Mechanisms of the inhibition of human erythrocyte pyridoxal kinase by drugs.
The aim of this study was to investigate the interaction between drugs chosen for their clinical neurotoxicity or chemical structure and vitamin B6 metabolism. After a preliminary screening of drugs to determine their potential inhibitory effect on erythrocyte nonpurified pyridoxal kinase (PLK) (EC 2.7.1.35), additional investigations, including kinetic studies and detection of chemical reactivity between the inhibiting drugs and pyridoxal (PL) or pyridoxal-5'-phosphate (PLP), using UV-visible spectrophotometry and mass analysis, were carried out to specify the mechanism of PLK inhibition. Depending on the results, the inhibiting drugs were divided into three groups. The first group included theophylline and progabide and inhibited PLK using either PL or pyridoxamine (PM) as substrate and thereby were true inhibitors. Moreover, they did not form covalent complexes with PL or PLP. The second group, which included cycloserine, dopamine, isoniazid, and thiamphenicol glycinate, inhibited PLK using PL, but not PM, as substrate. They were able to react with PL or PLP to form covalent complexes, and kinetic studies suggested that the observed PLK inhibition was due to these formed complexes. A third group, which consisted of levodopa, D-penicillamine, and muzolimine, inhibited PLK using PL, but not PM, as substrate. They formed, with PL or PLP, chemical derivatives that probably had no inhibitory effect on PLK. These results and the clinical consequences of such interactions are discussed and compared with results of previous studies.
Lainé-Cessac
P
P
Laboratoire de Pharmacologie Toxicologie, Centre Hospitalier Universitaire, Angers, France.
Cailleux
A
A
Allain
P
P
D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009156:Muzolimine / Q000494:pharmacology; D011730:Pyridoxal / Q000378:metabolism; D011731:Pyridoxal Kinase / Q000037:antagonists & inhibitors* / Q000097:blood; D013056:Spectrophotometry, Ultraviolet; D013839:Thiamphenicol / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D009156:Muzolimine; C017985:progabide; D011730:Pyridoxal; D005680:gamma-Aminobutyric Acid; D011731:Pyridoxal Kinase; D013839:Thiamphenicol; C028813:thiamphenicol glycinate