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Against Xenobiotic
Introduction
Xenos: stranger, synonims: biotransformation, drug
metabolism
Examples:
pharmaceuticals, pesticides, environmental pollutants (Pb,
CO), industrial chemicals, preservatives, colorings and
flavorings in food products
Topical Skin
Xenobiotics IV Blood
Inhalation Lung
Effect of xenobiotics:
the expected effects (the therapeutic effects
of drugs / cure or relieve symptoms of disease)
unexpected effects (side effects and toxic
effects of drugs)
Through the process of metabolism and excretion
processes, the body is able to eliminate all
influences that arise after a change in chemical
structure
Metabolism xenobiotics holds important meaning
in the process of elimination xenobiotics
Metabolism of Xenobiotics
Xenobiotics metabolism:
Mechanism of elimination of foreign and
undesirable compounds from the body
Control of levels of desirable compounds
Biochemical alteration in the body
Not detoxication reaction, because:
Pro drugs
Pro carcinogenesis
Metabolism increase biologic activity and/or
toxicity
Divided in 2 phases
Phase 1: hydroxylation
catalyzed by members of class of enzymes:
monooxygenase or cytovhrome P450s
Phase 2: conjugation
the hydroxylated or other compounds produced in phase 1
by spesific enzymes, converted to various polar metabolites
by conjugation with glucoronic acid, sulfate, acetate,
glutathion or certain amino acids, or by methylation
Phase I
Biochemically alter the xenobiotic to change its biologic
effect
Location:
› Liver (membranes of ER, cytoplasm)
› Other tissues (lungs, intestine, skin, kidneys)
Enzymes:
› Monooxygenases (hydroxylases, cytochrome P450,
Mixed Function Oxidase/MFO
Property of enzymes:
› Metabolism of endogenic substances, broad
substrate specificity, inducibility
Reactions: Hydrolysis, oxidation, reduction
RH + O2 + NADPH + H+ R-OH + H2O + NADP
lipophilic hydrophilic
active inactive
inactive active
Results:
› Lowering their toxicity
› Increasing their toxicity
› Bioactivation some xenobiotics (ex. procarcinogen
danger of cell, body damage)
› Increasing their water solubility
Lipophilic Hydrophilic
Non polar, hydrophobic Polar
The figure is from: Color Atlas of Biochemistry / J. Koolman, K.H.Röhm. Thieme 1996. ISBN 0-86577-584-2
Some properties of human cytochrome P450s (1)
Involved in phase I of the metabolism of innumerable xenobiotics,
including perhaps 50% of the drug administrated to humans; they may
increase, decrease or not affect the activities of various drugs
Involved in the metabolism of many endogenous compounds (steroid
etc)
All are hemoproteins
Often exhibit broad substrate specifity, thus acting on many
compounds; consequently, different P450s may catalyze formation of
the same product
Extremely versatile catalysts, perhaps catalyzing about 60 types of
reactions
Basically they catalyze reactions involving introduction of one atom of
oxygen into the substrate and one into water
Their hydroxylated products are more water-soluble than their generally
lipophilic substrates, facilitating excretion
Liver contains highest amounts, but found in most if not all tissues,
Some properties of human cytochrome P450s (2)
Located in the smooth endoplasmic reticulum or in mitochondria
(steroidogenic hormones)
Structure of human
cytochrome P450 CYP2C9
Some important drug reactions due to mutant or
polymorphic form of enzims or protein
Human CYP families and their main functions. Data adapted from (Gonzalez
1992, Nelson et al. 1996, White et al. 1997, Nelson 1999, Lund et al. 1999)
Enzymes: transferase
Conjugation Reactions
Glucuronidation
Endogen reactant: UDP glucuronic acid
Enzyme: UDP glucuronyl transferase
Location: microsome
Reactive site: OH, COOH, NH2, SH, C-C
Type of substrates: phenol, alcohols, carboxylic
