Pyridine nucleotide analog interference with metabolic processes in mitogen-stimulated human T lymphocytes.
The differential metabolic effects of three nicotinamide analogs, 6-aminonicotinamide, 3-aminobenzamide, and 5-methylnicotinamide, were analyzed in mitogen-stimulated preparations of human T lymphocytes. Mitogen stimulation with the phorbol ester TPA and a monoclonal antibody to the T3 cell surface antigen caused an increase in cellular NAD and ATP levels and a marked increase in glucose metabolism as demonstrated by an increase in cellular levels of glucose 6-phosphate and a sevenfold increase in radioactive CO2 formation from [l-14C]glucose. 6-Aminonicotinamide had drastic inhibitory effects on the mitogen-stimulated increases in NAD and ATP levels as well as on the metabolism of glucose. Treatment of the mitogen-stimulated cells with 6-aminonicotinamide also caused a marked increase in cellular levels of 6-phosphogluconate, suggesting inhibition of the hexose monophosphate shunt at 6-phosphogluconate dehydrogenase. Radioactive CO2 formation from [6-14C]glucose showed that metabolism through the tricarboxylic acid cycle was not used to compensate for the inhibition of the hexose monophosphate shunt pathway. Treatment of cells with 3-aminobenzamide had the opposite effect of 6-aminonicotinamide in that cellular NAD levels increased, presumable due to inhibition of poly(ADP-ribose) polymerase. 3-Aminobenzamide did not interfere with ATP or glucose 6-phosphate levels and did not cause significant elevations of 6-phosphogluconate. Thus, 6-aminonicotinamide appears to have direct inhibitory effects on the synthesis of both pyridine nucleotides and poly(ADP-ribose), whereas 3-aminobenzamide has its major inhibitory effect on poly(ADP-ribose) synthesis. 5-Methylnicotinamide also interferes with the mitogen-stimulated increase in NAD levels but not as effectively as 6-aminonicotinamide. The alterations in pyridine nucleotide metabolism resulting from treatment with these nicotinamide analogs can produce drastic and diverse alterations in pathways of glucose utilization and energy generation.
D015120:6-Aminonicotinamide / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000097:blood; D001549:Benzamides / Q000494:pharmacology; D002245:Carbon Dioxide / Q000097:blood; D005942:Gluconates / Q000097:blood; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000097:blood; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D009243:NAD / Q000097:blood*; D009249:NADP / Q000097:blood*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D001549:Benzamides; D005942:Gluconates; D005958:Glucosephosphates; D009243:NAD; D002245:Carbon Dioxide; D009536:Niacinamide; D015120:6-Aminonicotinamide; D009249:NADP; D019298:Glucose-6-Phosphate; C024785:5-methylnicotinamide; C025160:3-aminobenzamide; D000255:Adenosine Triphosphate; D013755:Tetradecanoylphorbol Acetate; C008884:6-phosphogluconic acid