Carboxylic metabolites of tiadenol as "proximate" inducers of hepatic peroxisomal beta-oxidation activity

Chronic exposure of rats to the hypolipidemic agent tiadenol causes a dramatic dose-dependent increase of peroxisomal β-oxidation activity. To elucidate which metabolite of the drug is the "proximate" inducer (tiadenol is eliminated completely in metabolized form after acute administration) we investigated the qualitative and quantitative metabolic profile of the drug at different doses (50, 150, 300 mg/Kg in two-weeks chronically treated rats, in parallel to that of a model compound, tiadenol-disulfoxide, a weak inducer of palmitoyl-CoA oxidation activity. No changes in the biodisposition of tiadenol (and tiadenol-disulfoxide) were found following chronic treatment for all the doses tested. For both the compounds a strict correlation was evidenced between the extent of formation of carboxylic metabolites and their inductive potencies on peroxisomal β-oxidation activity. This indicates that tiadenol carboxylic metabolites act as the enzymatic effectors.