Toxic effects of oxygen at high pressure on the metabolism of d-glucose by dispersions of rat brain

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Abstract
Marked and rapid depressions in the catabolism of D-glucose were observed in cell-free dispersions of rat brain during incubations in O at high pressure, commonly 5 atm. These results showed a better rate-correlation with phenomena in vivo than have previous neuro-chemical studies. The production of lactate from D-glucose increased rapidly during incubations in O at high pressure, with significant increases in the concentration of lactate occurring in less than 15 minutes. During incubations in O at 5 atm pressure, oxidation of uniformly Cl4-labelled D-glucose to Cl4O2 decreased to 20-33% of control values in O at 1 atm pressure within 30 minutes. This phenomenon was accompanied by a slightly decreased utilization of D-glucose, increased production of lactate and variable and usually insignificant alterations in the total production of CO2. The production of C14O2 from both [l-Cl4]-pyruvate and [2-C14]pyruvate decreased during incubations in O at 5 atm to 50-70% of control C14O2 produced in O at 1 atm, with again little significant alteration in total production of CO2. O at 5 atm pressure decreased the production of C14O2 from [alpha]-oxo[5-C14]glutarate to 45-70% of that produced in O at 1 atm and inhibited the production of Cl4O2 from DL-[1-Cl4]-glutamate almost as much. The production of C14O2 from [1, 4-C14 2]succinate was not altered during incubations in O at high pressure for 30 minutes. The addition of coenzyme A, thiamine pyrophosphate, catalase, reduced glutathione or mercaptoethanol to the brain dispersions did not result in any significant "protective effects" against the inhibitions in the oxidation of uniformly C14_labelled D-glucose and C14_labelled pyruvate caused by O at high pressure. Rapid depression of the activity of pyruvate oxidase in rat-brain mitochondria was observed during incubations in O at 5 atm pressure as measured by decreased production of C14O2 and acetyl phosphate from [1-C14]pyruvate. Rapid inhibition of the activity of [alpha]-oxoglutarate dehydrogenase in rat-brain mitochondria was observed during incubations in O at 5 atm pressure as determined by decreased production of C14O2 from [alpha]-oxo[l,2-C14 2] glutarate. A mechanism for the toxicity of high O pressure is proposed in which direct oxidation of the dithiol moiety of [alpha] -lipoic acid by O in high concentration interferes with the normal activity of pyruvate oxidase and [alpha]-oxoglutarate dehydrogenase.