Thyroid hyperactivity induced by methimazole, spironolactone and phenobarbital in marmosets (Callithrix jacchus): histopathology, plasma thyroid hormone levels and hepatic T4 metabolism.
To determine drug-induced hyperfunction of marmoset thyroids due to inhibition of synthesis or enhancement of metabolic elimination of thyroid hormones, males were orally administered 10 and 30 mg/kg/day methimazole (MMI), 30 and 100 mg/kg/day spironolactone (SPL), or 50 mg/kg/day phenobarbital (PB) for 4 weeks. MMI caused marked hypertrophy of follicular epithelial cells in accordance with a significant decrease in the plasma thyroxin (T4) level. Hypertrophied epithelial cells were filled with dilated rough endoplasmic reticulum and reabsorbed intracellular colloids, and the luminal surface was covered with abundant microvilli. The colloid included vacuoles positive to anti T4 immuno-staining. SPL and PB also caused similar histomorphological changes, although they were less severe than those due to MMI and were not clearly associated with decrease in the plasma T4 levels. Hepatic T4 UDPGT activities tended to increase due to SPL and PB treatment, however, which were not so significant as increases in microsomal cytochrome P-450 contents. Some animals treated with SPL and PB showed marked increases in thyroid weights due to inactive dilated follicles. In conclusion, hyperactivity of thyroid follicles was induced in marmosets not only due to inhibition of T4 synthesis produced by MMI but also because of enhancement of hepatic T4 elimination produced by SPL and PB. However, hypertrophic effects of SPL and PB were less severe than MMI, because plasma T4 levels were maintained at almost pretreatment or control levels after SPL or PB treatment.
Kurata
Y
Y
Mitsubishi Chemical Safety Institute Ltd., Kashima-gun, Ibaraki, Japan.
Wako
Y
Y
Tanaka
K
K
Inoue
Y
Y
Makinodan
F
F
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects*; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001706:Biopsy / Q000662:veterinary; D002144:Callithrix / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D008713:Methimazole / Q000008:administration & dosage / Q000009:adverse effects; D008854:Microscopy, Electron / Q000662:veterinary; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D010634:Phenobarbital / Q000008:administration & dosage / Q000009:adverse effects; D011863:Radioimmunoassay / Q000662:veterinary; D013148:Spironolactone / Q000008:administration & dosage / Q000009:adverse effects; D013959:Thyroid Diseases / Q000139:chemically induced / Q000662:veterinary*; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
D000927:Anticonvulsants; D013956:Antithyroid Agents; D000451:Mineralocorticoid Receptor Antagonists; D014284:Triiodothyronine; D013148:Spironolactone; D008713:Methimazole; D003577:Cytochrome P-450 Enzyme System; D013974:Thyroxine; D010634:Phenobarbital