bio transformation bibek singh mahat rn07

8/7/2019 Bio Transformation Bibek Singh Mahat RN07

1/20

BIOTRANSFORMATION

Page1of20. Preparedandsubmittedby:BibekSinghMahat,RollNo.07,M.Pharm.(Industrial),May2010

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


2/20

BIOTRANSFORMATION


TABLEOFCONTENTS:

1. Introduction

a) Xenobiotics

b) Chemical Reactions

c) Categorization of the Biotransformation reactions

2. Phase I Reactionsa) 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) Ageb) Genetic variability in biotransforming capability

c) Poor nutrition

d) Enzyme inhibition and enzyme induction

e) Dose level

6. References


3/20

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 sometimesnot 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 aswell 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.


4/20

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 itselfundergoing 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 areroutinely 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.


5/20

Page5of20.

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7/20

Page7of20.

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8/20

BIOTRANSFORMATION


PhaseIReactions

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


9/20

Page9of20.

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10/20

Page10of2

Toxicant

sufficien

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more eff

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11/20

Page11of2

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12/20

BIOTRANSFORMATION


PhaseIIReactions

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 permitelimination 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 themost 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:-


13/20

Page13of2

Glucuro

.

nide forma

O

OH

O

OH

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Prepared

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H

H

H

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32-


14/20

BIOTRANSFORMATION


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

OH

COH

O

salicylic acid

+

a glucuronidederivative

O

H

HO

H

HO

H

H

OHHO

CO2H UDP

UDP-glucuronide

UDP

O

H

HO

H

HO

H

H

OHHO

CO2H

C

OOH

HO N

N N

N

NH2

O

SO

OHO

POOS

OO

OO

O

P OO

O

O

O

O

The enzymes catalyzing

this type of reaction are

called sulfotransferases.

Sulfates are carried as

phosphoadenosine-

phosphosulfate derivatives

(PAPS) - a high energy form.

+


15/20

BIOTRANSFORMATION


Few Examples of other Phase II reactions are listed below:-

1.Methylation

2.Amino acid conjugation

OH

COH

H2N CH2COH

O

O OH

CNHCH2COH

O

O

salicylic acid

+

glycine

HO

HO

CHCH2NH2

OH

HO

HO

CHCH2NHCH3 CH3O

HO

CHCH2NH2

OH

dimethylmercury

(CH3)2HgCH3Hg+Hg2+

metanephrineepinephrinenorepinephrine


16/20

BIOTRANSFORMATION


Few Examples of biotransformation reactions are listed below:-

ACTIVE(more potent)ACTIVE narcotic analgesicnarcotic analgesicMorphineCodeine

OH3CO OH

H

H N CH3

OHO OH

H

H N CH3

ACTIVE analgesicanalgesic

Salicylic acidAcetylsalicylic Acid

ACTIVE

OCCH3

CO2H

O

OH

CO2H

ACTIVE TOXICTOXICCNS depressantFormic AcidFormaldehydeMethanol

() ()

CH3OH HCH

O

HCOH

O


17/20

BIOTRANSFORMATION


BiotransformationSites

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 capacityexists 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.


18/20

BIOTRANSFORMATION


ModifiersofBiotransformation

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 specificchemicals 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 ofenzymes 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 capabilityaccounts 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 slowacetylators, acetylation is so slow that blood or tissue levels of certain drugs (or Phase I

metabolites) 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:

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.


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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 ofdifferent 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

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.

bio transformation bibek singh mahat rn07

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