pharmacology lecture 6th week

8/13/2019 Pharmacology Lecture 6th Week

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Pharmacology Lecture

6thWeek

January 17,2014

Biotransformation


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Biotransformation

- is the chemical modification (or

modifications) made by an

organism on a chemical

compound.- If this modification ends in mineral

compounds like CO2, NH

4

+, or H2O,

the biotransformation is called

mineralisation.
http://en.wikipedia.org/wiki/Mineralization_(biology)http://en.wikipedia.org/wiki/Mineralization_(biology)


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Biotransformationmeans chemical alteration

of chemicals such as (but not limited to)

nutrients, amino acids, toxins, and drugsinthe body.

It is also needed to render nonpolar

compoundspolarso that they are notreabsorbed in renal tubules and are excreted.

Biotransformation of xenobiotics can

dominate toxicokineticsand the metabolitesmay reach higher concentrations in organisms

than their parent compounds
http://en.wikipedia.org/wiki/Nutrienthttp://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Toxinshttp://en.wikipedia.org/wiki/Chemical_polarityhttp://en.wikipedia.org/wiki/Chemical_polarityhttp://en.wikipedia.org/wiki/Toxicokineticshttp://en.wikipedia.org/wiki/Toxicokineticshttp://en.wikipedia.org/wiki/Chemical_polarityhttp://en.wikipedia.org/wiki/Chemical_polarityhttp://en.wikipedia.org/wiki/Chemical_polarityhttp://en.wikipedia.org/wiki/Toxinshttp://en.wikipedia.org/wiki/Amino_acidshttp://en.wikipedia.org/wiki/Nutrient


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Drug metabolism

The metabolismof a drugor toxinin a body is anexample of a biotransformation. The body

typically deals with a foreign compound by

making it more water-soluble, to increase the

rate of its excretion through the urine. There are

many different process that can occur; the

pathways of drug metabolism can be divided into:

phase

phase II
http://en.wikipedia.org/wiki/Metabolismhttp://en.wikipedia.org/wiki/Drughttp://en.wikipedia.org/wiki/Toxinhttp://en.wikipedia.org/wiki/Toxinhttp://en.wikipedia.org/wiki/Drughttp://en.wikipedia.org/wiki/Metabolism


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Drugs can undergo one of four potentialbiotransformations :

a. Active Drug to Inactive Metabolite,

b. Active Drug to Active Metabolite,

c. Inactive Drug to Active Metabolite,

d. Active Drug to Toxic Metabolite(biotoxification).


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Phase reaction

Includes oxidative, reductive, and hydrolyticreactions.

In these type of reactions, a polar group is eitherintroduced or unmasked, so the drug molecule

becomes more water-soluble and can be excreted. Reactions are non-synthetic in nature and in general

produce a more water-soluble and less activemetabolites.

The majority of metabolites are generated by acommon hydroxylating enzyme system known asCytochrome P450
http://en.wikipedia.org/wiki/Small_moleculehttp://en.wikipedia.org/wiki/Cytochrome_P450http://en.wikipedia.org/wiki/Cytochrome_P450http://en.wikipedia.org/wiki/Cytochrome_P450http://en.wikipedia.org/wiki/Cytochrome_P450http://en.wikipedia.org/wiki/Small_molecule


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Phase II reaction

These reactions involve covalent attachment

of small polar endogenous molecule such as

glucuronic acid, sulfate, or glycine to form

water-soluble compounds.

This is also known as a conjugation reaction.

The final compounds have a larger molecular

weigh


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Microbial biotransformation

Biotransformation of various pollutantsis a sustainable way to

clean up contaminated environments. These bioremediation

and biotransformation methods harness the naturally

occurring, microbial catabolic diversity to degrade, transform

or accumulate a huge range of compounds including

hydrocarbons(e.g. oil), polychlorinated biphenyls(PCBs),polyaromatic hydrocarbons(PAHs), pharmaceutical

substances, radionuclidesand metals. Major methodological

breakthroughs in recent years have enabled detailed genomic,

metagenomic, proteomic, bioinformatic and other high-throughput analyses of environmentally relevant

