THE EFFECTS OF METHYLPREDNISOLONE ON OXIDATIVE-PHOSPHORYLATION IN CONCANAVALIN-A-STIMULATED THYMOCYTES - TOP-DOWN ELASTICITY ANALYSIS AND CONTROL ANALYSIS

The glucocorticoid methylprednisolone has clinically important anti-in flammatory effects at high concentrations through unknown mechanisms. Methylprednisolone at 0.2 mg/10(7) cells inhibits respiration in Conca navalin-A(ConA)-stimulated thymocytes from rats by about 20%. We have used top-down elasticity analysis to identify the blocks of reactions within oxidative phosphorylation in thymocytes whose kinetics are sign ificantly affected by treatment with methylprednisolone. At this conce ntration methylprednisolone greatly inhibited the reactions of substra te oxidation and increased mitochondrial proton leak but did not signi ficantly affect the synthesis and turnover of ATP by the phosphorylati ng system. Metabolic control analysis showed that oxygen consumption b y ConA-treated thymocytes was controlled largely (0.51) by the phospho rylating system but also by proton leak (0.32) and substrate oxidation (0.17); this is similar to the distribution of control in hepatocytes , suggesting that this pattern may be general in cells. Methylpredniso lone lowered control by the phosphorylating system to 0.26 and raised control by substrate oxidation to 0.37. From these results we conclude that the inhibition of respiration in ConA-stimulated thymocytes by m ethylprednisolone at this concentration results from an inhibition of substrate oxidation and a smaller stimulation of mitochondrial proton leak, with only a minor contribution of any effects within the phospho rylating system.