The Effects Of Allelic Variations On Biotransformation Activity Of Cytochrome P450 206: Molecular Modelling Studies

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Date
2006-04
Authors
Mahdi Saleh, Elrashid Saleh
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Abstract
CYP2D6 is polymorphic and responsible for the metabolism of 25% of therapeutically used drugs. More than 80 different mutant alleles of CYP2D6 have been identified. CYP2D6*10 and CYP2D6*17 are two of them, which are associated with reduced CYP2D6 activity of 75% of Asians and 34% of Africans respectively. P34S and S486T are the mutations found in the protein encoded by CYP2D6*10 and CYP2D6*17 respectively producing an enzyme with T1071, R296C and S486T amino acid substitutions. This study examined the effects of these allelic variants on structural characteristics and catalytic activity of CYP2D6. Using molecular modelling studies, 3D structures of CYP2D6.1, CYP2D6.10 and CYP206.17 were built based on homology with human CYP2C8 structure using MODELLER 6 V 2. The models have been used to identify the possible effects of allelic variations on the biotransformation activity of CYP2D6. 10 substrates and 5 inhibitors of CYP2D6 were docked in the active sites of CYP2D6 models using AUTODOCK3.0.5. The results showed the dissociation (Kd), and inhibition (Ki) constants increased 2-6 and 2-5 times in CYP206.10 and CYP206.17 respectively compared to CYP206.1. It was also found that the mutations changed the geometry and chemistry of CYP206*10 active site's but only changed the geometry of CYP206*17 active site's residues. The overall capacity of these enzymes to metabolize each substrate is decreased in the order of CYP206.1 > CYP206.17 > CYP2D6.10. This study thus, proposed optimization of the initial dose of CYP206 substrate's to 15 - 50% and 20 - 50% for polymorphic individuals of CYP206*10 and CYP206*17 respectively.
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The Effects Of Allelic Variations , On Biotransformation Activity Of Cytochrome
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