microorganismsproviding unprecedented insights into

biotransformation and biodegradativepathways and the

ability of organisms to adapt to changing environmental

conditions
http://en.wikipedia.org/wiki/Pollutanthttp://en.wikipedia.org/wiki/Bioremediationhttp://en.wikipedia.org/wiki/Hydrocarbonhttp://en.wikipedia.org/wiki/Polychlorinated_biphenylshttp://en.wikipedia.org/wiki/Polyaromatic_hydrocarbonshttp://en.wikipedia.org/wiki/Radionuclidehttp://en.wikipedia.org/wiki/Microorganismhttp://en.wikipedia.org/wiki/Microbial_biodegradationhttp://en.wikipedia.org/wiki/Microbial_biodegradationhttp://en.wikipedia.org/wiki/Microorganismhttp://en.wikipedia.org/wiki/Radionuclidehttp://en.wikipedia.org/wiki/Polyaromatic_hydrocarbonshttp://en.wikipedia.org/wiki/Polyaromatic_hydrocarbonshttp://en.wikipedia.org/wiki/Polyaromatic_hydrocarbonshttp://en.wikipedia.org/wiki/Polychlorinated_biphenylshttp://en.wikipedia.org/wiki/Hydrocarbonhttp://en.wikipedia.org/wiki/Bioremediationhttp://en.wikipedia.org/wiki/Pollutant


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Biological processes play a major role in the removal of

contaminantsand pollutantsfrom the environment. Some

microorganisms possess an astonishing catabolic versatility to

degrade or transform such compounds. New methodologicalbreakthroughs in sequencing, genomics, proteomics,

bioinformaticsand imaging are producing vast amounts of

information. In the field of Environmental Microbiology, genome-

based global studies open a new era providing unprecedented in

silicoviews of metabolic and regulatory networks, as well as cluesto the evolution of biochemical pathways relevant to

biotransformation and to the molecular adaptation strategies to

changing environmental conditions. Functional genomic and

metagenomic approaches are increasing our understanding of the

relative importance of different pathways and regulatory networks

to carbon flux in particular environments and for particular

compounds and they are accelerating the development of

bioremediationtechnologies and biotransformation processes.[2]

Also there is other approach of biotransformation called enzymaticbiotransformation
http://en.wikipedia.org/wiki/Contaminanthttp://en.wikipedia.org/wiki/Pollutanthttp://en.wikipedia.org/wiki/Natural_environmenthttp://en.wikipedia.org/wiki/Sequencinghttp://en.wikipedia.org/wiki/Genomicshttp://en.wikipedia.org/wiki/Proteomicshttp://en.wikipedia.org/wiki/Bioinformaticshttp://en.wikipedia.org/wiki/Bioinformaticshttp://en.wikipedia.org/wiki/Microbiologyhttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Bioremediationhttp://en.wikipedia.org/wiki/Biotransformationhttp://en.wikipedia.org/wiki/Biotransformationhttp://en.wikipedia.org/wiki/Bioremediationhttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Microbiologyhttp://en.wikipedia.org/wiki/Bioinformaticshttp://en.wikipedia.org/wiki/Bioinformaticshttp://en.wikipedia.org/wiki/Proteomicshttp://en.wikipedia.org/wiki/Genomicshttp://en.wikipedia.org/wiki/Sequencinghttp://en.wikipedia.org/wiki/Natural_environmenthttp://en.wikipedia.org/wiki/Pollutanthttp://en.wikipedia.org/wiki/Contaminant


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Biotransformationis the process whereby a

substance is changed from one chemical to

another (transformed) by a chemical reaction

within the body.

Metabolism or metabolic transformations are

terms frequently used for the biotransformation

process. However, metabolism is sometimes not

specific for the transformation process but may

include other phases of toxicokinetics.
http://www.eoearth.org/article/Toxicokineticshttp://www.eoearth.org/article/Toxicokinetics


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Biotransformation is vital to survival in that it

transforms absorbed nutrients (food, oxygen, etc.)

into substances required for normal body functions.For some pharmaceuticals, it is a metabolite that is

therapeutic and not the absorbed drug.

For example, phenoxybenzamine (Dibenzyline), a

drug given to relieve hypertension, is biotransformed

into a metabolite, which is the active agent.

Biotransformationalso serves as an important defense

mechanism in that toxic xenobiotics and body wastesare converted into less harmful substances and

substances that can be excretedfrom the body.
http://www.eoearth.org/article/Absorption_of_Toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Absorption_of_Toxicants


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If you recall, toxicants that are lipophilic ('lipid-loving',dissolve easily in lipids), non-polar, and of lowmolecular weight are readily absorbedthrough the cell

membranes of the skin, gastrointestinal (GI) tract, andlung. Thesesame chemical and physical propertiescontrol the distributionof a chemical throughout thebody and its penetration into tissue cells.

