The molecular and enzyme kinetic basis for the diminished activity of the cytochrome P450 2D6.17 (CYP2D6.17) variant: Potential implications for CYP2D6 phenotyping studies and the clinical use of CYP2D6 substrate drugs in some African populations

• Published in: Biochemical pharmacology Vol. 64; no. 9; pp. 1387 - 1398
• Main Authors: Bapiro, Tashinga E, Hasler, Julia A, Ridderström, Marianne, Masimirembwa, Collen M
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-11-2002; Elsevier Science
• Subjects: Africa; Alleles; Amino Acid Sequence; Binding, Competitive; Biological and medical sciences; Bufuralol; CYP2D6 ∗17; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P450 2D6; Debrisoquine; Dextromethorphan; General pharmacology; Genetics, Population; Humans; Kinetics; Medical sciences; Metoprolol; Models, Biological; Models, Molecular; Molecular Sequence Data; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Phenotype; Sequence Homology, Amino Acid; Africa; Metoprolol; SRS, substrate recognition site; Dextromethorphan; Debrisoquine; CL int, intrinsic clearance; CYP2D6 ∗17; PM, poor metaboliser; EM, extensive metaboliser; MR, metabolic ratio; HLM, human liver microsomes; Bufuralol; CYP, cytochrome P450; RAF, relative activity factor; Cytochrome P450 2D6; Human; Morphinan derivatives; CYP2D617: Dextromethorphan; Cytochrome P450; Opiates; Guanidines; Metabolism; African; Substrate; Phenotype; Kinetics; Mutation
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)01351-5

In this study, the basis for the diminished capacity of CYP2D6.17 to metabolise CYP2D6 substrate drugs and the possible implications this might have for CYP2D6 phenotyping studies and clinical use of substrate drugs were investigated
in vitro. Enzyme kinetic analyses were performed with recombinant CYP2D6.1, CYP2D6.2, CYP2D6.17 and CYP2D6.T107I using bufuralol, debrisoquine, metoprolol and dextromethorphan as substrates. In addition, the intrinsic clearance of 10 CYP2D6 substrate drugs by CYP2D6.1 and CYP2D6.17 was determined by monitoring substrate disappearance. CYP2D6.17 exhibited generally higher
K
m values compared to CYP2D6.1. The
V
max values were generally not different except for metoprolol α-hydroxylation with the
V
max value for CYP2D6.17 being half that of CYP2D6.1. CYP2D6.1 and CYP2D6.2 displayed similar kinetics with all probe drugs except for dextromethorphan
O-demethylation with the intrinsic clearance value of CYP2D6.2 being half that of CYP2D6.1. CYP2D6.17 exhibited substrate-dependent reduced clearances for the 10 substrates studied. In a clinical setting, the clearance of some drugs could be affected more than others in individuals with the
CYP2D6
∗17
variant. The
CYP2D6
∗17
allele might, therefore, contribute towards the poor correlation of phenotyping results when using different probe drugs in African populations. To investigate effects of
CYP2D6
∗17
mutations on the structure of the enzyme, a homology model of CYP2D6 was built using the CYP2C5 crystal structure as a template. The results suggest an alteration in position of active-site residues in CYP2D6.17 as a possible explanation for the reduced activity of the enzyme.