PED2001: Drug Disposition and Pharmacokinetics - Non-P450 Mediated Phase I Metabolism
Non-P450 Mediated Phase I Metabolism: Overview
Non-P450 Phase I Metabolism
Flavin-Linked Monooxygenases (FMO)
FMO Reaction Mechanism
FMO Properties
N-hydroxylation of N-deacetyl ketoconazole
Metabolic Pathways of Tamoxifen
FMOs-Species and Tissue Variations
Peroxidase-Dependent Cooxidation
Prostaglandin H-Synthase (PGHS)
Co-oxidation of Xenobiotics by Prostaglandin H Synthase
Amine Oxidases
Monoamine Oxidase
Monoamine Oxidase (MAO)
Propranolol: MAOA
Oxidoreductases (Dehydrogenases)
Alcohol and Aldehyde Dehydrogenases
Alcohol Dehydrogenase
Aldehyde Dehydrogenase
Role of ALDH in Cyclophosphamide Metabolism
Carbonyl Reductase
Reduction of Doxorubicin
NAD(P)H: Quinone Oxidoreductase 1
Two Electron Versus Single Electron Reduction of Quinone
Esterases
Carboxylesterases
Butyrylcholinesterase
hCE1 Reactions
hCE-2 Reactions
Epoxide Hydrolases (EPH)
Importance of Epoxide Hydrolase on BaP Genotoxicity
Importance of Epoxide Hydrolase on BaP Genotoxicity
Paroxonase (PON) 1
PON1 and Paraoxon
PON1 hydrolyzes paraoxon to diethyl phosphate and p-nitrophenol.
PON3 and Statins
Lovastatin and simvastatin are prodrugs that are hydrolyzed to the active hydroxy acid by PON3 and hCE1.
Summary
There is more to Phase I metabolism than just CYPs.
Other Phase I enzymes such as oxidoreductases and hydrolases have received less attention but can be just as important for pharmacokinetics and toxicology.
The importance of non-CYP mediated phase I metabolism is now better understood.
Non-P450 Mediated Phase I Metabolism: Overview
Non-P450 Phase I Metabolism
Flavin-Linked Monooxygenases (FMO)
FMO Reaction Mechanism
FMO Properties
N-hydroxylation of N-deacetyl ketoconazole
Metabolic Pathways of Tamoxifen
FMOs-Species and Tissue Variations
Peroxidase-Dependent Cooxidation
Prostaglandin H-Synthase (PGHS)
Co-oxidation of Xenobiotics by Prostaglandin H Synthase
Amine Oxidases
Monoamine Oxidase
Monoamine Oxidase (MAO)
Propranolol: MAOA
Oxidoreductases (Dehydrogenases)
Alcohol and Aldehyde Dehydrogenases
Aldehyde Dehydrogenase
Role of ALDH in Cyclophosphamide Metabolism
Carbonyl Reductase
Reduction of Doxorubicin
NAD(P)H: Quinone Oxidoreductase 1
Two Electron Versus Single Electron Reduction of Quinone
Esterases
Carboxylesterases
Butyrylcholinesterase
hCE1 Reactions
hCE-2 Reactions
Epoxide Hydrolases (EPH)
Importance of Epoxide Hydrolase on BaP Genotoxicity
Importance of Epoxide Hydrolase on BaP Genotoxicity
Paroxonase (PON) 1
Multifunctional enzyme with arylesterase, lactonase and paroxonase activities (also hydrolyses other organophosphorus compounds).
Synthesised mainly in the liver, also found in plasma.
Has a role in degradation of oxidised lipids (protects LDL and HDL from lipid peroxidation).
Also do recently discovered PON2 and PON3.
PON1 and Paraoxon
PON1 hydrolyzes paraoxon to diethyl phosphate and p-nitrophenol.
PON3 and Statins
Lovastatin and simvastatin are prodrugs that are hydrolyzed to the active hydroxy acid by PON3 and hCE1.
Summary
There is more to Phase I metabolism than just CYPs.
Other Phase I enzymes such as oxidoreductases