Lipophilic toxicants are hard for the body to eliminate

and can accumulate to hazardous levels. However,most lipophilic toxicants can be transformed intohydrophilic ('water-loving', dissolve easily in water)metabolites that are less likely to pass throughmembranes of critical cells. Hydrophilic chemicals areeasier for the body to eliminate than lipophilicsubstances. Biotransformation is thus a key bodydefense mechanism.
http://www.eoearth.org/article/Absorption_of_Toxicantshttp://www.eoearth.org/article/Distribution_of_toxicants_in_the_bodyhttp://www.eoearth.org/article/Distribution_of_toxicants_in_the_bodyhttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Distribution_of_toxicants_in_the_bodyhttp://www.eoearth.org/article/Absorption_of_Toxicants


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Fortunately, the human body has a well-developedcapacity to biotransform most xenobiotics as well asbody wastes. An example of a body waste that must be

eliminated is hemoglobin,the oxygen-carrying iron-protein complex in red blood cells.

Hemoglobin is released during the normal destructionof red blood cells. Under normal conditions

hemoglobin is initially biotransformed to bilirubin, oneof a number of hemoglobin metabolites. Bilirubin istoxic to the brain of newborns and, if present in highconcentrations, may cause irreversible brain injury.

Biotransformationof the lipophilic bilirubin moleculein the liver results in the production of water-soluble(hydrophilic) metabolites excretedinto bile andeliminated via the feces
http://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Cells


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The biotransformation process is not perfect.When biotransformation results in metabolites oflower toxicity, the process is known as

detoxification.In many cases, however, themetabolites are more toxic than the parentsubstance.

This is known as bioactivation. Occasionally,

biotransformation can produce an unusuallyreactive metabolite that may interactwithcellular macromolecules (e.g., DNA). This can leadto very serious health effects, for example, canceror birth defects. An example is thebiotransformation of vinyl chloride to vinylchloride epoxide, which covalently binds to DNAand RNA, a step leading to cancer of the liver
http://www.eoearth.org/article/Interaction_of_chemicals_in_the_bodyhttp://www.eoearth.org/article/Interaction_of_chemicals_in_the_bodyhttp://www.eoearth.org/article/DNAhttp://www.eoearth.org/article/DNAhttp://www.eoearth.org/article/Interaction_of_chemicals_in_the_body


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Chemical Reactions Chemical reactions are continually taking place in the

body. They are a normal aspect of life, participating inthe building up of new tissue, tearing down of oldtissue, conversion of food to energy, disposal of wastematerials, and elimination of toxic xenobiotics.

Within the body is a magnificent assembly of chemicalreactions, which is well-orchestrated and called uponas needed. Most of these chemical reactions occur atsignificant rates only because specific proteins, knownas enzymes, are present to catalyze them, that is,

accelerate the reaction. A catalyst is a substance thatcan accelerate a chemical reaction of anothersubstance without itself undergoing a permanentchemical change
http://www.eoearth.org/article/Energyhttp://www.eoearth.org/article/Energy


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Enzymesare the catalysts for nearly all biochemical reactions

in the body. Without these enzymes, essential

biotransformation reactions would take place slowly or not at

all, causing major health problems. An example is the inability

of persons that have phenylketonuria (PKU) to use the

artificial sweetener, aspartame (in Equal). Aspartame is

basically phenylalanine, a natural constituent of most protein-

containing foods. Some persons are born with a geneticcondition in which the enzyme that can biotransform

phenylalanine to tyrosine (another amino acid), is defective.

As the result, phenylalanine can build up in the body and

cause severe mental retardation. Babies are routinely checkedat birth for PKU. If they have PKU, they must be given a special

diet to restrict the intake of phenylalanine in infancy and

childhood.


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These enzymatic reactions are not always simplebiochemical reactions. Some enzymes require thepresence of cofactors or co-enzymes in addition to the

substrate (the substance to be catalyzed) before theircatalytic activity can be exerted.These co-factors existas a normal component in most cellsand arefrequently involved in common reactions to convertnutrients into energy(vitamins are an example of co-

factors). It is the drug or chemical transformingenzymes that hold the key to xenobiotictransformation. The relationship of substrate, enzyme,co-enzyme, and transformed product is illustratedbelow:
http://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Energyhttp://www.eoearth.org/article/Energyhttp://www.eoearth.org/article/Energyhttp://www.eoearth.org/article/Cells


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Most biotransforming enzymes are high molecular weightproteins, composed of chains of amino acids linkedtogether by peptide bonds. A wide variety of

biotransforming enzymes exist. Most enzymes will catalyzethe reaction of only a few substrates, meaning that theyhave high "specificity".

