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Article

Dietary Thiamin Level Influences Levels of Its Diphosphate Form and Thiamin-Dependent Enzymic Activities of Rat Liver

Paul V. Blair*⁴, Rumi Kobayashi*, Hardy M. Edwards, III,, Neil F. Shay**, David H. Baker and Robert A. Harris*

^* Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202–5122 and Division of Nutritional Sciences, Department of Animal Sciences and ^** Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL 61801

This study was prompted by our incomplete understanding of the mechanism responsible for the clinical benefits of pharmacological doses of thiamin in some patients with maple syrup urine disease (MSUD) and the question of whether thiamin diphosphate (TDP), a potent inhibitor of the activity of the protein kinase that phosphorylates and inactivates the isolated branched-chain -ketoacid dehydrogenase (BCKDH) complex, affects the activity state of the complex. Rats were fed a chemically-defined diet containing graded levels of thiamin (0, 0.275, 0.55, 5.5, and 55 mg thiamin/kg diet). Maximal weight gain was attained over a 3-wk period only in rats fed diets with 5.5 and 55 mg thiamin/kg. Feeding rats the thiamin-free diet for just 2 d caused loss of nearly half of the TDP from liver mitochondria. Three more days caused over 70% loss, an additional 3 wk, over 90%. Starvation for 2 d had no effect, suggesting a mechanism for conservation of TDP in this nutritional state. Mitochondrial TDP was higher in rats fed pharmacological amounts of thiamin (55 mg thiamin/kg diet) than in rats fed adequate thiamin for maximal growth. Varying dietary thiamin had marked but opposite effects on the activities of -ketoglutarate dehydrogenase (-KGDH) and BCKDH. Thiamin deficiency decreased -KGDH activity, increased BCKDH activity, and increased the proportion of BCKDH in the active, dephosphorylated, state. Excess dietary thiamin had the opposite effects. TDP appears to be more tightly associated with -KGDH than BCKDH in thiamin-deficient rats, perhaps denoting retention of -KGDH activity at the expense of BCKDH activity. Thus, thiamin deficiency and excess cause large changes in mitochondrial TDP levels that have a major influence on the activities of the keto acid dehydrogenase complexes.

KEY WORDS: • rats • thiamin • liver • mitochondria • thiamin-dependent enzymes

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