Drug-biomolecule interactions: drug toxicity and vitamin coenzyme depletion.
Thirteen pyridine compounds, phenylbutazone, and three salicylates were studied for their effects upon the turnover of 7-14C-nicotinamide dinucleotides in the mouse. The compounds were administered at equitoxic doses (LD25) to 7-14C-nicotinic acid- (niacin) pretreated mice, and the induced excretion of urinary-14C was analyzed in terms of total 14C and percentage of total 14C as known metabolites of nicotinic acid. Of the 17 compounds, 12 afforded significant alterations in the total 14C excreted and five of these caused alterations in the disposition of the 7-14C-nicotinamide endogenously liberated from the 7-14C-nicotinamide adenine dinucleotide pool. Comparative depletions of 14C from brain, lungs, liver, and kidneys were studied with 10 of the pyridine compounds. Several tissues were found to be the sources of the urinary-14C, with the lungs being the most accessible source. Some compounds had effects at doses less than the LD25's, as shown by increased hexobarbital sleeping time in acute experiments with rats. These pyridine compounds were initially considered to act at the level of the nicotinamide dinucleotides in the normal biosynthetic pathway (nicotinic acid site) and/or at the level of glycohydrolase (nicotinamide site). In view of the inclusion of nicotinic acid, nicotinamide, salicylic acid, and phenylbutazone in this correlation between toxicity and 7-14C-nicotinamide mobilization, it is not necessary that the formation of compounds analogous to the nicotinamide dinucleotides plays a significant role in the toxic manifestations of the nicotinamide analogs. The displacement of 7-14C-nicotinamide dinucleotides from their corresponding apoenzymes with subsequent metabolism of the dinucleotides could explain the noted increased 7-14C-nicotinamide dinucleotide turnover and depletion which led to the toxic effects.
D000818:Animals; D003067:Coenzymes / Q000378:metabolism*; D005260:Female; D006591:Hexobarbital / Q000494:pharmacology; D007928:Lethal Dose 50; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009249:NADP / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000633:toxicity*; D009539:Nicotinic Acids / Q000494:pharmacology*; D009711:Nucleotides / Q000378:metabolism; D051381:Rats; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
D003067:Coenzymes; D009539:Nicotinic Acids; D009711:Nucleotides; D009536:Niacinamide; D009249:NADP; D006591:Hexobarbital