Bio Transformation Bibek Singh Mahat RN07

BIOTRANSFORMATION

BIOTRANSFORMATION

SUBMITTED FOR INTERNAL EVALUATION FOR
THE DEGREE IN MASTER IN PHARMACY
BY
BIBEK SINGH MAHAT, M. PHARM STUDENT,
2nd SEMESTER, BATCH OF 2009
SUBMITTED TO:
Dr. Dharma Prasad Khanal

DEPARTMENT OF PHARMACY
SCHOOL OF SCIENCE
KATHMANDU UNIVERSITY
DHULIKHEL, NEPAL
Page 1 of 20. Prepared and submitted by: Bibek Singh Mahat, Roll No. 07, M. Pharm. (Industrial), May 2010

BIOTRANSFORMATION

TABLE OF CONTENTS:

1. Introduction
a) Xenobiotics
b) Chemical Reactions
c) Categorization of the Biotransformation reactions
2. Phase I Reactions
a) Oxidation
b) Reduction
c) Hydrolysis
d) Cytochrome P450 system
3. Phase II Reactions
a) Glucuronide conjugation
b) Sulfate conjugation
4. Biotransformation Sites
5. Modifiers of Biotransformation
a) Age
b) Genetic variability in biotransforming capability
c) Poor nutrition
d) Enzyme inhibition and enzyme induction
e) Dose level
6. References


BIOTRANSFORMATION

Introduction
Biotransformation is 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 toxico-kinetics.
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, phenoxy-benzamine, a drug given to
relieve hypertension, is biotransformed into a metabolite, which is the active agent.
Biotransformation also serves as an important defense mechanism in those toxic xenobiotics and
body wastes are converted into less harmful substances and substances that can be excreted from
the body.
Toxicants that are lipophilic, non-polar, and of low molecular weight are readily absorbed
through the cell membranes of the skin, gastrointestinal (GI) tract, and lungs. These same
chemical and physical properties control the distribution of a chemical throughout the body 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 into
hydrophilic metabolites that are less likely to pass through membranes of critical cells.
Hydrophilic chemicals are easier for the body to eliminate than lipophilic substances.
Biotransformation is thus a key body defense mechanism.
Fortunately, the human body has a well-developed capacity to biotransform most xenobiotics as
well as body 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 destruction of red blood cells. Under normal conditions hemoglobin is initially
biotransformed to bilirubin, one of a number of hemoglobin metabolites. Bilirubin is toxic to the
brain of newborns and, if present in high concentrations, may cause irreversible brain injury.
Biotransformation of the lipophilic bilirubin molecule in the liver results in the production of
water-soluble (hydrophilic) metabolites excreted into bile and eliminated via the feces. The
biotransformation process is not perfect. When biotransformation results in metabolites of lower
toxicity, the process is known as detoxification. In many cases, however, the metabolites are
more toxic than the parent substance. This is known as bio-activation.
Occasionally, biotransformation can produce an unusually reactive metabolite that may interact
with cellular macromolecules (e.g., DNA). This can lead to very serious health effects, for
example, cancer or birth defects. An example is the biotransformation of vinyl chloride to vinyl
chloride epoxide, which covalently binds to DNA and RNA, a step leading to cancer of the liver.

