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Cytochrome P450 2D6: SMART Teams Exploring Molecular Structure
Author(s) -
Barr Kyla,
Dudley Tristan,
Homuth Madelyn,
Miller Talan,
Swanson Lindsay,
Wenzler Brian,
DeBoer Advisors Karen,
Nielsen Peter,
Sem Daniel
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.lb78-a
Subject(s) - chemistry , cytochrome p450 , cyp2d6 , quinidine , heme , cytochrome , biochemistry , binding site , pharmacology , hydroxylation , stereochemistry , enzyme , biology
Cytochrome P450 is a microsomal membrane‐bound protein that metabolizes xenophobic compounds, mainly pollutants, environmental compounds and drugs, and is principally located in the liver. CYP2D6 is one of several P450s that primarily metabolizes 30% of pharmaceuticals such as anti‐arrhythmic, anti‐depressants, and beta blockers. Research on P450s is extremely valuable to the pharmaceutical industry because CYP2D6 binds with, as substrates and inhibitors, drugs such as codeine, quinidine, fluoxetine, and ritonavir. Regarding metabolism and inhibition, it is possible to predict how drugs will work by how they fit into the CYP2D6 binding site. CYP2D6 has a heme group and five amino acids that particularly impact binding. These five include: glutamate 216 which is part of the F‐G helix, aspartate 301 which is along the I helix, and phenylalanine 102, 481, and 483. The heme group in the binding site is responsible for carrying out the hydroxylation of substrates. Unluckily, if a drug can fit well into the site it may be metabolized before it has worked; if a drug fits, but not close enough to the heme to get hydroxylated, it can result in interactions because it will block the site when another drug molecule needs access. Therefore, the Cytochrome P450 system has a key role in pharmacology.