KINESIOL 1Y03 Chapter Notes - Chapter 12: Retinoid X Receptor, Epoxide, Pregnane X Receptor
22 Jun 2018
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The metabolism of xenobiotics
Xenobiotics are metabolized by enzymes that have evolved to eliminate natural
compounds
Most metabolism occurs in the liver, but all tissues have some metabolic capacity
A drug must be lipid soluble to be absorbed into the body, generally metabolism
causes drugs to go from lipid soluble water soluble (hydrophilic) to be excreted
Generally produces less active (toxic) products
Xenobiotic metabolizing enzymes are often multi-gene families with unique but
overlapping specificities
Quantitative and qualitative differences between species, and differences is
expression across different tissues and sexes
Metabolism can be affected by environemtnal factors e.g. soking and diet
Extent of metabolism may be affected by enterohepatic recycling
Phase 1 metabolism
= chemical modification (i.e. “functionalisation”) of xenobiotics
introduced or uncovers POLAR functional groups like –OH or NH2which provide sites
for phase 2 metabolism
mainly by oxidation, reduction and hydrolysis
mostly carried out by CYP P450s in oxidation – metabolises 50% of all drugs
also: flavin monooxygenase (FMO), monoamine oxidase (MAO), reductases,
dehydrogenases, oxidases, esterases and amidases
P450
= a haemoprotein which uses NADPH as a source of reducing equivalents
it is the terinal oxidase in a mixed function oxidase (MFO) electron transfer system
locates in SER of tissues
the gene superfamily has 57 memebrs in 17 families; families 1-3 are involved in the
metabolism of most drugs with 10 important enzymes including: Cyp 1A2, 2A6, 2D6,
2C9, 2C8, 2C19, 2E1 which are most important
P450 catalyses: aliphatic + aromatic hydroxylation, dealkylaton, deamination, N-
oxidation, sulphoxidation, azo- and nitro-reduction
They are inducible i.e. other compounds can affect their expression
Example: analgesic effects of codeine from codeine -HCHO morphine by Cyp2A6
Example: Paracetemol converted by Cyp2E1 from N-acetyl-p-benzoquinone imine
protein oxidation + adduction. The protein oxidation leads to hepatotoxicity
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Xenobiotics are metabolized by enzymes that have evolved to eliminate natural compounds. Most metabolism occurs in the liver, but all tissues have some metabolic capacity. A drug must be lipid soluble to be absorbed into the body, generally metabolism causes drugs to go from lipid soluble water soluble (hydrophilic) to be excreted. Xenobiotic metabolizing enzymes are often multi-gene families with unique but overlapping specificities. Quantitative and qualitative differences between species, and differences is expression across different tissues and sexes. Metabolism can be affected by environemtnal factors e. g. soking and diet. Extent of metabolism may be affected by enterohepatic recycling. = chemical modification (i. e. functionalisation ) of xenobiotics introduced or uncovers polar functional groups like oh or nh2which provide sites for phase 2 metabolism. Mostly carried out by cyp p450s in oxidation metabolises 50% of all drugs also: flavin monooxygenase (fmo), monoamine oxidase (mao), reductases, dehydrogenases, oxidases, esterases and amidases. 2c9, 2c8, 2c19, 2e1 which are most important.
