Transcript Metabolism of xenobiotics I (general overview)

ENVR/TOXC 442 Fall 2010
Metabolism of Xenobiotics
I. General Overview
Aug 26, 2010
L.M. Ball
Rosenau 158
[email protected]
• Metabolism:
• Xenobiotic
Chemical reactions carried out by
and in living systems
– Breakdown of organic
matter (eg food) to release
energy (catabolism)
– Construction of cell
components (eg
carbohydrates, proteins,
lipids, nucleic acids, other
macromolecules) using
energy (anabolism)
– Carried out by enzymes (+
co-factors)
– Essential to life
– No metabolism = no life
Substance foreign (xenos =
foreign) to life (bios)
Chemical found in a living system
which is not “naturally” present
in that organism.
– Drugs (Drug metabolism)
– Environmental pollutants
– Not produced by organism
– Not useful to organism
– Metabolism carried out by
enzymes (+ co-factors)
– Metabolism serves to
eliminate xenobiotics
– Fundamental to toxicology
Why?
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Importance in Pharmacology/Therapeutics
Importance in Toxicology
Importance in Environmental Protection
Need to consider properties (therapeutic and/or
toxic) of metabolites as well as those of the
parent compound
• Need to know
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What metabolites are formed
Where they are formed
Kinetics of formation
Kinetics of elimination
International Society for Study of
Xenobiotics (ISSX) www.issx.org
Xenobiotica
Drug Metabolism and Disposition (ASPET)
Chemical Research in Toxicology (ACS)
Drug Metabolism Reviews (ISSX)
Current Drug Metabolism
Drug Metabolism Letters
Phase I – Phase II
• Phase I: Chemical modifications that introduce or
uncover functional groups on a xenobiotic that provide
sites for Phase II metabolism
OH
Benzene
Phenol
• Phase II: Synthetic reaction of a xenobiotic (or of a
Phase I metabolite of a xenobiotic) with an
endogenous substance that results in introduction of
polar, ionizable groups to enhance water solubility
and hence excretion
COOH
OH
o
o
HO
OH
OH
Identification of Metabolites
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Extraction from biological matrix
Separation/purification
Analytical techniques
Chromatography
– Thin-layer, gas, liquid, high-pressure liquid….
• Spectrometry
– Mass, nuclear magnetic resonance, UV-vis,
fluorescence
Systems studied
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Whole animals (humans, rats)
Isolated perfused organs
Reconstructed organs/tissues
Cells (primary isolates, cultures)
Subcellular fractions
– S9
– Microsomes
– Cytosol
• Purified enzymes
• Cells engineered to over/under express specific
enzymes
• Organisms with genes for specific enzymes knocked out
Overview: Uptake and distribution
(ADME)
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Major Portals of Entry
– Lung
– Intestinal Tract
– Skin
Major Sites of Metabolism
– Liver
– Lung
– Intestinal Tract
– Kidneys
– Skin
Target organs
Major Routes of Elimination
– Urine
– Feces
– Exhaled air
– Pharmacokinetic descriptors
Passage across membranes
• Passive diffusion (Fick’s Law)
– Flux is proportional to concentration gradient
J = -D * ΔC/Δx
• Transporters (can go against
concentration gradient)
• Metabolism generates a concentration
gradient
TCDD
http://www.dioxin2010.org