Lecture Notes on Biotransformation

Introduction

• Biotransformation is a continuation from the previous topic on absorption, distribution, and elimination (ADE).
• Chemical properties of xenobiotics influence absorption.
  • Lipophilic xenobiotics are more easily absorbed.
• Biotransformation is part of the elimination route.
• Humans are constantly exposed to xenobiotics (drugs, industrial chemicals, pollutants, etc.).

Importance of Biotransformation

• Necessary for eliminating fat-soluble xenobiotics.
• Prevents accumulation and toxicity in the body.
• Allows humans to live longer by eliminating toxic compounds.

Biotransformation Process

• Phase 1 and Phase 2
  • Phase 1: Metabolic transformation via oxidation, reduction, or hydrolysis.
    • Can result in bioactivation (more toxic) or detoxification (less toxic).
  • Phase 2: Conjugation process, usually detoxification.
    • Adds large polar molecules to increase solubility.

Factors Affecting Biotransformation

• Age, sex, nutritional status, existing disease, genetic variability.

Steps in Biotransformation

• Phase 1 Biotransformation

  • Involves oxidation, reduction, hydrolysis.
  • Produces polar metabolites, adds a 'handle' for Phase 2.
  • Enzymes: Cytochrome P450 (CYP) is vital.
  • Can result in either bioactivation or detoxification.

• Phase 2 Biotransformation

  • Conjugation: Adds bulky, water-soluble groups.
  • Generally results in detoxification.
  • Involves enzymes like transferases.

Example: Benzene

• Benzene is a probable carcinogen, not initially toxic.
• Different pathways lead to different metabolites.
  • Safe elimination routes and pathways leading to toxicity.

Enzymes and Biotransformation

• Enzymes catalyze reactions, modifying substrates (xenobiotics).
• Biological catalysts; specific to substrates (lock & key model).
• Enzymes like Cytochrome P450 catalyze both Phase 1 and Phase 2 reactions.

Enzyme Induction and Inhibition

• Induction: Increase in enzyme concentration due to exposure, e.g., alcohol increases alcohol dehydrogenase.
• Inhibition: Some chemicals inhibit enzyme activity, e.g., grapefruit affects drug metabolism.

Phase 1 Reaction Types

• Oxidation: Adds oxygen or removes hydrogen.
• Hydrolysis: Addition of water; breaks bonds.
• Reduction: Adds hydrogen, reveals functional groups.

Phase 2 Reaction Types

• Conjugation reactions add groups like glucuronide, sulfate, glutathione, and amino acids to increase solubility.

Summary

• Biotransformation involves multiple steps and enzymes.
• Purpose is to increase xenobiotic solubility for excretion.
• Understanding pathways helps predict drug interactions and toxicity.

Diagram Summary: Biotransformation Pathways

• Multiple pathways exist depending on solubility and enzymatic action.
• Water-soluble xenobiotics can be eliminated directly.
• Lipophilic xenobiotics require biotransformation to hydrophilic forms for excretion.