BIOTRANSFORMATION

Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or
expected to be present in it. It can also cover substances which are present in much higher
concentrations than are usual. Specifically, drugs such as antibiotics are xenobiotics in humans
because the human body does not produce them itself, nor are they part of a normal diet.
The body removes xenobiotics by xenobiotic metabolism. This consists of the deactivation and
the secretion of xenobiotics, and happens mostly in the liver. Secretion routes are urine, faeces,
breath, and sweat. Hepatic enzymes are responsible for the metabolism of xenobiotics by first
activating them (oxidation, reduction, hydrolysis and/or hydration of the xenobiotic), and then
conjugating the active secondary metabolite with glucuronic or sulphuric acid, or glutathione,
followed by excretion in bile or urine. An example of a group of enzymes involved in xenobiotic
metabolism is hepatic microsomal cytochrome P450. These enzymes that metabolize xenobiotics
are very important for the pharmaceutical industry, because they are responsible for the
breakdown of medications.
Chemical Reactions
Chemical reactions are continually taking place in the body. They are a normal aspect of life,
participating in the building up of new tissue, tearing down of old tissue, conversion of food to
energy, disposal of waste materials, and elimination of toxic xenobiotics. Within the body is a
magnificent assembly of chemical reactions, which is well-orchestrated and called upon as
needed. Most of these chemical reactions occur at significant rates only because specific
proteins, known as enzymes, are present to catalyze them, that is, accelerate the reaction. A
catalyst is a substance that can accelerate a chemical reaction of another substance without itself
undergoing a permanent chemical change. Enzymes are 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 genetic condition 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 checked at birth for PKU. If they have PKU, they must be given a special diet to
restrict the intake of phenylalanine in infancy and childhood.
These enzymatic reactions are not always simple biochemical reactions. Some enzymes require
the presence of cofactors or co-enzymes in addition to the substrate before their catalytic activity
can be exerted.

BIOTRRANSFORMATIO
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These coo-factors exist as a norrmal compoonent in most cells andd are frequeently involveed in
common reactions to t convert nutrients
n into energy. Itt is the druug or chemiical transforrming
enzymes that hold thhe key to xeenobiotic traansformationn. The relatioonship of suubstrate, enzzyme,
co-enzym
me, and transsformed prodduct is as follows:
Most biootransforming g enzymes are

a high molecular weighht proteins, composed
c off chains of amino
a
acids linkked togetherr by peptide bonds. A wide w variety of biotransfforming enzyymes exist. Most
enzymes will cataly yze the reacction of onlly a few suubstrates, meaning
m that they have high
"specificity". Specifiicity is a funnction of thee enzyme's structure
s andd its catalytiic sites. Whiile an
enzyme may encoun nter many different
d chhemicals, onnly those chhemicals (suubstrates) thhat fit
within thhe enzymes convoluted
c s
structure andd spatial arraangement wiill be lockedd on and affeected.
This is soometimes reeferred to as the "lock and a key" relaationship. As shown in FigureF 1, whhen a
substratee fits into th
he enzyme's structure, an a enzyme-ssubstrate coomplex can be formed. This
allows thhe enzyme to t react witth the substrrate with thhe result thaat two differrent productts are
formed. If the substrrate does noot fit into thhe enzyme, no n complex will be form med and thuus no
reaction can
c occur.
Fig 1: enzyme subbstrate fit or incompatiblle.
Page 5 of 20. Prepared aand submitted by: Bibek Singh Mahaat, Roll No. 07, M. Pharm. (Industriaal), May 2010

BIOTRRANSFORMATIO
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The arrayy of enzymes range from m, those haviing absolute specificity to
t those haviing broad annd
overlapping specificiity. In generaal, there are three main types
t of speccificity:
Examples:-
Formmaldehyde deehydrogenasse has absoluute specificitty since it caatalyzes onlyy the reactioon for
formaaldehyde.
Acetyylcholinesterrase has abbsolute speccificity for biotransforrming the neurotransm
n mitting
chem
mical, acetylccholine.
Alcohhol dehydro ogenase has group speccificity sincce it can biotransform several diffferent
alcohhols, includin
ng methanoll and ethanoll.
N-oxxidation can catalyze
c a reeaction of a nitrogen
n bonnd, replacingg the nitrogenn with oxygeen.
The nammes assigned to enzymess may seem confusing at a first. Howwever, exceptt for some of o the
originallyy studied en
nzymes (suchh as pepsin and
a trypsin),, a conventioon has been adopted to name
n
enzymes. Enzyme naames end in "ase" and ussually combiine the substtrate acted on o and the tyype of
reaction catalyzed. For example, alcohol dehydrogennase is an enzyme that biotransfforms
alcohols by the rem moval of a hydrogen. TheT result is a compleetely differeent chemicaal, an
aldehydee or ketone. The
T biotranssformation of ethyl alcohhol to acetalddehyde is deepicted below
w:
AD
DH = alcohool dehydrogeenase, a speccific catalyzing enzyme
The transformation of
o a specificc xenobioticc can be eithher beneficiaal or harmfuul—perhaps both
dependinng on the dose and circumstannces. An example e is the biotransformationn of

