In vitro accumulation of thyroid hormones by cultured rat hepatocytes and the biliary excretion of iodothyronines in rats treated with a novel histamine H2-receptor antagonist.
The administration of SK&F 93479, a novel histamine H2 antagonist, to Wistar rats has been shown to produce thyroid lesions associated with an increased clearance of plasma thyroxine (T4) and elevated plasma TSH concentrations. To determine if these changes were mediated via an increase in the hepatic clearance of thyroid hormones, the biliary clearance and hepatic accumulation of iodothyronines were measured in rats and cultured hepatocytes treated with SK&F 93479. Both the in vitro and in vivo results showed that treatment with SK&F 93479 caused an increased hepatic accumulation (approx. 200% of control) and biliary excretion (2-3-fold control values) of T4 but had little or no effect on T3 uptake. The in vitro studies showed that the treatment related increase in hepatic thyroxine accumulation was temperature and therefore probably energy dependent, while inhibition of cytochrome P-450 dependent enzyme activity did not alter the accumulation of T4 suggesting that the parent compound and not some oxidative metabolite was responsible for the hepatic effects. Chromatographic analysis of bile from SK&F 93479 and phenobarbitone-treated rats showed that in the latter animals 81% of the T4 was present as the glucuronide conjugate (consistent with enzyme induction) whereas in the SK&F 93479-treated rats only 25% was present as the conjugate with 75% being in the unconjugated form. These studies show that SK&F 93479 increases the hepatic accumulation and biliary clearance of T4 by a novel mechanism not associated with liver microsomal enzyme induction.
Poole
A
A
Department of Toxicology, Smith Kline & French Research Ltd., Welwyn, Herts, U.K..
Jones
R B
RB
Pritchard
D
D
Catto
L
L
Leonard
T
T
D000818:Animals; D001646:Bile / Q000378:metabolism*; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D006635:Histamine H2 Antagonists / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011744:Pyrimidinones / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013696:Temperature; D013963:Thyroid Hormones / Q000378:metabolism*; D013974:Thyroxine / Q000378:metabolism; D014230:Triazoles / Q000633:toxicity; D014284:Triiodothyronine / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D011744:Pyrimidinones; D013963:Thyroid Hormones; D014230:Triazoles; D014284:Triiodothyronine; C033020:1-aminobenzotriazole; C033275:SK&F 93479; D013974:Thyroxine; D010634:Phenobarbital