Thioridazine: a selective inhibitor of peroxisomal β‐oxidation in vivo

Abstract

In vivo administration of the phenothiazine drug, thioridazine, inhibits hepatic peroxisomal fl-oxidation in mice. In starving animals, 3-hydroxybutyrate concentration is not decreased by thioridazine treatment. These results provide the first demonstration of thioridazine as a selective inhibitor of peroxisomal /I-oxidation in intact animals. Thioridazine might supply a tool for simulation of pathological conditions in which peroxisomal #&oxidation is impaired. Peroxisome ~-Oxidation CatalaseIn vivo inkibit~on

Effect of Thioridazine or Chlorpromazine on Increased Hepatic NAD+ Level in Rats Fed Clofibrate, a Hypolipidaemic Drug

“…The activity of peroxi-soma1 B-oxidation, which produces H202 in the first step (Lazarow & de Duve 1976), was determined by measuring H202 generation. Van den Branden & Roels (1985) showed, by estimation of residual catalase activity, that in-vivo administration of thioridazine inhibited hepatic peroxisomal /?-oxidation in mice; they also showed that 3hydroxybutyrate concentration was not reduced by thioridazine treatment (50-250 pmol kg-' , in saline, given intraperitoneally) in fed or 24-h-starved mice. They subsequently discussed the short-and long-term influence of phenothiazines on liver peroxisomal fatty acid oxidation in rodents (Van den Branden et a1 1987).…”

“…Rats were killed by decapitation 2 h after intraperitoneal injection of 3-amino-1,2,4-triazole (1 g kg-' in 0.9% NaCl (saline))-methanol(3.5 mmol kg-I), an inhibitor of catalase-hydrogen peroxide complex (Oshino et a1 1973;Inestrosa et a1 1979;Mannaerts et a1 1979;Leighton et a1 1984;Van den Branden et a1 1984;Van den Branden & Roels 1985;Small et a1 1985;Van den Branden et a1 1987;Skorin et a1 1992). The liver was quickly removed and weighed and a portion was quickly frozen with blocks of dry ice and finely powdered.…”

“…One unit is the amount of catalase that breaks down 90% substrate (H202 1.5 mM) in 50mL at 0°C in 1 min; the maximum reaction time is 1Omin. Residual catalase activity is the catalase activity that remains after inhibition by aminotriazole-methanol (Van den Branden et a1 1984, 1987Van den Branden & Roels 1985). When residual catalase activity is low, H202 production is high, i.e.…”

Inhibition of peroxisomal beta‐oxidation and brain development in rats

“…Inhibition of peroxisomal beta-oxidation in vivo is achieved by administration of thioridazine, a phenothiazine drug (Van den Branden and Roels, 1985) for 2 weeks from day 8 till day 21, matching the period of maximal myelination with the effectivity range of the drug ( Van den Branden et al, 1987a). Preliminary results were published (Van den Branden et al, 1987b,c).…”

Short and long term influence of phenothiazines on liver peroxisomal fatty acid oxidation in rodents

“…An impairment of the former system resulting in the accumulation of VLCFA in body fluids and tissues exists in patients with peroxisomal diseases [2]. Although phenothiazines were demonstrated in rodent liver to inhibit peroxisomal &oxidation [3,4], no animal model for the chronic depression of this route has been studied.…”