Specificity is a function of the enzyme's structure and itscatalytic sites. While an enzyme may encounter many

different chemicals, only those chemicals (substrates) thatfit within the enzymes convoluted structure and spatialarrangement will be locked on and affected. This issometimes referred to as the "lock and key" relationship.As shown in Figure 1, when a substrate fits into theenzyme's structure, an enzyme-substrate complex can beformed. This allows the enzyme to react with the substratewith the result that two different products are formed. Ifthe substrate does not fit into the enzyme, no complex willbe formed and thus no reaction can occur.


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The array of enzymes range from those that haveabsolute specificity to those that have broad andoverlapping specificity. In general, there are three main

types of specificity


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For example, formaldehyde dehydrogenase

has absolute specificity since it catalyzes only

the reaction for formaldehyde.Acetylcholinesterasehas absolute specificity

for biotransforming the neurotransmitting

chemical, acetylcholine. Alcohol dehydrogenase has group specificity

since it can biotransform several different

alcohols, including methanol and ethanol. N-oxidation can catalyze a reaction of a nitrogen

bond, replacing the nitrogen with oxygen.
http://www.eoearth.org/article/Nitrogenhttp://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Nitrogen


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The names assigned to enzymes may seem

confusing at first. However, except for some of

the originally studied enzymes (such as pepsinand trypsin), a convention has been adopted

to name enzymes. Enzyme names end in "ase"

and usually combine the substrate acted onand the type of reaction catalyzed. For

example, alcohol dehydrogenase is an enzyme

that biotransforms alcohols by the removal of

a hydrogen. The result is a completely

different chemical, an aldehyde or ketone.
http://www.eoearth.org/article/Hydrogenhttp://www.eoearth.org/article/Hydrogen


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The biotransformation of ethyl alcohol to

acetaldehyde is depicted below:

ADH = alcohol dehydrogenase, a specificcatalyzing enzyme NAD = nicotinamide

adenine dinucleotide, a common cellular

reducing agent


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By now you know that the transformation of aspecific xenobiotic can be either beneficialorharmfulperhaps both depending on the dose

and circumstances. A good example is thebiotransformation of acetaminophen (Tylenol), acommonly used drug to reduce pain and fever.When the prescribed doses are taken, the desired

therapeutic response is observed with little or notoxicity. However, when excessive doses ofacetaminophen are taken, hepatotoxicity canoccur. This is because acetaminophen normallyundergoes rapid biotransformation with themetabolites quickly eliminated in the urine andfeces.
http://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dose


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At high doses, the normal level of enzymes maybe depleted and the acetaminophen is availableto undergo reaction by an additional biosyntheticpathway, which produces a reactive metabolitethat is toxic to the liver.

For this reason, a user of Tylenol is warned notto take the prescribed dose more frequently than

every 4-6 hours and not to consume more thanfour doseswithin a 24-hour period.Biotransforming enzymes, like most otherbiochemicals, are available in a normal amount

and in some situations can be "used up" at a ratethat exceeds the bodies ability to replenish them.This illustrates the frequently used phrase, the"Dose Makes the Poison."
http://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dose


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Biotransformation reactions are categorized not only by thenature of their reactions, e.g., oxidation, but also by thenormal sequence with which they tend to react with axenobiotic.

They are usually classified as Phase I and Phase II reactions.

I. Phase I reactions are generally reactions which modifythe chemical by adding a functional structure. This allowsthe substance to "fit" into the Phase II enzyme so that itcan become conjugated (joined together) with anothersubstance.

