RRC ID 17496
著者 Ishikawa T, Okinaga H, Takahashi S, Numakura M, Mashimo Y, Yoshimura N, Maeda T, Inoue D, Okazaki R, Kinoshita M, Jameson JL, Teramoto T.
タイトル Serum from methimazole-treated patients induces activation of aryl hydrocarbon receptor, a transcription factor that binds to dioxin-response elements.
ジャーナル Thyroid
Abstract BACKGROUND:The aryl hydrocarbon receptor (AhR) is a transcription factor that is activated by xenobiotic substances such as dioxin. After activation, it binds to dioxin response elements of DNA, thereby inducing transcription of a variety of xenobiotic metabolizing enzymes. To investigate whether AhR-activating substances accumulate in patients with endocrine disorders, we tested serum samples for AhR-stimulating activity.
METHODS:Serum AhR-stimulating activity was evaluated by exposing the HepG2 cells transiently transfected with an AhR-responsive reporter plasmid to serum samples. On the basis of preliminary findings that implicated methimazole (MMI), wild-type and AhR-null mice were treated with MMI, and their plasma AhR-stimulating activities and thyroxine levels were quantified.
RESULTS:In 28 randomly chosen patients, 7 out of 10 Graves' disease patients exhibited increased serum AhR-stimulating activity. The increased activity did not correlate with thyroid hormone status. However, we hypothesized that it might be caused by MMI. Subsequent analyses revealed that in 25 of 26 MMI-treated Graves' patients, serum samples collected after the MMI treatment had significantly higher AhR-stimulating activity compared to samples obtained when the same patients were not on MMI. By contrast, serum AhR-stimulating activity was unchanged in samples from the seven patients on propylthiouracil (PTU) compared to serum taken before the PTU treatment. In vitro experiments demonstrated that an MMI metabolite 3-methyl-2-thiohydantoin, but not MMI, activated AhR. MMI increased plasma AhR-stimulating activities and reduced plasma thyroxine concentrations, in both wild-type and AhR-deficient mice.
CONCLUSIONS:Graves' patients taking MMI have increased serum AhR-stimulating activity, which is unrelated to thyroid hormone status, but correlates with MMI treatment. The AhR activation is likely caused by 3-methyl-2-thiohydantoin. Further studies are required to determine the potency of 3-methyl-2-thiohydantoin as an AhR activator and the significance of the differences between MMI and PTU observed in this study.
巻・号 22(8)
ページ 769-77
公開日 2012-8-1
DOI 10.1089/thy.2012.0057
PMID 22784254
MeSH Adult Aged Aged, 80 and over Animals Female Graves Disease / blood Graves Disease / drug therapy Hep G2 Cells Humans Male Methimazole / metabolism Methimazole / therapeutic use* Mice Middle Aged Propylthiouracil / therapeutic use Receptors, Aryl Hydrocarbon / drug effects* Receptors, Aryl Hydrocarbon / metabolism* Thiohydantoins / pharmacology
IF 5.309
引用数 4
WOS 分野 ENDOCRINOLOGY & METABOLISM
リソース情報
実験動物マウス RBRC01712