BIOTRRANSFORMATIO
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acetaminnophen, a commonly useed drug to reeduce pain and a fever. When
W the prescribed dosees are
taken, thhe desired th herapeutic reesponse is observed
o wiith little or no toxicity. However, when
w
excessivee doses off acetaminopphen are taaken, hepattotoxicity can occur. This T is beccause
acetaminnophen norm mally underrgoes rapidd biotransformation with the mettabolites quuickly
eliminateed in the urinne and feces.
At high doses,
d the noormal level of
o enzymes may be depleted and the acetaminoophen is avaiilable
to underggo reaction by b an additioonal biosyntthetic pathwaay, which prroduces a reactive metabbolite
that is tooxic to the liiver. For this reason, a user
u is warnned not to taake the presccribed dose more
frequentlly than everry 4-6 hourss and not too consume more m than four
f doses within
w a 24--hour
period. Biotransform
B ming enzym mes, like moost other biiochemicals,, are availabble in a noormal
amount and a in somee situations can be "useed up" at a rate that exxceeds the body’s b abiliity to
replenishh them. This illustrates thhe frequentlyy used phrasse, the "Dosee Makes the Poison."
Categoriization of th
he Biotransfformation reactions:-
r
Biotransfformation reeactions aree categorized not only by the natture of theirr reactions, e.g.,
oxidationn, but also byy the normall sequence with
w which thhey tend to react
r with a xenobiotic. They
are usuallly classified
d as Phase I and
a Phase II reactions.
Phase I reactions arre generally reactions whichw modiffy the chem mical by addding a functtional
structure. This allow ws the substtance to "fitt" into the Phase
P II enzzyme so thaat it can beccome
conjugateed (joined toogether) withh another subbstance.
Phase II reactions co onsist of thoose enzymattic reactionss that conjuggate the moddified xenobbiotic
with anoother substan nce. The coonjugated prroducts are larger
l moleccules than thet substratee and
generallyy polar in nature
n (waterr-soluble). Thus,
T they can
c be readdily excretedd from the body.
b
Conjugatted compoun nds also have poor abilitty to cross ceell membrannes.
In some cases, the xenobiotic
x a
already has a functional group thatt can be connjugated and the
xenobiotic can be biotransform
b med by a Phhase II reacction withouut going thrrough a Phase I
reaction. An examplee is phenol thatt can be directly
d conjugated into a metabolitee that can theen be
excreted.. The biotrannsformation of benzene requires
r bothh Phase I and Phase II reeactions.

BIOTRANSFORMATION

Phase I Reactions
Phase I biotransformation reactions are simple reactions as compared to Phase II reactions. In

Phase I reactions, a small polar group (containing both positive and negative charges) is either
exposed on the toxicant or added to the toxicant. The three main Phase I reactions are oxidation,
reduction, and hydrolysis.
1. Oxidation
Oxidation is a chemical reaction in which a substrate loses electrons. There are a number of
reactions that can achieve the removal of electrons from the substrate. Addition of oxygen was
the first of these reactions discovered and thus the reaction was named oxidation. However,
many of the oxidizing reactions do not involve oxygen. The simplest type of oxidation reaction is
dehydrogenation that is the removal of hydrogen from the molecule. Another example of
oxidation is electron transfer that consists simply of the transfer of an electron from the substrate.
Examples of these types of oxidizing reactions are illustrated below:
The specific oxidizing reactions and oxidizing enzymes are numerous. Most of the reactions are
self-evident from the name of the reaction or enzyme involved. Few of them are listed below:-
Oxidizing reactions.
Alcohol dehydrogenation
Aldehyde dehydrogenation
Alkyl/acyclic hydroxylation
Aromatic hydroxylation
Deamination / Desulfuration
N-hydroxylation
N-oxidation
Sulphoxidation

