Comparison of the Effects of SK&F 93479 and Phenobarbitone Treatment on Thyroid Toxicity and Hepatic Thyroid Hormone Metabolising Enzymes in the Rat
Deiodination and glucuronidation are major routes of T3 and T4 metabolism in rodents and both the deiodinases and uridine diphosphate glucuronyl transferase (UDP-GT) are affected by drug treatment (see review by Cavalieri and Pitt Rivers 1981). The phenobarbitone (PB)-induced thyroid stimulation and thyroid tumour-promoting potential in rats (Hiasa et al. 1982) follows from enhanced hepatic thyroxine elimination (Oppenheimer et al. 1968) which may result in part from stimulation of UDP-GT activity, since hepatic T4 conjugation is rate limiting for biliary T4 clearance. PB is also known to enhance the UDP-GT isoenzyme activity preferentially conjugating T4 and para-nitrophenol (PNP) in rats (Watkins et al. 1982). The histamine H2-antagonist SK&F 93479 (2-(2-(5-(dimethylaminome-thyl)furan-2-ylmethylthio)-ethylamino)-5-(6-methylpyrid-3-ylmethyl)-pyrimidin-4-one trihydrochloride) has been previously shown to produce similar thyroid lesions to PB at toxicological doses (see Brown et al. 1987), resulting from rapid increases in T4 clearance (approx. 6 h following treatment) and subsequent increases in TSH drive (approx. 24 h following treatment). It was further demonstrated that the increased T4 clearance did not correlate with changes in hepatic or renal 5′-deiodinase activity (Jones et al. 1987). Therefore, the onset of increases in T4 clearance produced by the two drugs in rats has been compared with changes in both hepatic UDP-GT and β-glucuronidase activities in an attempt to define the exact hepatocellular mechanism associated with the endocrinological changes.
KeywordsHistamine Phen Furan Phenobarbital Thyroxine
Unable to display preview. Download preview PDF.