The effects on rat thyroid function of an hepatic microsomal enzyme inducer.
1. Following daily administration to male albino rats for 2 weeks, beta-naphthoflavone (25 and 60 mg kg-1, i.p.) and phenobarbitone (100 mg kg-1, p.o.) produced their characteristic patterns of induction of P450-related enzyme activities. beta-naphthoflavone also induced p-nitrophenol glucuronidation by 160% over controls, while phenobarbitone produced only a 45% induction of this conjugation activity. 2. beta-Naphthoflavone produced significant reductions in plasma thyroxine (T4) concentrations on days 4 and 16 and also decreased tri-iodothyronine (T3) on day 4. Thyroid-stimulating hormone (TSH) was significantly increased on day 16 by the higher dose of beta-naphthoflavone. Thyroid weight was significantly increased at both dose levels on day 16 and liver weight was significantly increased on both days 4 and 16. No histopathological changes were seen in the liver or pituitary, but 30% of the animals showed minimal to mild follicular epithelial hypertrophy of the thyroid gland. 3. Phenobarbitone had no effect on T4 concentrations, but significantly decreased T3 on day 4. TSH increased by 60% on day 16, but was not statistically significantly compared with controls. Thyroid weight was significantly increased on day 16 and liver weight was significantly increased on days 4 and 16. Mild to moderate thyroid follicular epithelial hypertrophy and moderate hepatocyte hypertrophy occurred in all animals. No histopathological changes were seen in the pituitary. 4. The early changes in T4 and/or T3 were probably due to increased hepatic clearance by induction of thyroxine glucuronidation with both compounds. Thyroid hypertrophy would be expected to follow as a result of activation of the hypothalamic-pituitary-thyroid axis.(ABSTRACT TRUNCATED AT 250 WORDS)
Johnson
S
S
ICI Pharmaceuticals, Safety of Medicines Department, Macclesfield, Cheshire, UK.
McKillop
D
D
Miller
J
J
Smith
I K
IK
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology / Q000633:toxicity*; D003864:Depression, Chemical; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology / Q000633:toxicity; D010902:Pituitary Gland / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000187:drug effects*; D013963:Thyroid Hormones / Q000097:blood; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D013963:Thyroid Hormones; D014284:Triiodothyronine; D019324:beta-Naphthoflavone; D013972:Thyrotropin; D006899:Mixed Function Oxygenases; D013974:Thyroxine; D010634:Phenobarbital