CYP2D6 Allelic Variants *17-2 & 17-3 Metabolize the Same Substrates as *1 but are Less Susceptibility to Inactivation by SCH 66712
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Cytochrome P450 (CYPs), is a superfamily of heme-thiolate containing enzymes, and these superfamilies contain over 100 allelic variants. CYP P450s are of interest because of their capability to catalyze the oxidative biotransformation of most drugs including endogenous molecules (steroids) and xenobiotics (therapeutic drugs) into more hydrophilic compounds. One superfamily of CYP P450 is CYP2D6, which contains the variant CYP2D6*17, a poor metabolizer that is commonly found in people of African descent. The goal of this project was to understand how mutations to CYP2D6 *1 effects its susceptibility to inactivation by a known mechanism based inactivator, SCH 66712, and to determine the metabolites produced by *17-2 and *17-3. The allelic variants *17-2 and *17-3 exhibited less inactivation than *1 and required a higher concentration of SCH 66712 than *1 for the enzyme to be inactivated. Based on spectral binding titrations with dextromethorphan, CYP2D6*1 had a Kd of 80±21uM andCYP2D6*17-2 had a Kd of 120 ±87uM.The genetic differences in metabolic rates ofCYP2D6 can lead to adverse drug reactions (ADR) due to changes in the architecture of the active site via pH range and regioselectivity of the oxidation states that ultimately effects the enzyme's binding affinity.