Evaluation of possible inhibition of human liver drug metabolizing cytochromes P450 by two new acetylcholinesterase oxime-type reactivators
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26747974
DOI
10.1016/j.fct.2015.11.024
PII: S0278-6915(15)30135-6
Knihovny.cz E-resources
- Keywords
- AChE reactivation, Acetylcholinesterase, CYP, Cytochrome P450, Human microsomes, K027, K203, Oximes,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Cytochrome P-450 Enzyme Inhibitors pharmacology MeSH
- Microsomes, Liver enzymology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Oximes pharmacology MeSH
- Pyridinium Compounds pharmacology MeSH
- Cholinesterase Reactivators pharmacology MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Browser
- 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
- Acetylcholinesterase MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Oximes MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
- Cytochrome P-450 Enzyme System MeSH
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.
References provided by Crossref.org
In Vitro Interaction of Binuclear Copper Complexes with Liver Drug-Metabolizing Cytochromes P450
