Comparison of Cytochrome P450 2D6 and Variants in Terms of Drug Oxidation Rates and Substrate Inhibition

Abstract

This review focuses on identification of the important active site residues of CYP2D6 in terms of CYP2D6 polymorphism. A meta-analysis was performed on the reported literature regarding (1) values of the Michaelis-Menten constant (K(m)), maximal velocity (V(max)), and intrinsic clearance (V(max)/K(m)) for 41 metabolic reactions of 31 substrates mediated by human cytochrome P450 2D6 and its variants and mutants and (2) inhibition constants (K(i)) for 15 inhibitors. The mean ratios of V(max)/K(m) values with respect to the wild type (CYP2D6.1) for CYP2D6.2 (R296C/S486T), CYP2D6.10 (P34S/S486T), CYP2D6.17 (T107I/R296C/S486T), CYP2D6.31 (R296C/R440H/S486T), CYP2D6.34 (R296C), CYP2D6.36 (P34S/S486T and 6 other amino acids substitutions), CYP2D6.49 (P34S /F120I/S486T), and P34S and G42R mutants but not CYP2D6.39 (S486T) were in the range 0.03-0.61, and the median ratios were in the range 0.03-0.57. More than 90% of V(max)/K(m) values for CYP2D6.10, CYP2D6.17, and CYP2D6.36 were less than half of those for CYP2D6.1. In addition, 20-59% of V(max)/K(m) values for these variants were less than one-tenth those of the wild type. These results suggest that the CYP2D6 polymorphism may affect the metabolic activities of many compounds. However, the kinetic behaviors of these variants and mutants depended on the metabolic reaction. The K(i) values of many of the inhibitors of CYP2D6.10 and CYP2D6.17 were comparable with or higher than those for CYP2D6.1. Collectively, these findings provide insights into the contributions of CYP2D6 polymorphisms to drug metabolism and adverse drug interactions.

Effect of 24 cytochrome P450 2D6 variants found in the Chinese population on theN-demethylation of amitriptylinein vitro

“…As expected, CYP2D6*10 exhibited significantly increased K m (2-fold), nearly 10-fold V max and 5-fold intrinsic clearance value compared to the wild-type one. The results were brought into correspondence with the previous study (Ramamoorthy et al 2001;Niwa et al 2011), which showed that Sf21 expression system and metabolic activity analysis system was suitable for evaluating the functional characteristic of the other CYP2D6 allelic variants.…”

“…The variants have been manually arranged into six different groups (A-F) in the order of the designated allele names. Niwa et al 2011). Aside from above, no more other reported CYP2D6 mediated AT evaluated the metabolic characteristics.…”

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

“…These genetic variants can be associated with increased, decreased or abolished enzymatic functions, which results in differences of up to 30-to 40-fold changes in substrate drug clearance values. Consequently, these differences in CYP2D6 activity have been demonstrated to be prominent contributors to interindividual drug response variability [2,5,6].It has been reported that significant ethnic and geographic differences exist in CYP2D6 alleles [7,8]. For Eastern Asians, only 1-2% of individuals have been found to be poor metabolizers (PMs), and approximately 57% of the Chinese population are intermediate metabolizers (IMs) [9,10].…”

“…These genetic variants can be associated with increased, decreased or abolished enzymatic functions, which results in differences of up to 30-to 40-fold changes in substrate drug clearance values. Consequently, these differences in CYP2D6 activity have been demonstrated to be prominent contributors to interindividual drug response variability [2,5,6].…”

Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine

“…Moreover, this number continues to increase (8,9). Interestingly, CYP2D6 polymorphism has been demonstrated to have some relationship with the behavior of an individual (10,11).…”