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.

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