Effects of low-level lead on glycolytic enzymes and pyruvate dehydrogenase of rat brain in vitro: relevance to sporadic Alzheimer's disease?
Lead is known to be a potent inhibitor of many enzymes working in the brain, thus possibly inducing functional problems in the brain under pathophysiological conditions. Among such enzymes are those involved in glucose metabolism and energy production. We investigated the inhibitory effects of low-level lead on brain hexokinase (HK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase (PK) and pyruvate dehydrogenase complex (PDHc) with rat brain homogenate. PDHc was distinctively inhibited when low-dose lead acetate was added last of all (IC50 = 5 microM) to the reaction mixture. The other enzymes were completely resistant to 5 microM of lead acetate. When the homogenate was preincubated with lead acetate HK was dramatically inhibited by low-level lead acetate (1-5 microM), in a manner dependent on both preincubation time and lead concentration. However, the inhibitory effect was abolished by coincubation with its substrates, glucose or ATP. The results suggest that exposure to low levels of lead may increase the risk of cerebral hypometabolism caused by direct inhibition of specific glucose-utilizing enzymes. In this context, lead might be regarded as a risk factor in the abnormal glucose metabolism seen in some kinds of neurodegenerative disorders such as sporadic Alzheimer's disease.
Yun
S W
SW
Department of Pathochemistry and General Neurochemistry, University of Heidelberg, Federal Republic of Germany.
Hoyer
S
S
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D002614:Chelating Agents / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000378:metabolism; D066298:In Vitro Techniques; D007854:Lead / Q000633:toxicity*; D008297:Male; D009942:Organometallic Compounds / Q000633:toxicity*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002614:Chelating Agents; D009942:Organometallic Compounds; D011768:Pyruvate Dehydrogenase Complex; D007854:Lead; D000255:Adenosine Triphosphate; D004492:Edetic Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D006593:Hexokinase; D011770:Pyruvate Kinase; D003545:Cysteine; C008261:lead acetate; D004229:Dithiothreitol