Effect of acetylcholinesterase oxime-type reactivators K-48 and HI-6 on human liver microsomal cytochromes P450 in vitro.
Substances K-48 and HI-6, oxime-type acetylcholinesterase (AChE) reactivators, were tested for their potential to inhibit the activities of human liver microsomal cytochromes P450 (CYP). The compounds were shown to bind to microsomal cytochromes P450 with spectral binding constants of 0.25+/-0.05 microM (K-48) and 0.54+/-0.15 microM (HI-6). To find which cytochrome P450 from the human liver microsomal fraction interacts with these compounds, an inhibition of enzyme activities specific for nine individual CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) was studied. The results have shown no prominent inhibition of individual CYP activities with both compounds except the CYP2E1 activity and the HI-6 reactivator. However, the inhibition of this activity was less than 50% which makes the possible drug interactions highly unlikely. Hence, the interaction of K-48 and HI-6 oxime-type AChE reactivators with human liver microsomal CYP enzymes does not seem to be clinically significant and both compounds could be taken in this respect as antidotal drugs with low risk of drug interactions.
Veinlichova
Alena
A
Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Jancova
Petra
P
Siller
Michal
M
Anzenbacher
Pavel
P
Kuca
Kamil
K
Jun
Daniel
D
Fusek
Josef
J
Anzenbacherova
Eva
E
D000110:Acetylcholinesterase / Q000378:metabolism*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010091:Oximes / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*
D002801:Cholinesterase Reactivators; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C520230:K-48 compound; D010091:Oximes; D020033:Protein Isoforms; D011726:Pyridinium Compounds; D003577:Cytochrome P-450 Enzyme System; D000110:Acetylcholinesterase; C022870:asoxime chloride