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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
BIOTRANSFORMATION
Purpose
Converts lipophilic to hydrophilic compounds Facilitates excretion
Consequences
Changes in PK characteristics Detoxification Metabolic activation
Biotransformation of Xenobiotics
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
still lipophilic possibly reactive poorly water soluble poorly excretable catalyzed by P450s
not lipophilic usually not reactive water soluble products excretable catalyzed by transferases
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
References
http://en.wikipedia.org/wiki/Xenobiotic_metabolism Textbook of Biochemistry DM Vasudevan and Sreekumari s
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