acids, hydroxylamines, sulfonamides
Examples: acetaminophen, nitrophenol
Sulfate conjugation
› Endogen reactant: phosoadenosyl phosphosulfate
› Enzyme: sulfotransferase
› Location: cytosol
› Reactive site: NH2, OH
› Type of substrates: phenol, alcohols, aromatic amines
› Examples: aniline, phenol, acetaminophen
Acetylation
› Endogen reactant: acetyl-CoA
› Enzyme: n-Acetyltransferase
› Location: cytosol
› Reactive site: NH2, SO2NH2, OH
› Type of substrates: amines
› Examples: isoniazid, sulfonamides
Glutathione conjugation
› Endogen reactant: glutathione
› Enzyme: glutathione S-transferase
› Location: cytosol
› Reactive site: epoxides, organic halides, organic nitro
compounds, unsaturated compounds
› Type of substrates: epoxides, arene oxides, nitro groups,
hydroxylamines
› Examples: bromobenzene
Methylation
› Endogen reactant: s-adenosyl-methionine
› Enzyme: transmethylase
› Location: cytosol
› Reactive site: NH2, SH, OH
› Type of substrates: phenols, amines, catecholamines
› Examples: pyridine, histamine, epinephrine
Xenobiotics Drug Metabolism
Drugs that are active →
phase 1 metabolism
xenobiotik to change
the active drug into
inactive
Drugs that have not been
active → phase 1
metabolism xenobiotik
convert an inactive drug
becomes active.
Alcohol
METHANOL (CH3OH)
lower narcotic effect than ethanol
slower excretion from the body
metabolized by the same enzymes as ethanol
causes harder sickness (formaldehyde)
serious intoxication: 5 – 10 ml (lethal dose 30 ml)
no symptoms immediately after drunkenness (6 – 30
hours)
headache, pain in back, loss of sight
metabolic acidosis
therapy: ethanolemia 1 ‰ (1 - 2 days), liquids
Ethanol
A small molecule; both lipid and water soluble
Readily absorbed from the intestine by passive diffusion
Small percentage of ingested ethanol (0-5%) enters the
mucosal cells of the upper GI tract (tongue, mouth,
esophagus, and stomach)
The remainder enters the blood, of which 85 to 98% is
metabolized in the liver, and only 2 to 10% is excreted
through the lungs or kidneys
Distribution of ethanol in the body:
› the equilibrium concentration of ethanol in a tissue
depends on the relative water content of that tissue
› ethanol is practically insoluble in fats and oils, although
like water, it can readily pass through biological
membranes
› No plasma protein binding ethanol
Factors affecting ethanol absorption:
› concentration of ethanol, passive diffusion (higher
concentrationgreater absorption), blood flow at site of
absorption
(efficient blood flow greater absorption), rate of
ingestion, food (presence of food in stomach retards
gastric emptying, reduces absorption of ethanol)
Factors that determine the rate and route of
ethanol oxidation in individuals include:
genotype polymorphic forms of ADH and
acetaldehyde dehydrogenase can greatly
affect the rate of ethanol oxidation and the
accumulation
Drinking history the level of gastric ADH
decreases and CYP2E1 increase with the
progression from a naïve, to a moderate, a
heavy and chronic consumer of alcohol
Gender blood levels of ethanol after
consuming a drink normally higher for women
than men, because of lower levels of gastric ADH
activity
Factors that determine the rate and route of
ethanol oxidation in individuals include:
Quantity—The amount of ethanol an individual
consumes over a small amount of time
determines its metabolic route.
Metabolism of Ethanol
Metabolism occurs by two pathways
The first pathway comprises two steps
The first step, catalyzed by the enzyme alcohol
dehydrogenase, takes place in the cytoplasm:
Inhibition of most oxidations that use liver NAD Inhibition of some drug and hormone metabolism
ADH ADH
MEOS
Inter polate into Acetaldeyde ed
membranes NADH/NAD+
4. Glycophosphate
Dehydrogenase
Fatty Liver leading to
glycrophosphate