BIOL 4370_5370 Chapter 6

BIOTRANSFORMATION OF XENOBIOTICS

• Presenter: Amie K. Lund, Ph.D.

• Course: BIOL 4370/5370 - Chapter 6

Definition of Biotransformation

• Biotransformation: The metabolic conversion of chemicals (both endogenous and xenobiotic) to more water-soluble compounds for easier excretion from the body.

• Mechanism: Involves various enzymes, both constitutive and those induced by xenobiotics.

  • Key Reaction Types:

    • Hydrolysis

    • Reduction

    • Oxidation

    • Conjugation (e.g., glucuronidation, sulfonation, methylation)

Location of Biotransformation Enzymes

• Enzymes are distributed across various tissues and subcellular compartments, predominantly located in the liver, with additional presence in:

  • Skin

  • Lung

  • Nasal mucosa

  • Kidney

  • Eye

  • GI tract

• Inside the Cell: Primarily found in the endoplasmic reticulum (E.R.), with some in cytoplasm, mitochondria, nuclei, and lysosomes.

Phases of Biotransformation

Phase I Reactions

• Reactions that introduce or unmask a polar group to increase water solubility of the xenobiotic for excretion.

Phase II Reactions

• Involves covalent attachment of small polar endogenous molecules to form water-soluble compounds to facilitate excretion.

Solubility of Compounds

• Examples of compounds classified by water solubility:

  • Alkene: Not soluble

  • Aldehyde: Somewhat soluble

  • Alcohol: Soluble

  • Amine: Soluble

  • Carboxylic Acid: Soluble

• Structure-related properties dictate solubility levels and transformation reactions.

Phase I Reaction Mechanisms

• Types of Reactions Include:

  • Hydrolysis: Conversion of xenobiotics; involves various enzymes located throughout the body (e.g., carboxylesterase).

  • Reduction: Often involves the reduction of certain metals, aldehydes, and other oxidized forms.

  • Oxidation:

    • Managed primarily by Cytochrome P450 (CYP) enzymes located mainly in the liver's E.R.

    • Catalyzes monooxygenation and other oxidation reactions using NADPH.

Specific Enzymatic Activities (Oxidation)

• Key Enzymes:

  • Alcohol dehydrogenase (ADH)

  • Aldehyde dehydrogenase

  • Dihydrodiol dehydrogenase

  • Xanthine oxidase

  • Flavin monooxygenase (FMO)

• These enzymes play crucial roles in the transformation and detoxification of xenobiotics.

Phase II Reaction Mechanisms

• Conjugation Reactions: Involve covalent attachment of functional groups to xenobiotics to improve hydrophilicity and excretion. Key pathways include:

  • Glucuronidation (using UDP-glucuronic acid)

  • Sulfonation (using PAPS)

  • Acetylation (using acetyl coenzyme A)

  • Methylation (using S-adenosylmethionine)

• Most conjugation reactions are facilitated by transferase enzymes.

Phase II Conjugation Examples

• Glucuronidation: Endogenous substrates include hormones and bilirubin.

• Sulfonation: Transfer of sulfates from PAPS to xenobiotics with -OH groups.

• Acetylation: Major route for aromatic amines; catalyzed by N-acetyltransferases.

• Amino Acid Conjugation: Limited but specific to certain xenobiotics.

• Glutathione Conjugation: Targets electrophile xenobiotics for detoxification and excretion; crucial for safety against reactive compounds.

Factors Affecting CYP Enzymes

-Individual variations in CYP enzyme levels and activity are affected by:

• Genetic mutations

• Environmental factors (other xenobiotic exposures, dietary habits, diseases)

• Interaction between drugs resulting in either inhibition or induction of enzyme activity.

Conclusion

• Understanding biotransformation pathways is critical for predicting responses to drugs, potential toxicity, and the overall impact on metabolism in humans. It informs therapeutic interventions and safety assessments of chemicals.