Serum from methimazole-treated patients induces activation of aryl hydrocarbon receptor, a transcription factor that binds to dioxin-response elements.
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.
Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan. tishi-tky@umin.ac.jp
Toshio
T
Ishikawa
Hiroko
H
Okinaga
Satoshi
S
Takahashi
Maiko
M
Numakura
Yamato
Y
Mashimo
Nakayuki
N
Yoshimura
Tomomi
T
Maeda
Daisuke
D
Inoue
Ryo
R
Okazaki
Makoto
M
Kinoshita
J Larry
JL
Jameson
Tamio
T
Teramoto
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000188:drug therapy; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D008713:Methimazole / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008875:Middle Aged; D011441:Propylthiouracil / Q000627:therapeutic use; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism*; D013867:Thiohydantoins / Q000494:pharmacology
D018336:Receptors, Aryl Hydrocarbon; D013867:Thiohydantoins; D008713:Methimazole; C023447:methylthiohydantoin; D011441:Propylthiouracil