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CYP families in Humans isozyme CYP3A4 subfamily family Major Phase I enzymes: ~90% of Phase I metabolism [CYP family: Heme-thiolate enzymes] Involves in Hormone synthesis and metabolism, cholesterol synthesis, Vit. D metabolsim Metabolizes potentially toxic compounds, including drugs and products of endogeneous metabolism such as bilirubin, principally in the liver. Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies. isozyme CYP3A4 Cytochrome P450은 heme을 prosthetic group으로 가지는 superfamily 효소군으로 대부분의 약물이나 환경물질들 등의 다양한 외인성 물질 또는 스테로이드나 지질 등의 내인성 물질에 대해 산화적 대사 작용을 수행하는 생명체에 필수적인 촉매효소로 알려졌다. subfamily family
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CYP450
2014. 2. 21.
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CYP families in Humans
• Major Phase I enzymes: ~90% of Phase I metabolism
[CYP family: Heme-thiolate enzymes]• Involves in Hormone synthesis and metabolism, cholesterol synthesis, Vit. D metabolsim Metabolizes potentially toxic compounds, including drugs and products of endogeneous metabolism such as bilirubin, principally in the liver.
• Humans have 57 genes and more than 59 pseudogenes divided among 18 families of cytochrome P450 genes and 43 subfamilies.
CYP3A4
familysubfamily
isozyme
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~73% ~75% 46%
16%
12%
9%
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Mechanism of CYP450 reactions• Monooxygenase reactions involving TWO-stage reduction of molecular oxygen• Single oxygen atom insertion into substrate molecules• R-H + O2 + NADPH + H+ → R-OH + H2O + NADP+
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Targeting, retention and transport microsomal CYP proteins
Curr Opin Drug Devel 2010 78
• Human CYPs are Primarily membrane-associated proteins.(Inner membrane of mitochondria or Endo-
plasmic reticulum cell)
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Why dose we concern about CYP450?
• Drug-Drug interactions can occur when two drugs are co-administered and compete for the same enzyme.• In CYP inhibition, one drug (perpetrator) binds to the isozyme and the other drug (victim) is excluded from metabolism, thus increasing to a toxic concentration.• Irreversible binding inactivates CYP: Mechanism-based inhibition.• CYP inhibition can cause withdrawal from Clinical use or restrictive labeling for a drug.
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Importance of CYP inhibition
• Terfenadine (Seldane) - Antihistamine - Prodrug completely metabolised to the active form Fexofenadine - Risk of Torsa de Point (QT interval prolongation)
Fexofenadine
-8-DDT 2005 4 825
Binding mode reversible vs irreversible
Reversible Irreversible
Activated by the enzymes to form a reactive metabolitethat covalently binds to the apoprotein.
Irreversible Quasi-Irreversible
inhibitor blocks access of the drug to me metabolized to the active sites of the enzyme
inhibitor is activated by the enzyme to form a reactiveintermediate that covalently binds to the prosthetichaem group.
inhibitor is activated by the enzyme to form an intermediateThat results in the destruction of the prosthetic haem group(metabolic intermediate complex).
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in vitro CYP inhibition
• Criteria at the Early Stage of drug discovery
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in vivo CYP inhibition
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Case Study
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Structural modification strategy
• Pyridine analogs• Terminal imidazoles• Terminal olefin• Terminal acetylene• Quinolines• Amines • Hydrazines• Hydrazones• Methylene dioxyphenyls etc. Current Drug Metab 2000 67
Molecules 2007 1910
Isoform Specificity?
Curr Opin Drug Devel 2010 66
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Isoform Specificity
DDT 2002, 7(17), 918
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Isoform Specificity
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CYP1A2 Substrates
• CYP1A2 tends to catalyze the metabolism of planar amines and amides
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CYP2D6 Substrates
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CYP2D6 Substrates
• A large No. of drugs have basic N atoms CYP2D6 metabolizes ~30% of drugs• Low abundance(~2%) may be saturable and result in a Non-linear increase in drug concentration with dose• Polymophism: 7~10% of white population lacks CYP2D6 Toxicity!
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CYP2C9 Substrates
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CYP2C9 Substrates
7.8Å
4.0Å
Cationic 2C9
82o
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CYP3A4 Substrates
• Macrolide immunosuppressant Sirolimus (Rapamycin)• Prophylaxis against graft rejection in kidney transplant patients in combination with cyclosporine
r < 2.7Å Iq-180OI <45O
JMC 2001 44 2027
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CYP3A4 Substrates
• Introduction of Steric Hinderance at 2-, 6- position of N of heterocycles• Electronic substitution (Halogen) to reduce pKa of N
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Methods
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Screening methods
DDT 2002, 7(17), 918
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Assessing DDI
NRDD 2005 4 825