Evaluation of HI-6 oxime: potential use in protection of human acetylcholinesterase inhibited by antineoplastic drug irinotecan and its cyto/genotoxicity in vitro.
The function of acetylcholinesterase (AChE) is the rapid hydrolysis of the neurotransmitter acetylcholine (ACh), which is involved in the numerous cholinergic pathways in both the central and the peripheral nervous system. Therefore, AChE measurement is of high value for therapy management, especially during the course of intoxication with different chemicals or drugs that inhibit the enzyme. Pyridinium or bispyridinium aldoximes (oximes) are able to recover the activity of the inhibited enzyme. Since their adverse effects are not well elucidated, in this study the efficiency of HI-6 oxime in protection and/or reactivation of human erythrocyte AChE inhibited by the antineoplastic drug irinotecan as well as its cyto/genotoxicity in vitro were investigated. HI-6 was effective in protection of AChE and increased its activity up to 30%; the residual activity after irinotecan inhibition was 7%. Also, it reactivated the enzyme previously inhibited by 50% irinotecan (4.6 microg/ml) applied at 1/4 of the IC50 value. The tested concentrations of HI-6 exhibited acceptable genotoxicity towards white blood cells, as estimated by the alkaline comet assay, DNA diffusion assay and cytogenetic endpoints (structural chromosome aberrations and cytokinesis-block micronucleus assay). The results obtained warrant the further investigation of HI-6 in vivo, as well as its development for possible application in chemotherapy.
Radić
Bozica
B
Institute for Medical Research and Occupational Health, Zagreb, Croatia.
Vrdoljak
Ana Lucić
AL
Zeljezić
Davor
D
Fuchs
Nino
N
Berend
Suzana
S
Kopjar
Nevenka
N
D000110:Acetylcholinesterase / Q000378:metabolism*; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D002869:Chromosome Aberrations / Q000187:drug effects; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010091:Oximes; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D002800:Cholinesterase Inhibitors; D010091:Oximes; D011726:Pyridinium Compounds; D000077146:Irinotecan; D000110:Acetylcholinesterase; C022870:asoxime chloride; D002166:Camptothecin