THE EFFECT OF CHLORPROMAZINE ON ¹⁴C‐GLUCOSE METABOLISM IN MOUSE LIVER AND BRAIN

Abstract

Chlorpromazine in high concentrations decreases energy production in tissues in vitro by inhibiting cellular respiration and phosphorylation (Quastel, 1965). Berger (1957) found uncoupling of phosphorylation in liver, but not in brain mitochondria exposed to chlorpromazine. The precise site of uncoupling of the respiratory enzyme chain in the liver has been identified by Dawkins, Judah & Rees (1959), who also observed similar effects in the brain in the presence of 2 x 10-'M chlorpromazine. Chance (1959) has demonstrated that the controlling metabolite for coupled respiration is adenosine diphosphate (ADP) and thus in normal conditions the rate of aerobic energy production is limited by the concentration of ADP. Chance & Baltscheffsky (1958) have employed the concept of respiratory control ratio which is defined as the ratio of respiratory rate in the presence of added ADP to that rate obtained following its expenditure. The use of this measurement enables more sensitive detection of loosely coupled respiration than that obtained by direct P/O ratios.Administration of chlorpromazine to rats does not affect the oxygen uptake of homogenates of their tissues in vitro (Grenell, Mendelson & McElroy, 1955). In the presence of uncoupled respiration, however, impaired carbohydrate utilization can occur even though oxygen consumption is normal. This paper describes an investigation of the fate of [U-"C]-glucose in mice after the administration of chlorpromazine in order to detect alterations in energy dependent processes which would occur if significant respiratory uncoupling occurred in the intact animal. The ability of ADP to stimulate the respiration of brain and liver homogenates in the presence of chlorpromazine concentrations similar to those attained therapeutically has also been studied. METHODSSAS/ICI adult albino mice of either sex weighing 18-25 g were used.Tissue respirationOxygen uptake of tissue homogenates was measured manometrically at 37' C in a Warburg respirometer. Untreated mice were killed by cervical fracture and exsanguination. The brain and liver were rapidly removed and immediately plunged into ice-cold Hanks balanced salt solution. The tissues were then blotted, weighed on a torsion balance and homogenized in ice-cold Hanks EM

Phenothiazines Enhance the Hypothermic Preservation of Liver Grafts: A Pilot in Vitro Study

“…The neuroleptic drugs chlorpromazine and promethazine (C+P), both derivatives of the drug phenothiazine, have been used for their anti-psychotic and sedative effects since the 1950s 5 , 6 . Often administered in combination 6 – 9 , C+P appear to exert their effects on the nervous system through the inhibition of carbohydrate oxidation 8 , 10 ; several studies have reported beneficial antioxidant effects achieved with these agents 7 , 9 , 11 , 12 . Additionally, recent unpublished data from our group have demonstrated that phenothiazines applied after stroke suppress brain metabolism and decrease peroxide production.…”