pyrimidinones and 1-aminobenzotriazole

Rats treated with temelastine (SK&F 93,944), a novel histamine H1-receptor antagonist, develop thyroid lesions characterized by hypertrophy and colloid depletion. To investigate the mechanism underlying the lesion the biliary clearance and hepatocellular accumulation of radio-labelled iodothyronines was measured in rats or cultured rat hepatocytes. Treatment with temelastine increased both the biliary clearance (approximately 300% of control) and hepatocellular accumulation (approximately 200%) of thyroxine (T4) but had little or no effect on tri-iodothyronine (T3). Chromatographic analysis of bile samples from temelastine-treated rats showed that the majority (approximately 78%) of T4 was present in the unconjugated form. This contrasted with data from phenobarbitone-treated rats which showed that approximately 80% of T4 in the bile was present as the glucuronide conjugate. Studies with cultured hepatocytes showed that the hepatocellular accumulation of T4 was energy dependent. At 4 degrees C the treatment-related increases in accumulation of T4 were abolished, suggesting that temelastine is specifically affecting the high affinity, energy dependent system which preferentially transports thyroxine into hepatocytes. Because temelastine is metabolized extensively, investigations were undertaken to discover if the hepatic effects were caused by the parent compound or an oxidative metabolite. The results showed that the hepatocellular accumulation of T4 remained increased in hepatocytes co-incubated with temelastine and 1-aminobenzotriazole (a suicide inhibitor of cytochrome P450), even though no measurable P450 could be found in the cells. Also, in studies with two major "rat" metabolites of temelastine, i.e. 93,944-Met I or 93,944-Met VIII, treatments failed to reproduce the responses seen with the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bile; Cells, Cultured; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme Inhibitors; Female; Histamine H1 Antagonists; Liver; Pyrimidinones; Rats; Rats, Inbred Strains; Temperature; Thyroxine; Triazoles; Triiodothyronine

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.

Topics: Animals; Bile; Cells, Cultured; Cytochrome P-450 Enzyme Inhibitors; Histamine H2 Antagonists; Liver; Male; Phenobarbital; Pyrimidinones; Rats; Rats, Inbred Strains; Temperature; Thyroid Hormones; Thyroxine; Triazoles; Triiodothyronine