Prevention of endotoxin-induced changes in oxidative phosphorylation in hepatic mitochondria.
E. coli endotoxemia affects hepatic energy linked function by uncoupling oxidation from phosphorylation. This study was done to determine whether a steroid, methylprednisolone sodium succinate (MPS), as well as excess substrate sodium succinate (SS), alters directly the effects of endotoxin on hepatic mitochondria. An assay system using alpha-ketoglutarate (alpha-Kg) was developed to test this hypothesis. Isolated rat hepatic mitochondria were first incubated in concentrations of MPS, ranging from 2.0 to 6.0 mg/ml. At these concentrations uncoupling identical to that occurring with addition of endotoxin resulted. However, a more dilute solution of MPS, 0.12 mg/ml, permitted normal mitochondrial function. Preincubation of MT in 0.12 mg/ml of MPS, as well as with sodium succinate, prevented endotoxin-induced uncoupling. Both endotoxin and steroid resulted in increased ATPase activity in  the medium. While preincubation with MPS blocks the endotoxin effect, very high steroid concentrations alone are harmful. A direct action of steroids on mitochondria is evident, as well as a weaker protective effect due to excess substrate (alpha-Kg + SS). Since mitochondria are probably in direct communication with extracellular fluid, the assay system permits interaction of endotoxin, steroids, and substrates which mimic those which occur in vivo. The results of this study account for the previously reported variable effects obtained when steroids have been tested in vivo.
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D051381:Rats; D013386:Succinates / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D004731:Endotoxins; D013386:Succinates; D014475:Uncoupling Agents; D000251:Adenosine Triphosphatases; D008775:Methylprednisolone