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The Effects on Rat Thyroid Function of an Hepatic Microsomal Enzyme Inducer

ICI Pharmaceuticals, Safety of Medicines Department, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

D. McKillop

ICI Pharmaceuticals, Safety of Medicines Department, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

J. Miller

ICI Pharmaceuticals, Safety of Medicines Department, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

I.K. Smith

ICI Pharmaceuticals, Safety of Medicines Department, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK

1 Following daily administration to male albino rats for 2 weeks, β-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. β-naphthoflavone also induced p-nitrophenol glucuronidation by 160% over controls, while phenobarbitone produced only a 45% induction of this conjugation activity.

2 β-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 β-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 significant 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. Data for the two compounds suggest some variation in the precise mechanism of action, which has not yet been fully elucidated.

Human & Experimental Toxicology, Vol. 12, No. 2, 153-158 (1993)
DOI: 10.1177/096032719301200210


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