Thiamine utilization in the pathogenesis of alcohol-induced brain damage.
There is increasing evidence for the role of thiamine deficiency in ethanol neurotoxicity and in development of alcoholic organic brain disorders other than Wernicke-Korsakoff syndrome [WKS] and cerebellar degeneration. Investigations in humans and in animal models have implicated a reduction in the activities of thiamine-utilizing enzymes as the metabolic basis of tissue injury due to thiamine deficiency. We have investigated the interactions of the thiamine-utilizing enzyme transketolase [Tk], derived from human fibroblasts, lymphoblasts, and various brain regions, with its cofactor, thiamine pyrophosphate [TPP], in an attempt to elucidate the molecular basis of selective brain damage in alcoholism-associated thiamine deficiency. There were no significant differences in the isoelectric pattern of Tk among the nine brain regions (white matter and grey matter) examined. However, Tk activity/mg protein, increase in Tk activity with addition of excess TPP (TPP effect), and TPP-dependent rate of formation of active Tk holoenzyme (tau) varied 2.5-, 6-, and 4-fold, respectively, among these brain regions. These differences in tissue requirements for TPP may contribute to the selective vulnerability of certain brain regions to alcoholism-associated thiamine deficiency, and may influence the pattern of clinical impairment in the individual patient.
Martin
P R
PR
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37240, USA.
Pekovich
S R
SR
McCool
B A
BA
Whetsell
W O
WO
Singleton
C K
CK
D000425:Alcohol Amnestic Disorder / Q000209:etiology / Q000378:metabolism; D000437:Alcoholism / Q000150:complications* / Q000378:metabolism*; D000818:Animals; D001930:Brain Injuries / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D013831:Thiamine / Q000378:metabolism*; D013832:Thiamine Deficiency / Q000209:etiology / Q000378:metabolism; D013835:Thiamine Pyrophosphate / Q000378:metabolism; D014018:Tissue Distribution; D014174:Transketolase / Q000378:metabolism; D014899:Wernicke Encephalopathy / Q000209:etiology / Q000378:metabolism
D014174:Transketolase; D013835:Thiamine Pyrophosphate; D013831:Thiamine