II. Phase II reactions consist of those enzymatic reactionsthat conjugate the modified xenobiotic with anothersubstance. The conjugated products are larger moleculesthan the substrate and generally polar in nature (water-soluble). Thus, they can be readily excretedfrom thebody. Conjugated compounds also have poor ability tocross cell membranes
http://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicants


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In some cases, the xenobiotic already has a functional group that can beconjugated and the xenobiotic can be biotransformed by a Phase II reactionwithout going through a Phase I reaction. A good example is phenol that can bedirectly conjugated into a metabolite that can then be excreted. The

biotransformation of benzene requires both Phase I and Phase II reactions. Asillustrated below, benzene is biotransformed initially to phenol by a Phase Ireaction (oxidation). Phenol has the functional hydroxyl group that is thenconjugated by a Phase II reaction (sulphation) to phenyl sulfate.
http://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicants


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The major transformation reactions for

xenobiotics are listed below:


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Phase I Reactions

Phase I biotransformation reactions are simple reactions ascompared to Phase II reactions. In Phase I reactions, a small polargroup (containing both positive and negative charges) is eitherexposed on the toxicant or added to the toxicant. The three mainPhase I reactions are oxidation, reduction, and hydrolysis.

Oxidationis a chemical reaction in which a substrate loseselectrons. There are a number of reactions that can achievetheremoval of electrons from the substrate. Addition of oxygenwasthe first of these reactions discovered and thus the reaction wasnamed oxidation. However, many of the oxidizing reactions do notinvolve oxygen. The simplest type of oxidation reaction is

dehydrogenation, that is the removal of hydrogenfrom themolecule. Another example of oxidation is electron transfer thatconsists simply of the transfer of an electron from the substrate.

Examples of these types of oxidizing reactions are
http://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Hydrogenhttp://www.eoearth.org/article/Hydrogenhttp://www.eoearth.org/article/Oxygen


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Examples of these types of oxidizing reactions are

illustrated below:


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The specific oxidizing reactions and oxidizing enzymes are

numerous and several textbooks are devoted to this subject. Most

of the reactions are self-evident from the name of the reaction or

enzyme involved.Listed are several of these oxidizing reactions.

alcohol dehydrogenation

aldehyde dehydrogenation

alkyl/acyclic hydroxylation

aromatic hydroxylation

deamination

desulfuration

N-dealkylation

N-hydroxylation

N-oxidation

O-dealkylation

sulphoxidation


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Reductionis a chemical reaction in which the substrate gains electrons.Reductions are most likely to occur with xenobiotics in which oxygencontent

is low.Reductions can occur across nitrogen-nitrogen double bonds (azo

reduction) or on nitro groups (NO2). Frequently, the resulting aminocompounds are oxidized forming toxic metabolites. Some chemicals such as

carbon tetrachloride can be reduced to freeradicals, which are quite reactive

with biological tissues. Thus, reduction reactions frequently result in activation

of a xenobiotic rather than detoxification. An example of a reduction reaction in

which the nitro group is reduced is illustrated below:
http://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Oxygen


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There are fewer specific reduction reactionsthan oxidizing reactions. The nature of these

reactions is also self-evident from their name.Listed are several of the reducing reactions.

azo reduction

dehalogenation disulfide reduction

nitro reduction

N-oxide reduction sulfoxide reduction


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Toxicants that have undergone Phase I

biotransformation are converted to metabolitesthat are sufficiently ionized, or hydrophilic, to be

either eliminated from the body without further

biotransformation or converted to an

intermediate metabolite that is ready for Phase II

biotransformation. The intermediates from

Phase I transformations may be

pharmacologically more effective and in manycases more toxic than the parent xenobiotic.


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Phase II Reactions

A xenobiotic that has undergone a Phase Ireaction is now a new intermediatemetabolite that contains a reactive chemical

group, e.g., hydroxyl (-OH), amino (-NH2), andcarboxyl (-COOH). Many of these intermediatemetabolites do not possess sufficienthydrophilicity to permit elimination from the

body. These metabolites must undergoadditional biotransformation as a Phase IIreaction.


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Phase II reactions are conjugation reactions, that is, amolecule normally present in the body is added to thereactive site of the Phase I metabolite. The result is a

conjugated metabolite that is more water-soluble thanthe original xenobiotic or Phase I metabolite. Usuallythe Phase II metabolite is quite hydrophilic and can bereadily eliminated from the body.

