Abstract
Accelerating cocaine metabolism through enzymatic hydrolysis at cocaine benzoyl ester is recognized as a promising therapeutic approach for cocaine abuse treatment. Our more recently designed A199S/F227A/S287G/A328W/Y332G mutant of human BChE, denoted as cocaine hydrolase-3 (CocH3), has a considerably improved catalytic efficiency against cocaine and has been proven active in blocking cocaine-induced toxicity and physiological effects. In the present study, we have further characterized the effects of CocH3 on the detailed metabolic profile of cocaine in rats administrated intravenously (IV) with 5 mg/kg cocaine, demonstrating that IV administration of 0.15 mg/kg CocH3 dramatically changed the metabolic profile of cocaine. Without CocH3 administration, the dominant cocaine-metabolizing pathway in rats was cocaine methyl ester hydrolysis to benzoylecgonine (BZE). With the CocH3 administration, the dominant cocaine-metabolizing pathway in rats became cocaine benzoyl ester hydrolysis to ecgonine methyl ester (EME), and the other two metabolic pathways (i.e. cocaine methyl ester hydrolysis to BZE and cocaine oxidation to norcocaine) became insignificant. The CocH3-catalyzed cocaine benzoyl ester hydrolysis to EME was so efficient such that the measured maximum blood cocaine concentration (∼38 ng/ml) was significantly lower than the threshold blood cocaine concentration (∼72 ng/ml) required to produce any measurable physiological effects.
Original language | English |
---|---|
Pages (from-to) | 104-109 |
Number of pages | 6 |
Journal | Chemico-Biological Interactions |
Volume | 259 |
DOIs | |
State | Published - Nov 25 2016 |
Bibliographical note
Funding Information:This work was supported by the National Institutes of Health (NIH) through the NIDA Translational Avant-Garde Award ( UH2 DA041115 ) and R01 grants ( R01 DA035552 , R01 DA032910 , R01 DA013930 , and R01 DA025100 ). The authors gratefully acknowledge helpful discussions with Dr. Markos Leggas and Ms. Jamie Horn who trained X.C. to use the LC-Q-TOF instrument for the research.
Publisher Copyright:
© 2016 Elsevier Ireland Ltd
Keywords
- Cocaine hydrolase
- Drug abuse
- Drug metabolism
- Enzyme
- Metabolite
ASJC Scopus subject areas
- Toxicology