EVALUATION OF HUMAN BLOOD-LYMPHOCYTES AS A MODEL TO STUDY THE EFFECTSOF DRUGS ON HUMAN MITOCHONDRIA - EFFECTS OF LOW CONCENTRATIONS OF AMIODARONE ON FATTY-ACID OXIDATION, ATP LEVELS AND CELL-SURVIVAL

Human lymphocytes were assessed as a cellular model for determining th e effects of drugs on human mitochondria. Formation of total oxidized C-14-products was maximal with 1 mM [U-C-14]-palmitic acid, was linear for 90 min, linear with the number of lymphocytes, and decreased by 9 5% and 77% in the presence of 30 muM rotenone and 2 mM KCN. Seven drug s were tested which had previously been shown to inhibit beta-oxidatio n in animals; all decreased formation of total oxidized C-14-products by human lymphocytes, but with different IC50 values: 35 muM with amio darone, 2.75 mM with tetracycline and amineptine, 3.75 mM with tianept ine, and more than 10 mM for valproic acid and the ibuprofen enantiome rs. Formation of [C-14]CO2 either increased or decreased, in relation to the various effects of these drugs on coupling, beta-oxidation, and the tricarboxylic acid cycle. There was a general trend for some rela tionship between inhibition of fatty acid oxidation and loss of cellul ar ATP. Those compounds, however, which uncoupled oxidative phosphoryl ation (2,4-dinitrophenol, amiodarone, ibuprofen) and/or inhibited the mitochondrial respiratory chain (amiodarone, rotenone, KCN) resulted i n comparatively higher ATP depletion. Amiodarone, a drug which produce s several effects (uncoupling, inhibition of beta-oxidation, of the tr icarboxylic acid cycle and of the respiratory chain), caused a dramati c decrease in cellular ATP and cell viability at low concentrations (2 0-100 muM). Both these effects were prevented by the addition of 5 mM glucose, a substrate for anaerobic glycolysis. We conclude that human lymphocytes may be a useful model for assessing the effects of drugs o n human mitochondrial function. IC50 values determined with this model may not necessarily apply, however, to other cells.