Inhibition in vitro of the enzymes of the oxidative pathway of tryptophan metabolism and of nicotinamide nucleotide synthesis by benserazide, carbidopa and isoniazid.
The effects of three hydrazine derivatives on the enzymes of the tryptophan oxidative pathway and of nicotinamide nucleotide synthesis have been studied using preparations from rat liver. The compounds used were Benserazide and Carbidopa, two inhibitors of aromatic amino acid decarboxylase used together with dopa in the treatment of Parkinson's disease, and the anti-tubercular agent isoniazid. All three drugs inhibited tryptophan oxygenase and kynureninase, at concentrations that are likely to be encountered in vivo following administration to patients or experimental animals. Isoniazid, but not Benserazide or Carbidopa, also inhibited 3-hydroxy-anthranilate oxidase and nicotinamide phosphoribosyltransferase. However, these two enzymes were of the drug far in excess of those likely to be encountered in vivo. On the basis of the in vitro enzyme inhibition studies, it is not possible to explain why patients treated with isoniazid (without supplementary vitamin B(6)) develop clinical pellagra, while those treated with Benserazide or Carbidopa do not, despite biochemical evidence of niacin deficiency. It is suggested that this difference may be due either to differences in the intake of dietary niacin in these two groups of patients, or more probably to differences in the metabolism of the drugs and in their interactions with enzymes in vivo that are not apparent in vitro.
Bender
D A
DA
Courtauld Institute of Biochemistry, The Middlesex Hospital Medical School, London, W1P 7PN, UK.
D000818:Animals; D001545:Benserazide / Q000494:pharmacology*; D002230:Carbidopa / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology*; D008297:Male; D009536:Niacinamide / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014364:Tryptophan / Q000378:metabolism*
D009711:Nucleotides; D009536:Niacinamide; D001545:Benserazide; D014364:Tryptophan; D002230:Carbidopa; D007538:Isoniazid