BIOTRRANSFORMATIO
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2. Redu uction
Reductioon is a chem mical reactioon in which the substraate gains eleectrons. Redductions are most
likely to occur with xenobioticss in which oxygen
o conteent is low. Reductions
R can occur across
a
nitrogen--nitrogen do ouble bondss (azo reducction) or onn nitro grouups (NO2). Frequentlyy, the
resulting amino com mpounds aree oxidized forming
fo toxic metabolitees. Some chhemicals succh as
carbon teetrachloride can be reduuced to freee radicals, which
w are quuite reactivee with bioloogical
tissues. Thus,
T reducction reactioons frequenttly result in activation of a xenobbiotic rather than
detoxificcation. An example
e of a reductionn reaction inn which thee nitro grouup is reduced is
illustrated below:
There arre fewer specific reducction reactioons than oxxidizing reacctions. The nature of these
reactionss is also self--evident from
m their namee. Few of theem are listedd below:-
Azo reduction
A n
D
Dehalogenati ion
D
Disulfide reduuction
N
Nitro reductio
on
N
N-oxide redu
uction
Sulfoxide red
duction
3. Hydrrolysis
Hydrolyssis is a chem mical reactioon in whichh the additioon of water splits the toxicant
t intoo two
fragmentts or smallerr molecules. The hydrooxyl group (OH-)( is inccorporated innto one fraggment
and the hydrogen
h atoom is incorpporated into the other. Larger
L chemmicals such as
a esters, ammines,
hydrazines, and carb bamates aree generally biotransform
b med by hydrrolysis. Thee example of o the
biotransfformation off procaine (loocal anestheetic) which iss hydrolyzedd to two smaaller chemiccals is
illustrated below:

BIOTRRANSFORMATIO
ON
Toxicantts that have undergone Phase

P I biottransformatioon are convverted to meetabolites thaat are
sufficienttly ionized, or hydrophhilic, to be either elimminated from m the bodyy without fuurther
biotransfformation or convertedd to an inttermediate metabolite
m t
that is readdy for Phase II
biotransfformation. The
T intermeddiates from Phase I trannsformationss may be phharmacologiically
more effeective and in
n many casess more toxicc than the parrent xenobiootic.
Few Examples of reaactions are liisted below:--
1. Hydrrolysis of Essters :-
COOH COOH
OCCH 3 OH HO
OCCH 3
+ H2O +
O O
acetylsalicylic acid

2. Hydrrolysis of Amides:-
A

H2N S
O O CH3
RCNH RC
COH N CH3
S
O
CH3
OH
COO
N CH3 +H2O
O
O
COOH RCNH
penicillins S
CH3
C
HOOC N CH3
H
OOH
CO

0. Prepared and submitted byy: Bibek Singh Mah
Page 10 of 20 hat, Roll No. 07, M
M. Pharm. (Industrial), May 2010

BIOTRRANSFORMATIO
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Cytoch
hrome P
P450 sysstem
The princcipal reactio

on of drug/toxin metaboliism is OXIDDATION.Thhe enzymes responsible
r a
are
oxido-redductases; caalled mixed-ffunction oxiidases.Most prominent and
a importannt among theese is
the cytocchrome P450 0 system connsists of Cyt P 450 and Cyt
C P 450 redductase .

