xenobiotics

• A xenobiotic is a compound that is foreign to the body
• may be accidentally ingested or taken as drugs or compounds produced in the body by bacterial metabolism (Greek, xenos = strange).
• They are  metabolized,  a process called  biotransformation(detoxification).
• Metabolism  of  xenobiotics  in  two  phases (phase I and phase II).
• The cytochrome P450 enzymes are involved in the biotransformation reactions, the most important  enzyme present on smooth endoplasmic reticullum.
• They are heme containing enzymes, localized in the endoplasmic reticulum of liver.
• so, Liver  is  the  major site  for  metabolism  of xenobiotics.
• Cytochrome P450 contains phosphatidyl choline.
• Phase one is the alteration of the foreign molecule, so as to add a functional group.
• The products of metabolic transformations are either excreted directly or undergo further meta-bolism by phase two reactions.

Phase |  (non-synthetic)  reactions

1. Oxidative Reactions:

• metabolism of compounds by oxidation (including hydroxylation), reduction, hydrolysis, cyclization and decyclization.
• The oxidation and detoxification of alcohol is also an important function of the liver.
• the alcohol dehydrogenase is an NAD linked enzyme, which is located in the cytosol. Aldehyde dehydrogenase is an NAD⁺dependent mitochondrial enzyme.

2. Reduction Reactions: 

• compounds which are reduced and detoxified by the liver are nitro compounds, These are reduced to their amines, while aldehydes or ketones are reduced to alcohols.

3. Hydrolysis:

• addition of water splits the toxicant into two fragments or smaller molecules., 
• Esters, amines,hydrazines, amides, glycosidic bonds and carba-mates are generally biotransformed by hydrolysis.

PHASE TWO REACTIONS; CONJUGATIONS:

• a new metabolite from phase 1  contains a reactive chemical group, e.g. hydroxyl (-OH),amino (-NH2), and carboxyl (-COOH).
• Glucuronide conjugation is the most common Phase two reactions. Bilirubin is a good example for a compound conjugated and excreted as its glucuronide.
• Formation of bilirubin diglucuronide is a normal metabolic reaction for detoxification of bilirubin by phase 2 reactions.
• The glucuronic acid is added to xenobiotics by UDP-glucuronyl transferases, present in the endo-plasmic reticulum.
• sulfation decreases the toxicity of xenobiotics, for eg Phenolic and alcoholic compounds are conju-gated with sulfate.(steroids and indole compounds.)
• cysteine is derived from glutathione, which is the active conjugating agent,
• For example, catechol-O-methyl transferase converts epinephrine to metanephrine. Pyridine is excreted as N-methyl pyridine.
• Mercapto ethanol is excreted as 5-methyl mercapto ethanol.

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