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Lecture 13. Xenobiotics Phases and Mechanisms of Biotransformation, The Role of Cytochrome P450

This document provides an overview of xenobiotic metabolism. It discusses that xenobiotics undergo two phase biotransformation primarily in the liver. Phase I involves reactions like hydroxylation catalyzed by cytochrome P450 enzymes. Phase II involves conjugating phase I products with molecules like glucuronic acid, sulfate, glutathione, or amino acids to make them more polar and excretable. Key enzymes and reactions of each phase are described in detail. The document emphasizes the important role of the liver and phase I/II enzymes in the metabolic detoxification of exogenous and endogenous compounds.

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Віталій Михайлович Нечипорук
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25 views15 pages

Lecture 13. Xenobiotics Phases and Mechanisms of Biotransformation, The Role of Cytochrome P450

This document provides an overview of xenobiotic metabolism. It discusses that xenobiotics undergo two phase biotransformation primarily in the liver. Phase I involves reactions like hydroxylation catalyzed by cytochrome P450 enzymes. Phase II involves conjugating phase I products with molecules like glucuronic acid, sulfate, glutathione, or amino acids to make them more polar and excretable. Key enzymes and reactions of each phase are described in detail. The document emphasizes the important role of the liver and phase I/II enzymes in the metabolic detoxification of exogenous and endogenous compounds.

Uploaded by

Віталій Михайлович Нечипорук
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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National Pirogov Memorial Medical University, Vinnytsya

Department of Biochemistry and General chemistry

Lecture № 13

Topic: «Xenobiotics: phases and mechanisms


of biotransformation, the role of cytochrome
P450. Ethanol metabolism»

Prepared:
Associate Professor Filchukov Denis
Lecture plan:
1. The concept of xenobiotics and general patterns of their metabolism.
2. Structure and functions of microsomal electronic transport chains.
3. Phase I biotransformation of xenobiotics.
4. The phenomenon of induction of xenobiotic metabolism enzymes and its biomedical
significance. The concept of metabolic activation of xenobiotics and its consequences for
the body.
5. Phase II biotransformation of xenobiotics and endogenous metabolites.
6. The concept of phase III metabolism of xenobiotics and its biological significance.
7. Metabolism of ethanol and the mechanism of its toxic action. Synthesis and biological
role of endogenous ethanol.
Literature :
Basic
1. Chatterjea M.N., Shinde Rana. Textbook of Medical Biochemistry. – Jaypee Brothers
Medical publishers (P) LTD, 2012. 876 c.
2. Gubsky Yu. Biological chemistry. – Vinnytsia: Nova Knyha. – 2016. – 512 p.
3. Satyanarayana U., Chakrapani U. Biochemistry (Third Ed.). Arunabha Sen BOOKS
AND ALLIED (P) Ltd, 2013. 799 p.

Additionally
4. Harper’s Illustrated Biochemistry / V.W. Rodwell, D.A. Bender, K.M. Botham et al. –
Mc Graw Hill Edu- cation, 2015. – 817 p.
Role of the liver in detoxification processes.
A xenobiotics is a compound that is foreign to the body. The
principal classes of xenobiotics of medical relevance are
drugs, chemical cancerogens, and various compounds that
have found their way into our environment by one route or
another (insecticides, herbicides, pesticides, food additions,
cosmetics, domestic chemical substances).
Some internal substances also have toxic properties (for
example, bilirubin, free ammonia, bioactive amines,
products of amino acids decay in the intestine).
Moreover, all hormones and mediatores must be
inactivated.
Reactions of detoxification take place in the liver.
Big molecules like bilirubin excreted with the bile to intestine
and leaded out with feces. Small molecules go to the blood
and excreted via kidney with urine.
General ways of xenobiotics biotransformation and their localization in cell
REACTION ENZYME LOCALIZATION

PHASE I
Hydrolysis Esterase Peptidase Microsomes, cytosol, lysosomes, blood
Epoxide hydrolase lysosomes
Microsomes, cytosol

Azo- and nitro-reduction Microflora, microsomes, cytosol


Reduction Carbonyl reduction Cytosol, blood, microsomes
Disulfide reduction Cytosol
Sulfoxide reduction Cytosol

Oxidation Alcohol dehydrogenase Cytosol Mitochondria,


Aldehyde dehydrogenase cytosol Cytosol
Aldehyde oxidase Xanthine Cytosol
oxidase Monoamine
oxidase Diamine oxidase Mitochondria
Flavin-monooxygenases Cytosol
Cytochrome P450 Microsomes
Microsomes

