Presenter: Amie K. Lund, Ph.D.
Course: BIOL 4370/5370 - Chapter 6
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)
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.
Reactions that introduce or unmask a polar group to increase water solubility of the xenobiotic for excretion.
Involves covalent attachment of small polar endogenous molecules to form water-soluble compounds to facilitate excretion.
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.
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.
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.
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.
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.
-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.
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.