Diffferent classses of reactiions by cytoochrome P4550 systems


BIOTRANSFORMATION

Phase II Reactions
A xenobiotic that has undergone a Phase I reaction is now a new intermediate metabolite that
contains a reactive chemical group, e.g., hydroxyl (-OH), amino (-NH2), and carboxyl (-COOH).
Many of these intermediate metabolites do not possess sufficient hydrophilicity to permit
elimination from the body. These metabolites must undergo additional biotransformation as a
Phase II reaction.
Phase II reactions are conjugation reactions, that is, a molecule normally present in the body is
added to the reactive site of the Phase I metabolite. The result is a conjugated metabolite that is
more water-soluble than the original xenobiotic or Phase I metabolite. Usually the Phase II
metabolite is quite hydrophilic and can be readily 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
1. Glucuronide conjugation
Glucuronide conjugation is one of the most important and common Phase II reactions. One of the
most popular molecules added directly to the toxicant or its phase I metabolite is glucuronic acid,
a molecule derived from glucose, a common carbohydrate (sugar) that is the primary source of
energy for cells.
The sites of glucuronidation reactions are substrates having an oxygen, nitrogen, or sulfur bond.
This includes a wide array of xenobiotics as well as endogenous substances, such as bilirubin,
steroid hormones and thyroid hormones. Glucuronidation is a high-capacity pathway for
xenobiotic conjugation.
Glucuronide conjugation usually decreases toxicity, although there are some notable exceptions,
for example, the production of carcinogenic substances. The glucuronide conjugates are
generally quite hydrophilic and are excreted by the kidney or bile, depending on the size of the
conjugate. The glucuronide conjugation of aniline is illustrated below:-

BIOTRRANSFORMATIO
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Glucuronide formattion
H CO2H
HO
OH HO
gluconic acid
ac H
HO O32-
OPO
OH H OH
CO
OOH
H H
OH
HO UTP
OH
OH
O OH
O PPi
OH COOH
H
HO
O OH H CO2H
O
g
glucose
OH
H HO UDP
P
OH HO
O
H
HO H
HO O
H OH
glucuronnic acid OH
H H

BIOTRANSFORMATION
UDP
O
OH O
H CO2H UDP H CO2H OH
COH HO HO C
+
HO HO
HO O HO O
H OH H OH
salicylic acid H H H H
a glucuronide
UDP-glucuronide
derivative
2. Sulfate conjugation
Sulfate conjugation is another important Phase II reaction that occurs with many xenobiotics. In
general, sulfation decreases the toxicity of xenobiotics. Unlike glucuronic acid conjugates that
are often eliminated in the bile, the highly polar sulfate conjugates are 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.
Sulfate ester formation

NH2
HO + N N O
N N O SO
O O
Sulfates are carried as O S O PO O
phosphoadenosine- O
phosphosulfate derivatives O O The enzymes catalyzing
(PAPS) - a high energy form. this type of reaction are
HO O called sulfotransferases.
O P O
O


BIOTRANSFORMATION

Few Examples of other Phase II reactions are listed below:-
1. Methylation
OH OH
HO CHCH2NH2 HO CHCH2NHCH 3 CH 3O CHCH 2NH 2
HO HO HO
norepinephrine epinephrine metanephrine
Hg 2+ CH 3Hg + (CH 3)2Hg

dimethylmercury

2. Amino acid conjugation

OH O OH
+ H2N CH2COH O
COH CNHCH2COH
salicylic acid glycine
O O


BIOTRANSFORMATION

Few Examples of biotransformation reactions are listed below:-

Codeine Morphine
ACTIVE narcotic analgesic ACTIVE (more potent) narcotic analgesic
H N CH3 H N CH3
H H
H3CO O OH O
HO OH
Acetylsalicylic Acid Salicylic acid

ACTIVE analgesic ACTIVE analgesic
CO2H CO2H
OCCH3 OH
O
Methanol Formaldehyde Formic Acid

