title: Evaluation of possible inhibition of human liver drug metabolizing cytochromes P450 by two new acetylcholinesterase oxime-type reactivators.
abstract: Two non-symmetric bispyridine oxime - based reactivators of acetylcholinesterase enzyme (AChE), labeled as K027 (1-(4-carbamoylpyridinium)-3-(4-hydroxyiminomethylpyridinium)-propane dibromide) and K203 ((E)-1-(4- carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide) were tested for their potential to inhibit activities of human liver microsomal cytochromes P450 (CYP). Both oximes are very potent reactivators of organophosphate-inhibited AChE. An interaction of both compounds with CYP in human liver microsomal preparation was detected using difference spectroscopy. The compounds were shown to bind to CYP enzymes with spectral binding constants of 5.04 ± 1.79 nM (K027) and 5.2 ± 2.6 nM (K203). Enzymology studies were subsequently performed aimed at determining which of the nine most important CYP involved in drug is affected by this interaction. The results have shown no prominent inhibition of individual CYP activities with either compounds except in the case of CYP2E1 and K203. Diagnostic Dixon plot revealed that K203 acted as an uncompetitive inhibitor of CYP2E1. Inhibition of this activity however is not as prominent as to make a potent drug interaction likely. Hence, the interaction of K027 and K203 oxime-type AChE reactivators with human liver microsomal CYP enzymes does not seem to be of prominent clinical importance and both compounds could be safely used in this respect as antidotes with low risk of drug interactions.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Spicakova
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Liskova
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, 500 01 Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital Hradec Kralove, 500 01 Hradec Kralove, Czech Republic. Electronic address: kamil.kuca@fnhk.cz.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defense, 500 01 Hradec Kralove, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Fusek
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic. Electronic address: eva.anzenbacherova@upol.cz.
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherova
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*
chemical_list: C524716:1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene; C481758:1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide; D002801:Cholinesterase Reactivators; D065607:Cytochrome P-450 Enzyme Inhibitors; D010091:Oximes; D011726:Pyridinium Compounds; D003577:Cytochrome P-450 Enzyme System; D000110:Acetylcholinesterase
keywords: AChE reactivation; Acetylcholinesterase; CYP; Cytochrome P450; Human microsomes; K027; K203; Oximes