UDP-GT involvement in the enhancement of cell proliferation in thyroid follicular cell proliferative lesions in rats treated with thiourea and vitamin A.
The mechanisms underlying enhanced cell proliferation in thyroid proliferative lesions of rats simultaneously treated with large amounts of vitamin A (VA) and thiourea (TU) were investigated. Male F344 animals were initiated with N-bis(2-hydroxypropyl)nitrosamine (2800 mg/kg body weight, single s.c. injection). Starting 1 week later, groups received water containing 0.2% TU (TU group), diet containing 0.1% VA (VA group), both 0.2% TU and 0.1% VA (TU + VA group) or tap water/basal diet without supplement (control group) for 10 weeks. The serum levels of triiodothyronine (T3) and thyroxine (T4) were decreased and the thyroid stimulating hormone (TSH) levels were elevated in the TU and TU + VA groups, with the degree of change being significantly greater in the combined treatment group. The induction of P450 isoenzymes by TU was not enhanced by VA supplementation, but uridine diphosphate glucuronosyltransferase (UDP-GT) activity in the liver was significantly increased in the TU + VA group compared to the TU group. Thyroid weights were increased in both the TU and TU + VA groups, this being more pronounced with VA supplementation. Thyroid follicular cell hyperplasias and neoplasias were induced to similar extents in both TU treated groups, but their cell proliferation appeared to be increased by the VA supplementation. The results of the present study suggest that enhanced cell proliferation is due to increased TSH stimulation, resulting from the decrease in serum T3/T4 levels brought about by induction of liver UDP-GT activity with the combined action of TU + VA as well as inhibition by TU of thyroid hormone synthesis in the thyroid.
Takegawa
K
K
Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
Mitsumori
K
K
Onodera
H
H
Mutai
M
M
Kitaura
K
K
Takahashi
M
M
Uneyama
C
C
Yasuhara
K
K
Takahashi
M
M
Yanai
T
T
Masegi
T
T
Hayashi
Y
Y
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D014453:Glucuronosyltransferase / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D013890:Thiourea / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000139:chemically induced* / Q000201:enzymology*; D014284:Triiodothyronine / Q000097:blood; D014801:Vitamin A / Q000494:pharmacology*
D013956:Antithyroid Agents; D002273:Carcinogens; D007527:Isoenzymes; D014284:Triiodothyronine; D014801:Vitamin A; D014453:Glucuronosyltransferase; D013890:Thiourea