Xenobiotic Metabolism Overview

Xenobiotic Metabolism

• Xenobiotic metabolism is the breakdown of foreign substances in the body.
• Detoxification is a common goal but not always successful.
• Some metabolites become more reactive, increasing potential harm.

Outline of Xenobiotic Metabolism

• Introduction to xenobiotics and biotransformation
• Absorption of xenobiotics (passive diffusion, facilitated diffusion, and active transport)
• Distribution of xenobiotics (binding to proteins, storage in various tissues)
• Biotransformation (metabolism) processes (two phases)
• Excretion (biliary, renal, respiration, sweat)

Terminology

• Xenobiotic: foreign substance in the body
• Detoxification: process of eliminating or reducing the toxicity of xenobiotics, sometimes not always correct
• Metabolites: product of metabolic reactions on xenobiotics. These can be active or inert
• Prodrugs: inactive compounds that are converted into active drugs by the body
• Procarcinogens: inactive compounds that can become carcinogens in the body

Xenobiotics

• Chemicals entering the body through various routes (GI tract, lungs, skin, mucosa)
• Include compounds from foods, medicines, environmental pollutants, household chemicals, cosmetics and agricultural chemicals, and bacterial compounds.

Aim of Biotransformation

• Transform toxic, foreign compounds into less toxic metabolites.
• Make metabolites more water-soluble to facilitate excretion.
• More than 200,000 manufactured/ environmental chemicals exist.

Drug Introduction Methods

• Enteral (oral): ingested
• Parenteral: other than oral
  • Intravenous injection
  • Intramuscular injection
  • Subcutaneous injection
  • Inhalation
  • Skin/mucosa contact

Four Stages of Drugs in the Body

• Absorption
• Distribution
• Metabolism
• Excretion

Absorption

• Drugs and chemicals are absorbed from the digestive tract.
  • Passive diffusion (major route)
  • Facilitated diffusion
  • Active transport
• Hydrophobic compounds penetrate cell membranes more easily than charged/hydrophilic compounds. Charged compounds need transporters. Acidic drugs absorb in the stomach, while basic drugs absorb in the intestines

Distribution

• Drugs/chemicals in the blood bind to albumin and are transported.
• These drug-protein complexes dissociate.
• The free drug enters cells.
• Examples of storage locations for specific drugs:
  • Tetracyclines: bones, teeth
  • Thiopental: adipose tissue
  • Iodine: thyroid gland
• Fat-soluble drugs can cross the blood-brain barrier
• Liver: main site of biotransformation

Metabolism (Biotransformation)

• Transformations of active to inactive drugs or vice versa.
  • Converts inactive to active drugs.
  • Converts active to inactive drugs.
  • Converts one active drug to another active drug.
  • Converts less toxic drugs to more toxic metabolites.
  • Examples of drug reactions:
    • Codeine → Morphine
    • Diazepam → Oxazepam
    • Isoniazid (used in TB treatment) → metabolites due to acetylation + pyridoxine deficiency

Xenobiotic Metabolism (2 phases)

• Phase 1: chemical modification
• Phase 2: conjugation (after phase 1)
• Leads to excretion

Phase 1

• Chemical modification: Increases reactivity to facilitate conjugation (attaching of polar groups to make the substance more water soluble).
• Adding reactive groups (-OH) via conjugation with amino acids, glucuronic acid, sulfate, acetate, etc.
  • Products are more water-soluble and able to be excreted in urine or bile.
• Very hydrophobic xenobiotics will stay in adipose tissue if not converted to more polar forms. Reactions include hydroxylation, deamination, dehalogenation, desulfuration, epoxidation, peroxygenation, and reduction. Hydrolysis is catalyzed by enzymes such as esterases.

Phase 1 Reactions: Oxidation

• Addition of polar and reactive groups.
• Non-microsomal oxidation: occurs in cytoplasm and mitochondria. Examples include monoamine oxidases, alcohol dehydrogenase, and aldehyde dehydrogenase.
• Microsomal oxidation: takes place in smooth endoplasmic reticulum, most often using cytochrome P450 enzymes.
  • One oxygen atom is incorporated into the xenobiotic, and the other reduces to produce water
  • Cytochrome P450 involves multiple forms (CYP1, CYP2, CYP3)
    • Substrate specificity varies among CYP isoforms
    • ~50% of common drugs are metabolized using cytochrome P450.
    • CYP isoforms are important for steroid hormones, vitamin D, carcinogens, and pollutants.

Phase 1 Reactions: Other

• Hydroxylaiton: aromatic, aliphatic, alicyclic, heterocyclic
• N-, S-, O-dealkylation
• Deamination
• Epoxidation Following aromatic hydroxylation. Epoxides are important because they react with cellular constituents.

Phase 2 Reactions

• Conjugation reactions: attach polar groups to the xenobiotic
• Add endogenous polar groups to the products of phase 1 reactions.
• Products become more water-soluble and more readily excreted from the body.

Phase 2 Reactions: Specific Conjugation Types

• Glucuronidation: Transfer of glucuronic acid from UDPGA to xenobiotics.
  • UDP-glucuronosyl transferase catalyzes reaction in ER.
  • This reaction exists in several forms with varying substrate specificity.
• Sulfate conjugation: Adding sulfate groups from PAPS to xenobiotics.
  • Sulphotransferases catalyze reaction.
  • Found in the cytosol of liver and GI mucosa.
• Glutathione conjugation: Combining glutathione with xenobiotics via nucleophilic cysteine in a glutathione S-transferase reaction
  • GSH is a tripeptide.
• Acetylation: Adding acetyl group from acetyl-CoA.
  • Substrate specificity varies among isoforms.
• Methylation: Adding methyl groups using S-adenosylmethionine as methyl donor.
  • Catalyzed by methyltransferases in the cytosol and ER.

Excretion

• Biliary excretion: Glucuronides, sulfates, GSH derivatives secreted into the bile (can undergo enterohepatic cycling in part).
• Renal excretion: excreted in the urine.
• Respiration (exhalation): Volatile substances can be exhaled.
• Sweat: Some substances can be excreted through sweat.

Clinical Implications

• Drug interactions can occur when one drug affects the metabolism of another drug via the CYP450 system.
• Warfarin (anticoagulant) metabolism can be influenced by prior phenobarbital exposure resulting in an increase of warfarin metabolism altering its effectiveness if dosage is not adjusted.

Explore the complex processes involved in xenobiotic metabolism, including absorption, distribution, biotransformation, and excretion. Learn about key terminology such as xenobiotics, detoxification, and metabolites. Understand the implications of these processes on drug efficacy and potential toxicity.