PHASE II
Glucuronide conjugation Microsomes
Sulfate conjugation Cytosol, microsomes
Glutathione conjugation Cytosol
Amino acid conjugation Mitochondria, cytosol
Acetylation Mitochondria, microsomes
Methylation Cytosol, microsomes, blood
The metabolism of xenobiotics has 2 phases:
In phase 1, the major reaction involved is
hydroxylation, catalyzed by members of a class of
enzymes referred to as monooxygenases or
cytochrome P-450 species. These enzymes can also
catalyze deamination, dehalogenation, desulfuration,
epoxidation, peroxidation and reduction reaction.
Hydrolysis reactions and non-P-450-catalyzed
reactions also occur in phase 2.
Cytochrom P450
The highest concentration – in endoplasmic reticulum of
hepatocytes (microsomes).

Hem containing protein.

Catalyzes monooxigenation of oxygen atom into substrate;


another oxygen atom is reduced to water

Electrons are transferred from NADPH to


cytochrome P450 through flavoprotein NADPH-
cytochrome P450 reductase.
In phase 2, the hydroxylated or other compounds
produced in phase 1 are converted by specific enzymes
to various polar metabolites by conjugation with
glucuronic acid, sulfate, acetate, glutathione, or certain
amino acids, or by methylation.
In certain cases, phase 1 metabolic reaction convert
xenobiotics from inactive to biologically active
compounds. In these instances, the original xenobiotics
are referred to as prodrugs or procarcinogens. In other
cases, additional phase 1 reactions convert the active
compounds to less active or inactive forms prior to
conjugation. In yet other cases, it is the conjugation
reactions themselves that convert the active product of
phase 1 to less active or inactive species, which are
subsequently excreted in the urine or bile. In a very few
cases, conjugation may actually increase the biologic
activity of a xenobiotics.
There are at least 5 types of phase 2 reactions:
1. Glucuronidation. UDP-glucuronic acid is the
glucuronyl donor, and a variety of glucuronyl
transferases, present in both the ER and cytosol, are
the catalysts. Molecules such as bilirubin, thyroxin, 2-
acetylaminofluorene (a carcinogen), aniline, benzoic
acid, meprobromate (a tranquilizer), phenol, crezol,
indol and skatol, and many steroids are excreted as
glucuronides. The glucuronide may be attached to
oxygen, nitrogen, or sulfur groups of substrates.
2. Sulfation. Some alcohols, arylamines, and phenols are
sulfated. The sulfate donor in these and other biologic
sulfation reactions is adenosine 3´- phosphate-5´-
phosphosulfate (PAPS); this compound is called active
sulfate
3. Conjugation with Glutathione. Glutathione (γ-
glutamylcysteinylglycine) is a tripeptide consisting of
glutamic acid, cysteine, and glycine. Glutathione is
commonly abbreviated to GSH; the SH indicates the
sulfhydryl group of its cysteine and is the business part
of the molecule. A number of potentially toxic
electrophilic xenobiotics (such as certain carcinogens)
are conjugated to the nucleophilic GSH. The enzymes
catalyzing these reactions are called glutathione S-
transferases and are present in high amounts in liver
cytosol and in lower amounts in other tissues.
Acetylation. These reactions is represented by X + Acetyl- CoA
→ Acetyl-X + CoA, where X represents a xenobiotic. These
reactions are catalyzed by acetyltransferases present in the cytosol
of various tissues, particularly liver. The different aromatic
amines, aromatic amino acids, such drug as isoniazid, used in the
treatment of tuberculosis, and sulfanylamides are subjects to
acetylation. Polymorphic types of acetyltransferases exist,
resulting in individuals who are classified as slow or fast
acetylators, and influence the rate of clearance of drugs such as
isoniazid from blood.
5. Methylation. A few xenobiotics (amines, phenol, tio- substances,
inorganic compounds of sulphur, selen, mercury, arsenic) are
subject to methylation by methyltransferases, employing S-
adenosylmethionine as methyl donor. Also catecholamines and
nicotinic acid amid (active form of vitamin PP) are inactivated due
to methylation.
Very important way of detoxification is ureogenes (urea
synthesis). Free ammonia, which formed due to metabolism of
amino acids, amides and amines, removed from organism in shape
of urea.

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