XENOBIOTICS: BIOTRANSFORMATION AND DETOXIFICATION

BY: HEDIEH TAZEROUNI 2010PH05 ZOYA ALI 2010PH06

INTRODUCTION
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. 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

Xenobiotics : Principle classes

Drugs : antibiotics, antipyretics/analgesics, supplements, cardiac drugs, etc. Carcinogens: food, dyes, preservatives, nitrosamines, alcohol, artificial sweeteners, etc. Environmental Chemicals/Pollutants: 200,000 manufactured environmental chemicals/pollutants in existence.

BIOTRANSFORMATION
Purpose
Converts lipophilic to hydrophilic compounds Facilitates excretion

Consequences
Changes in PK characteristics Detoxification Metabolic activation

Biotransformation of Xenobiotics

Biological basis for xenobiotic metabolism:

To convert lipid-soluble, non-polar, non-excretable forms of chemicals to water-soluble, polar forms that are excretable in bile and urine. Biotransformation is not exactly synoynms with detoxification, since in many cases, the metabolites are more toxic than the parent substance. This is known as Bioactivation or toxication. Eg: vinyl chloride to vinyl chloride epoxide.

Biotransformation of Xenobiotics

Biotransformation Reactions
Phase I Reactions Enzymatic reactions that add or expose functional groups to xenobiotics such as -OH, -SH, -NH2 or COOH Functional groups are analogous to having a trailer hitch on a vehicle

Biotransformation Reactions
Phase II Reactions Enzymatic reactions that result in the conjugation of large water-soluble, charged (polar)biomolecules to xenobiotics For these reactions to occur, a functional group must be present on either the parent compound or its Phase I product

The Truck-Hitch-Trailer Analogy to Xenobiotic Biotransformation

Foreign Chemical (xenobiotic) Phase 1 enzymes add or expose a functional group Phase 2 enzymes conjugate (transfer) endogenous molecules* to the functional group

lipophilic not charged not water soluble poorly excretable

still lipophilic possibly reactive poorly water soluble poorly excretable catalyzed by P450s

not lipophilic usually not reactive water soluble products excretable catalyzed by transferases

Biotransformation Reactions : Phase I Exposing a Functional Group on the Starting Compound

Biotransformation Reactions: Phase I and Phase II - Adding a Functional Group

Drug metabolizing enzymes

Cytochrome P450 (CYP 450) is the major drug metabolizing enzyme system in the body. Comprised of multiple proteins. Active site or core of the enzyme system is a heme protein Also known as mixed function mono oxygenases

 Substrate specificity is very low Varied drugs, chemicals are metabolised by the CYP 450 enzyme system. Powerful oxidising property Lipid solubility is important for substrate. Attributes Enzyme Induction Enzyme Inhibition Genetic Polymorphism

DETOXIFICATION
These Xenobiotics must be metabolized and should be excreted, if they stay longer time they damage the cells.

Phases of detoxification
Phase I Modification Phase II Conjugation Phase III Further Modification and Excretion

Phase I : Modification
In phase I, a variety of enzymes acts to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixedfunction oxidase system These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates.

Phase II : Conjugation
In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. These reactions are catalysed by a large group of broadspecificity transferases. One of the most important of these groups are the glutathione S-transferases (GSTs). The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported

Phase III : Modification and Excretion

After phase II reactions, the xenobiotic conjugates may be further metabolised Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the multidrug resistance protein (MRP) family. These proteins act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted.

References
http://en.wikipedia.org/wiki/Xenobiotic_metabolism Textbook of Biochemistry DM Vasudevan and Sreekumari s

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