ACTIVE CNS depressant TOXIC (1 ) TOXIC (1 )
CH3OH HCH HCOH
O O


BIOTRANSFORMATION

Biotransformation Sites
Biotransforming enzymes are widely distributed throughout the body. However, the liver is the
primary biotransforming organ due to its large size and high concentration of biotransforming
enzymes. The kidneys and lungs are next with 10-30% of the liver's capacity. A low capacity
exists in the skin, intestines, testes, and placenta. Since the liver is the primary site for
biotransformation, it is also potentially quite vulnerable to the toxic action of a xenobiotic that is
activated to a more toxic compound.
Within the liver cell, the primary subcellular components that contain the transforming enzymes
are the microsomes (small vesicles) of the endoplasmic reticulum and the soluble fraction of the
cytoplasm (cytosol). The mitochondria, nuclei, and lysosomes contain a small level of
transforming activity.
Microsomal enzymes are associated with most Phase I reactions. Glucuronidation enzymes,
however, are contained in microsomes. Cytosolic enzymes are non-membrane-bound and occur
free within the cytoplasm. They are generally associated with Phase II reactions, although some
oxidation and reduction enzymes are contained in the cytosol. The most important enzyme
system involved in Phase I reactions it the cytochrome P-450 enzyme system. This system is
frequently referred to as the "mixed function oxidase (MFO)” system. It is found in microsomes
and is responsible for oxidation reactions of a wide array of chemicals.
The fact that the liver biotransforms most xenobiotics and that it receive blood directly from the
gastrointestinal tract renders it particularly susceptible to damage by ingested toxicants. Blood
leaving the gastrointestinal tract does not directly flow into the general circulatory system.
Instead, it flows into the liver first via the portal vein. This is known as the "first pass"
phenomena. Blood leaving the liver is eventually distributed to all other areas of the body;
however, much of the absorbed xenobiotic has undergone detoxication or bioactivation. Thus,
the liver may have removed most of the potentially toxic chemical. On the other hand, some
toxic metabolites are in high concentration in the liver.


BIOTRANSFORMATION

Modifiers of Biotransformation
The relative effectiveness of biotransformation depends on several factors, including species,

age, gender, genetic variability, nutrition, disease, exposure to other chemicals that can inhibit or
induce enzymes, and dose levels. Differences in species capability to biotransform specific
chemicals are well known. Such differences are normally the basis for selective toxicity, used to
develop chemicals effective as pesticides but relatively safe in humans. For example, malathion
in mammals is biotransformed by hydrolysis to relatively safe metabolites, but in insects, it is
oxidized to malaoxon, which is lethal to insects.
Safety testing of pharmaceuticals, environmental and occupational substances is conducted with

laboratory animals. Often, differences between animal and human biotransformation are not
known at the time of initial laboratory testing since information is lacking in humans. Humans
have a higher capacity for glutamine conjugation than laboratory rodents. Otherwise, the types of
enzymes and biotransforming reactions are basically comparable. For this reason, determination
of biotransformation of drugs and other chemicals using laboratory animals is an accepted
procedure in safety testing.
1. Age:
Age may affect the efficiency of biotransformation. In general, human fetuses and neonates
(newborns) have limited abilities for xenobiotic biotransformations. This is due to inherent
deficiencies in many, but not all, of the enzymes responsible for catalyzing Phase I and Phase II
biotransformations. While the capacity for biotransformation fluctuates with age in adolescents,
by early adulthood the enzyme activities have essentially stabilized. Biotransformation capability
is also decreased in the aged. Gender may influence the efficiency of biotransformation for
specific xenobiotics. This is usually limited to hormone-related differences in the oxidizing
cytochrome P-450 enzymes.
2. Genetic variability in biotransforming capability :

Genetic variability in biotransforming capability accounts for most of the large variation among
humans. The Phase II acetylation reaction in particular is influenced by genetic differences in
humans. Some persons are rapid and some are slow acetylators. The most serious drug-related
toxicity occurs in the slow acetylators, often referred to as "slow metabolizers". With slow
acetylators, acetylation is so slow that blood or tissue levels of certain drugs (or Phase I
metabolites) exceeds their toxic threshold.