The primary Phase II reactions are: glucuronide conjugation - most important reaction

sulfate conjugation - important reaction

acetylation

amino acid conjugation glutathione conjugation

methylation


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Glucuronide conjugation is one of the most important andcommon Phase II reactions. One of the most popularmolecules added directly to the toxicant or its phase I

metabolite is glucuronic acid, a molecule derived fromglucose, a common carbohydrate (sugar) that is theprimary source of energyfor cells. The sites ofglucuronidation reactions are substrates having an oxygen,nitrogen, or sulfur bond. This includes a wide array ofxenobiotics as well as endogenous substances, such asbilirubin, steroid hormones and thyroid hormones.Glucuronidation is a high-capacity pathway for xenobioticconjugation. Glucuronide conjugation usually decreasestoxicity, although there are some notable exceptions, forexample, the production of carcinogenic substances. The

glucuronide conjugates are generally quite hydrophilic andare excretedby the kidney or bile, depending on the size ofthe conjugate. The glucuronide conjugation of aniline isillustrated below:
http://www.eoearth.org/article/Energyhttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Energyhttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Nitrogenhttp://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Nitrogenhttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Nitrogenhttp://www.eoearth.org/article/Oxygenhttp://www.eoearth.org/article/Cellshttp://www.eoearth.org/article/Energy


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Sulfate conjugation is another important

Phase II reaction that occurs with many

xenobiotics. In general, sulfationdecreasesthe toxicity of xenobiotics. Unlike glucuronic

acid conjugates that are often eliminated in

the bile, the highly polar sulfate conjugatesare readily secreted in the urine. In general,

sulfation is a low-capacity pathway for

xenobiotic conjugation. Often glucuronidation

or sulfation can conjugate the same

xenobiotics.


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Biotransformation Sites

Biotransforming enzymes are widely distributedthroughout the body. However,the liver is theprimary biotransforming organdue to its largesize and high concentration of biotransforming

enzymes. The kidneys and lungs are next with10-30% of the liver's capacity. A low capacityexists in the skin, intestines, testes, and placenta.Since the liver is the primary site for

biotransformation, it is also potentially quitevulnerable to the toxic action of a xenobiotic thatis activated to a more toxic compound
http://www.eoearth.org/article/Distribution_of_toxicants_in_the_bodyhttp://www.eoearth.org/article/Organ_systems_and_organshttp://www.eoearth.org/article/Organ_systems_and_organshttp://www.eoearth.org/article/Organ_systems_and_organshttp://www.eoearth.org/article/Distribution_of_toxicants_in_the_body


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Within the liver cell, the primary subcellular

components that contain the transforming

enzymes are the microsomes (small vesicles)

of the endoplasmic reticulum and the solublefraction of the cytoplasm (cytosol). The

mitochondria, nuclei, and lysosomes contain a

small level of transforming activity


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Microsomal enzymes are associated with mostPhase I reactions. Glucuronidation enzymes,however, are contained in microsomes. Cytosolic

enzymes are non-membrane-bound and occurfree within the cytoplasm. They are generallyassociated with Phase II reactions, although someoxidation and reduction enzymes are containedin the cytosol. The most important enzymesystem involved in Phase I reactions it thecytochrome P-450 enzyme system. This system isfrequently referred to as the "mixed functionoxidase (MFO) " system. It is found in microsomes

and is responsible for oxidation reactions of awide array of chemicals


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The fact that the liver biotransforms most xenobioticsand that it receives blood directly from thegastrointestinal tract renders it particularly susceptible

to damage by ingested toxicants. Blood leaving thegastrointestinal tract does not directly flow into thegeneral circulatory system. Instead, it flows into theliver first via the portal vein. This is known as the "first

pass" phenomena. Blood leaving the liver is eventuallydistributedto all other areas of the body; however,much of the absorbedxenobiotic has undergonedetoxication or bioactivation. Thus, the liver may have

removed most of the potentially toxic chemical. On theother hand, some toxic metabolites are in highconcentration in the liver
http://www.eoearth.org/article/Distribution_of_toxicants_in_the_bodyhttp://www.eoearth.org/article/Absorption_of_Toxicantshttp://www.eoearth.org/article/Absorption_of_Toxicantshttp://www.eoearth.org/article/Distribution_of_toxicants_in_the_body


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Modifiers of Biotransformation

The relative effectiveness of biotransformationdepends on several factors, including species, age,gender, genetic variability, nutrition, disease,exposure to other chemicals that can inhibit or induceenzymes, and doselevels. Differences in speciescapability to biotransform specific chemicals are wellknown. Such differences are normally the basis forselective toxicity, used to develop chemicals effectiveas pesticides but relatively safe in humans.

