6-Aminonicotinamide inhibition of the pentose phosphate pathway in rat neocortex.
6-Aminonicotinamide (6-AN) is thought to inhibit the pentose phosphate pathway (PPP) since large increases in 6-phosphogluconate are observed following its administration. Immediately following 45 min i.v. infusion of [2-(13)C]glucose to controls and 6-AN-treated (50 mg/kg i.p. given 4 h previously) Sprague-Dawley rats (n = 5 for both groups), metabolism was arrested using freeze-funnel fixation. Chloroform-methanol-water neocortical extracts from animals administered with 6-AN demonstrated elevated levels of 6-phosphogluconate and 6-phosphoglucono-delta-lactone, both of which demonstrated labeling through metabolism of [2-(13)C]glucose. Comparison of the C-2 and C-3 lactate positions using 1H NMR spectroscopy showed that the fraction of glucose metabolized through the PPP is unchanged by 6-AN (14+/-0.6% vs 14+/-0.3% in control animals). It is hypothesized that as the PPP is inhibited by metabolites of 6-AN in the neocortex, glycolysis is inhibited in a proportionate manner through an inhibitory effect on phosphoglucose isomerase by 6-phosphogluconate and/or 6-phosphoglucono-delta-lactone.
Tyson
R L
RL
Seaman Family MR Research Centre, Department of Clinical Neurosciences, University of Calgary, AB, Canada.
Perron
J
J
Sutherland
G R
GR
D015120:6-Aminonicotinamide / Q000494:pharmacology*; D000409:Alanine / Q000378:metabolism; D000818:Animals; D005942:Gluconates / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D019579:Neocortex / Q000187:drug effects* / Q000378:metabolism*; D010427:Pentose Phosphate Pathway / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005942:Gluconates; C048956:6-phosphonoglucono-delta-lactone; D015120:6-Aminonicotinamide; D019344:Lactic Acid; D000409:Alanine; C008884:6-phosphogluconic acid