The Effect of Thiamine Treatment on the Activity of Pyruvate Dehydrogenase: Relation to the Treatment of Leigh's Encephalomyelopathy

Abstract

ExtractRats received intraperitoneal injection of thiamine (125 mg'/kg body wt) for 4 consecutive days. There was less inhibition by ATP (9% ± 2%) of the pyruvate dehydrogenase complex of isolated liver mitochondria from treated rats than in liver mitochondria from control rats (30% ± 8%). The liver mitochondria of the treated animals contained about 25% more thiamine pyrophosphate than the mitochondria of the controls (0.48 ± 0.03 and 0.36 ± 0.01 nmoles/mg mitochondrial protein, respectively) .Roche and Reed have demonstrated inhibition of the phosphorylation of the pyruvate dehydrogenase complex by thiamine pyrophosphate, thereby maintaining pyruvate dehydrogenase in the active form. It is suggested that the therapeutic effect of high doses of thiamine given to patients who suffer from Leigh's disease is, at least in part, due to maintainance of the pyruvate dehydrogenase complex in its active form, thus facilitating the oxidation of pyruvate. Speculation

Thiamine Diphosphate Content of Liver Mitochondria of the Pregnant and Developing Rat

“…The thiamine diphosphate content of mitochondria is, therefore, an indi cation for the control of pyruvate oxidation as it has been shown that, by increasing the thiamine diphosphate content of liver mitochondria by intraperitoneal injection of thiamine, the inhibition of pyruvate oxidation by ATP can be decreased [6,7]. The nutritional status with respect to thiamine is, therefore, not only important for the assessment of thiamine deficiencies but also for the normal physiological control mechanisms.…”

“…The integrity of the mitochondria was checked by a determination of the P/O ratio and the respiratory control ratio with succinate as substrate [1]. Thiamine diphosphate was determined fluorometrically according to the procedure of Cooper et al [2] modified as described previously [6]. Thiamine pyrophosphokinase activity of rat liver was assayed according to D eus [5], using the procedure described by Koike and Y usa [9] for the separation of thiamine phosphates.…”

“…That such a regulatory role may be of physiological importance has been demonstrated in studies on the rate of pyruvate oxidation in fetal rat liver cells [7] as well as on the effect of administration of high dosis of thiamine in cases of Leigh's disease [6],…”

Thiamine dependency in a patient with congenital lacticacidaemia due to pyruvate dehydrogenase deficiency

“…ROCHE and REED [21] showed that TPP inhibits phosphorylation of PDH, maintaining PDH in its active form. HOMMES [22] studied the effect of 125 mg/kg thiamine given intraperitoneally to rats for 4 days. This treatment resulted in a decreased sensitivity of PDH to inhibition by ATP.…”

Pyruvate Decarboxylase Deficiency in Subacute Necrotizing Encephalomyelopathy

“…The TTP is the active form of thiamine in the brain and stimulates PDC activa¬ tion by inhibiting PDHC-kinase. 40 Loose coupling of oxidative phosphorylation in cytochrome-C oxidase defi¬ ciency increases the NADH/NAD ratio, which favors PDC deactivation.18·41 Decreased PDC activity, either pri¬ mary or secondary, is the common metabolic feature in patients with SNE, and is proposed as the mecha¬ nism of the syndrome.…”