MECHANISMS OF THE INHIBITION OF HUMAN ERYTHROCYTE PYRIDOXAL KINASE BYDRUGS

The aim of this study was to investigate the interaction between drugs chosen for their clinical neurotoxicity or chemical structure and vit amin B-6 metabolism. After a preliminary screening of drugs to determi ne their potential inhibitory effect on erythrocyte nonpurified pyrido xal kinase (PLK) (EC 2.7.1.35), additional investigations, including k inetic studies and detection of chemical reactivity between the inhibi ting drugs and pyridoxal (PL) or pyridoxal-5' phosphate (PLP), using U V-visible spectrophotometry and mass analysis, were carried out to spe cify the mechanism of PLK inhibition. Depending on the results, the in hibiting drugs were divided into three groups. The first group include d theophylline and progabide and inhibited PLK using either PL or pyri doxamine (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 g lycinate, inhibited PLK using FL, but not PM, as substrate. They were able to react with PL or PLP to form covalent complexes, and kinetic s tudies suggested that the observed PLK inhibition was due to these for med complexes. A third group, which consisted of levodopa, D-penicilla mine, and muzolimine, inhibited PLK using FL, 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 consequenc es of such interactions are discussed and compared with results of pre vious studies. (C) 1997 Elsevier Science Inc.