الفهرس 
General IntroductionOnly 14 pages are availabe for public view
 |  | from | 149 |  |  |
| | | from | 149 | | |
Abstract
In this study, the metabolic activities of four major hepatic CYP isoforms (2C19, 2D6, 2C9 and 3A4) were investigated on structurally different central nervous system (CNS) acting drugs, amitriptyline, imipramine fluphenazine, and dothiepin. We concluded that 2C19 could be predominant for metabolic activity on tricyclic antidepressants, but not on phenothiazine-related antipsychotic drugs. In addition, the reciprocal mutants of CYP2C9 and 2C19 on oppositely charged residues were investigated. Mutations at positions 72 (CYP2C19 E72K and CYP2C9 K72E mutants) and 241 (CYP2C19 E241K and CYP2C9 K241E mutants) revealed that Glu72 plays a more predominant role than Glu241 in the metabolism of TCA drugs. The effects of mutations were also assessed by plotting the Kd values against the Km values. These results suggest that the reciprocal residue could be critical for drug discrimination in CYP2C19 and 2C9 with the involvement of several residues in the B’C-loop adjacent to the drug binding site.