D-AMPHETAMINE-INDUCED HEPATOXICITY - POSSIBLE CONTRIBUTION OF CATECHOLAMINES AND HYPERTHERMIA TO THE EFFECT STUDIED IN ISOLATED RAT HEPATOCYTES

Amphetamines are indirect-acting sympathomimetic drugs widely abused d ue to their physical and psychostimulating effects. However, the use o f these drugs has been associated with numerous reports of hepatotoxic ity. While glutathione depletion induced by amphetamines contributes t o the exposure of hepatocytes to oxidative damage, other indirect effe cts attributed to amphetamines may have a role in cell injury. To exam ine this possibility, Wistar rats were used for plasma measurements of d-amphetamine and catecholamines (noradrenaline, adrenaline and dopam ine) (15 min) after i.p. injection of d-amphetamine (5, 20 and 80 mg/k g). Freshly isolated rat hepatocytes were put into contact for 2 h wit h concentrations of d-amphetamine and catecholamines similar to those found in vivo. Since hyperthermia is a common consequence of acute amp hetamine intake, the study using isolated hepatocytes was conducted at 37 degrees C and also at 41 degrees C in order to simulate high tempe rature levels, We found that hyperthermia was an important cause of ce ll toxicity: in vitro, a rise in incubation temperature from 37 to 41 degrees C causes oxidative stress in freshly isolated rat hepatocytes, as shown by a depletion of reduced glutathione (GSH; 23%), an increas e of oxidized glutathione (GSSG; 157%), the induction of lipid peroxid ation with 77% increase of thiobarbituric acid substances TBARS) and t he consequent loss of cell viability (less than or equal to 44%). Sing le treatment of isolated hepatocytes with catecholamines at 37 degrees C induced lipid peroxidation (29% increase of TEARS) but had no effec t on glutathione or cell viability. Conversely, a single treatment wit h d-amphetaGSH) with no effect on lipid peroxidation or cell viability . Also, d-amphetamine potentiated the induction by catecholamines of l ipid peroxidation at 37 degrees C (less than or equal to 48% increase of TEARS), while concomitant treatment of d-amphetamine and catecholam ines potentiated cell death at 41 degrees C (less than or equal to 56% of cell death) although no effect on viability was seen at 37 degrees C, It is concluded that the aforementioned modifications induced by d -amphetamine In vivo are cytotoxic to freshly isolated rat hepatocytes .