BIOTRANSFORMATION

Examples of drugs that build up to toxic levels in slow metabolizers that have specific genetic-
related defects in biotransforming enzymes are listed below:
3. Poor nutrition:
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 can impair an individual's capacity
to biotransform xenobiotics. A good example, is hepatitis (a liver disease), which is well known
to reduce hepatic biotransformation to less than half normal capacity.
4. Enzyme inhibition and enzyme induction:

Enzyme inhibition and enzyme induction can be caused by prior or simultaneous exposure to
xenobiotics. In some situations exposure to a substance will inhibit the biotransformation
capacity for another chemical due to inhibition of specific enzymes. A major mechanism for the
inhibition is competition between the two substances for the available oxidizing or conjugating
enzymes is the presence of one substance uses up the enzyme that is needed to metabolize the
second substance.
Enzyme induction is a situation where prior exposure to certain environmental chemicals and
drugs results in an enhanced capability for biotransforming a xenobiotic. The prior exposures
stimulate the body to increase the production of some enzymes. This increased level of enzyme
activity results in increased biotransformation of a chemical subsequently absorbed. Examples of
enzyme inducers are alcohol, isoniazid, polycyclic halogenated aromatic hydrocarbons (e.g.,
dioxin), phenobarbital, and cigarette smoke. The most commonly induced enzyme reactions
involve the cytochrome P-450 enzymes.

BIOTRANSFORMATION

5. Dose level:
Dose level can affect the nature of the biotransformation. In certain situations, the
biotransformation may be quite different at high doses versus that seen at low dose levels. This
contributes to the existence of a dose threshold for toxicity. The mechanism that causes this
dose-related difference in biotransformation usually can be explained by the existence of
different biotransformation pathways. At low doses, a xenobiotic may follow a biotransformation
pathway that detoxifies the substance. However, if the amount 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 different
biotransformation pathway that may result in the production of a toxic metabolite.
An example of a dose-related difference in biotransformation occurs with acetaminophen. At

normal doses, approximately 96% of acetaminophen is biotransformed to non-toxic metabolites
by sulfate and glucuronide conjugation. At the normal dose, about 4% of the acetaminophen is
oxidized to a toxic metabolite; however, that toxic metabolite is conjugated with glutathione and
excreted. With 7-10 times the recommended therapeutic level, the sulphate and glucuronide
conjugation pathways become saturated and more of the toxic metabolite is formed. In addition,
the glutathione in the liver may also be depleted so that the toxic metabolite is not detoxified and
eliminated. It can react with liver proteins and cause fatal liver damage.
References:
1. National Library of Medicine; Emily Monosson ; 2008 "Biotransformation”.

2. Encyclopedia of Earth; Eds. Cutler J. Cleveland, Washington, D.C.: Environmental
Information Coalition,
3. National Council for Science and the
Environment<http://www.eoearth.org/article/Biotransformation>
4. Diaz E (editor). (2008). Microbial Biodegradation: Genomics and Molecular Biology (1st ed.
ed.). Caister Academic Press. ISBN 978-1-904455-17-2. http://www.horizonpress.com/biod.
5. www. wikipedia, the free encyclopedia.

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BIOTRANSFORMATION

Dr. Dharma Prasad Khanal

Most biootransforming g enzymes are

Fig 1: enzyme subbstrate fit or incompatiblle.

Phase I biotransformation reactions are simple reactions as compared to Phase II reactions. In

Toxicantts that have undergone Phase

The princcipal reactio

The primary Phase II reactions are:

Sulfate ester formation

HO CHCH2NH2 HO CHCH2NHCH 3 CH 3O CHCH 2NH 2

Hg 2+ CH 3Hg + (CH 3)2Hg

Acetylsalicylic Acid Salicylic acid

Methanol Formaldehyde Formic Acid

CH3OH HCH HCOH

The relative effectiveness of biotransformation depends on several factors, including species,

Safety testing of pharmaceuticals, environmental and occupational substances is conducted with

2. Genetic variability in biotransforming capability :

4. Enzyme inhibition and enzyme induction:

An example of a dose-related difference in biotransformation occurs with acetaminophen. At

1. National Library of Medicine; Emily Monosson ; 2008 "Biotransformation”.

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