For example, malathion in mammals isbiotransformed by hydrolysis to relatively safemetabolites, but in insects, it is oxidized to malaoxon,which is lethal to insects
http://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dose


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Age may affect the efficiency of biotransformation. Ingeneral, human fetuses and neonates (newborns)have limited abilities for xenobiotic

biotransformations. This is due to inherent deficienciesin many, but not all, of the enzymes responsible forcatalyzing Phase I and Phase II biotransformations.While the capacity for biotransformation fluctuateswith age in adolescents, by early adulthood theenzyme activities have essentially stabilized.Biotransformation capability is also decreased in theaged.

Gender may influence the efficiency ofbiotransformation for specific xenobiotics. This isusually limited to hormone-related differences in theoxidizing cytochrome P-450 enzymes


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Genetic variability in biotransformingcapability accounts for most of the largevariation among humans. The Phase IIacetylation reaction in particular is influencedby genetic differences in humans. Somepersons are rapid and some are slow

acetylators. The most serious drug-relatedtoxicity occurs in the slow acetylators, oftenreferred to as "slow metabolizers". With slowacetylators, acetylation is so slow that blood

or tissue levels of certain drugs (or Phase Imetabolites) exceeds their toxic threshold


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Examples of drugs that build up to toxic levels in slow

metabolizers that have specific genetic-related defects in

biotransforming enzymes are listed below:


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Poor nutrition can have a detrimental effect

on biotransforming ability. This is related to

inadequate levels of protein, vitamins, and

essential metals. These deficiencies can

decrease the ability to synthesize

biotransforming enzymes. Many diseases canimpair an individual's capacity to biotransform

xenobiotics. A good example, is hepatitis (a

liver disease), which is well known to reducehepatic biotransformation to less than half

normal capacity.

i hibi i d i d i


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Enzyme inhibition and enzyme induction canbe caused by prior or simultaneous exposureto xenobiotics. In some situations exposure toa substance will inhibit the biotransformationcapacity for another chemical due toinhibition of specific enzymes. A major

mechanism for the inhibition is competitionbetween the two substances for the availableoxidizing or conjugating enzymes, that is thepresence of one substance uses up the

enzyme that is needed to metabolize thesecond substance.


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Enzyme induction is a situation where priorexposure to certain environmental chemicals and

drugs results in an enhanced capability forbiotransforming a xenobiotic. The prior exposuresstimulate the body to increase the production ofsome enzymes. This increased level of enzyme

activity results in increased biotransformation ofa chemical subsequently absorbed. Examples ofenzyme inducers are alcohol, isoniazid, polycyclichalogenated aromatic hydrocarbons (e.g., dioxin),

phenobarbital, and cigarette smoke. The mostcommonly induced enzyme reactions involve thecytochrome P-450 enzymes.
http://www.eoearth.org/article/Absorption_of_Toxicantshttp://www.eoearth.org/article/Absorption_of_Toxicants


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Doselevel can affect the nature of thebiotransformation. In certain situations, thebiotransformation may be quite different at high doses

versus that seen at low dose levels. This contributes to theexistence of a dose threshold for toxicity. The mechanismthat causes this dose-related difference inbiotransformation usually can be explained by theexistence of different biotransformation pathways. At low

doses, a xenobiotic may follow a biotransformationpathway that detoxifies the substance.However, if theamount of xenobiotic exceeds the specific enzyme capacity,the biotransformation pathway is "saturated". In that case,it is possible that the level of parent toxin builds up. In

other cases, the xenobiotic may enter a differentbiotransformation pathway that may result in theproduction of a toxic metabolite
http://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Dose


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An example of a dose-related difference inbiotransformation occurs with acetaminophen(Tylenol). At normal doses, approximately 96% of

acetaminophen is biotransformed to non-toxicmetabolites by sulfate and glucuronide conjugation. Atthe normal dose, about 4% of the acetaminophen isoxidized to a toxic metabolite; however, that toxicmetabolite is conjugated with glutathione and

excreted. With 7-10 times the recommendedtherapeutic level, the sulphate and glucuronideconjugation pathways become saturated and more ofthe toxic metabolite is formed. In addition, theglutathione in the liver may also be depleted so that

the toxic metabolite is not detoxified and eliminated. Itcan react with liver proteins and cause fatal liverdamage
http://www.eoearth.org/article/Dosehttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Excretion_of_toxicantshttp://www.eoearth.org/article/Dose


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The nd

pharmacology lecture 6th week

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