneine-specific transporter, organic cations/carnitine transporter-1 (OCTN1). Selenoneine was incorporated into human embryonic kidney HEK293 cells transiently overexpressing OCTN1 and zebrafish blood cells by OCTN1. The K m for selenoneine uptake was 13.0 μM in OCTN1-overexpressing HEK293 cells and 9.5 μM in zebrafish blood cells, indicating high affinity of OCTN1 for selenoneine in human and zebrafish cells. When such OCTN1-expressing cells and embryos were exposed to MeHg-cysteine (MeHgCys), MeHg accumulation was decreased and the excretion and demethylation of MeHg were enhanced by selenoneine. In addition, exosomal secretion vesicles were detected in the culture water of embryos that had been microinjected with MeHgCys, suggesting that these may be responsible for MeHg excretion and demethylation. In contrast, OCTN1-deficient embryos accumulated MeHg, and MeHg excretion and demethylation were decreased. Furthermore, Hg accumulation was decreased in OCTN1-overexpressing HEK293 cells, but not in mock vector-transfected cells, indicating that selenoneine and OCTN1 can regulate MeHg detoxification in human cells. Thus, the selenoneine-mediated OCTN1 system regulates secretory lysosomal vesicle formation and MeHg demethylation.
authors.affiliation: National Research Institute of Fisheries Science, 2-12-4 Fukuura, Yokohama, Kanagawa, 236-8648, Japan. mic@affrc.go.jp
authors.forename: Michiaki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Tamami
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kani
authors.forename: Nanami
authors.initials: N
authors.lastname: Mizusawa
authors.forename: Shintaro
authors.initials: S
authors.lastname: Imamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Takemoto
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Hara
authors.forename: Md Anwar
authors.initials: MA
authors.lastname: Hossain
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yabu
authors.forename: Ken
authors.initials: K
authors.lastname: Touhata
mesh_terms: D000818:Animals; D016375:Antisense Elements (Genetics); D015153:Blotting, Western; D005453:Fluorescence; D057809:HEK293 Cells; D006639:Histidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008658:Inactivation, Metabolic / Q000502:physiology*; D007814:Larva / Q000187:drug effects; D008247:Lysosomes / Q000378:metabolism; D008767:Methylmercury Compounds / Q000493:pharmacokinetics* / Q000633:toxicity; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D027981:Symporters; D014461:Ultracentrifugation; D015027:Zebrafish / Q000378:metabolism / Q000502:physiology*
chemical_list: D016375:Antisense Elements (Genetics); D008767:Methylmercury Compounds; D027701:Organic Cation Transport Proteins; D016566:Organoselenium Compounds; C109807:SLC22A4 protein, human; D027981:Symporters; C550322:selenoneine; D006639:Histidine