In vivo biliary excretion and in vitro cellular accumulation of thyroxine by rats or cultured rat hepatocytes treated with a novel histamine H1-receptor antagonist.

摘要: 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 lesion biliary clearance hepatocellular accumulation of radio-labelled iodothyronines was measured in rats or cultured rat hepatocytes. Treatment increased both (approximately 300% control) 200%) thyroxine (T4) but had little no effect on tri-iodothyronine (T3). Chromatographic analysis bile samples from — showed that majority 78%) T4 present unconjugated form. This contrasted data phenobarbitone which approximately 80% as glucuronide conjugate. Studies hepatocytes energy dependent. At 4° C treatment related increases were abolished, suggesting is specifically affecting high affinity, dependent system preferentially transports into Because metabolized extensively, investigations undertaken to discover if hepatic effects caused parent compound an oxidative metabolite. The results remained co-incubated 1-aminobenzotriazole (a suicide inhibitor cytochrome P450), even though measurable P450 could be found cells. Also, studies two major “rat” metabolites temelastine, i.e. 93944-Met I VIII, treatments failed reproduce responses seen compound. These suggest it not some metabolite responsible for effect. It concluded produces observed changes increasing T4, leading TSH release resulting gland. appears mediated via associated induction metabolizing enzyme systems.