Metabolism of Xenobiotics Introduction

Metabolism of Xenobiotics

• Xenobiotics are foreign compounds like drugs, pollutants, food additives, cosmetics, pesticides, etc. that enter the body accidentally or intentionally.
• These compounds may be absorbed from the GI tract and enter the organs and tissues of the body, and thus need to be removed quickly.

Detoxification (Biotransformation)

• Detoxification is the process of converting foreign, toxic, and water-insoluble molecules into non-toxic, water-soluble, and excretable forms.
• The purpose of detoxification is to increase the water solubility (polarity) and thus facilitate excretion from the body.
• However, in some cases, detoxification reactions may increase the toxicity of a foreign compound, which is called entoxification.

Medical Importance of Detoxification

• Detoxification reduces the level of toxins in the body, protecting the body and its organs from deleterious effects of toxins.
• Reducing toxin levels in the body reduces the strain on the immune system.
• Detoxification removes most of the drugs consumed from the body.

Methanol Toxicity

• The metabolism of formic acid is slow, leading to accumulation in the body, which results in metabolic acidosis.
• The major damage occurs to the optic nerve.
• Ethanol is given as an antidote, as it is a substrate of ADH, which spares methanol.

Oxidation of Xenobiotics

• Aldehydes are oxidized to corresponding acids.
• Oxidation of aromatic hydrocarbons forms phenolic compounds, which can further conjugate with glucuronic acid (or) sulfuric acid in phase II reactions.
• Primary aliphatic amines undergo oxidation to form the corresponding acids and nitrogen is converted to urea.
• Anilids are oxidized to corresponding phenols.
• Sulfur compounds: Organic sulfur is oxidized to sulfuric acid.

Oxidation (Entoxification)

• Oxidation of certain compounds may result in the production of more toxic compounds (entoxification).
• Halogenated alcohols are oxidized to halogenated acids.
• Ethylene glycol is oxidized to oxalic acid.

Cytochrome P450

• Most oxidation reactions of detoxification are catalyzed by monooxygenase (or) cytochrome P450.
• Cytochrome P450 is a hemoprotein, exhibiting broad substrate specificity and versatility as a catalyst.
• It is located in the smooth ER of the liver and other tissues.
• It is a NADPH-dependent enzyme, and the products of some reactions may be mutagenic or carcinogenic.
• It is an inducible enzyme, and its synthesis is increased by administration of drugs such as phenobarbitol.

Reduction

• Reduction is less common and less important than oxidation in human beings.
• Examples of reduction reactions include the reduction of aldehydes and nitro compounds.

Hydroxylation

• Detoxification of a number of drugs and steroids occurs by hydroxylation.
• These reactions are catalyzed by cytochrome P450-dependent monooxygenases.

Hydrolysis

• Certain therapeutic compounds undergo hydrolysis, including ester, glycoside, and amide bonds.
• Examples of compounds undergoing hydrolysis include aromatic acids, phenols, secondary and tertiary aliphatic alcohols, antibiotics, hormones, and carcinogens.

Conjugation with Bilirubin

• Most of the bilirubin excreted in the bile is in the form of bilirubin diglucuronide.
• Bilirubin-UGT activity can be induced by certain drugs, which increases the formation of glucuronide.

Sulfation

• Compounds conjugated with sulfate include phenols, cresols, indole, steroids, oestrogen, and androgen.
• The active form of sulfate is 3’phosphoadenosine 5’phosphosulfate (PAPS), which is involved in conjugation reactions catalyzed by sulfotransferase.

Acetylation

• Compounds conjugated with acetic acid include sulphanilamide, PABA, and isoniazid.
• Acetyl coA is the active form of acetic acid, and the reactions are catalyzed by acetyl transferase in the cytosol of various tissues, particularly the liver.