PHASE I AND II REACTIONS

Introduction

  • Living organisms are exposed to various chemical substances.

  • Substances can be exogenous (xenobiotics) or endogenous (endobiotics).

  • These substances undergo a metabolic process, mainly in the liver, to facilitate excretion—referred to as biotransformation.

  • Biotransformation changes the chemical structure of substances and is primarily catalyzed by enzymes.

  • The liver has high levels of drug-metabolizing enzymes; thus, it is the main organ for biotransformation.

  • Other organs also metabolize substances but to a lesser extent, ordered from highest to lowest: liver > lungs > kidneys > intestine > placenta > adrenals > skin (adipocytes, brain, testes, muscles, spleen have smaller roles).

Biotransformation

  • A metabolic process changing substances from a hydrophobic (lipophilic) form to a hydrophilic (lipophobic) form for elimination.

  • Enzymes involved are mainly microsomal.

  • Outcomes of biotransformation:

    • Inactivation of substances.

    • Activation of substances to a more active form.

    • Creation of toxic metabolites.

  • The biotransformation pathway consists of:

    • Phase I: Involves modification of chemical structure.

    • Phase II: Involves conjugation of products from Phase I.

    • Phase III: Involves excretion of conjugated metabolites.

Factors Affecting Biotransformation

  • Physicochemical Nature of Substance: affects how substances are metabolized.

  • Biochemical Factors: variations in enzymes responsible for metabolism.

  • Environmental Factors: external conditions impacting enzymatic action.

  • Biological Factors: including:

    • Gender: Females have higher CYP3A4 activity, leading to better bile acid detoxification, while males show higher overall drug metabolism.

    • Age: CYP450 activities vary from neonatal to adult, and decrease in older age.

    • Lifestyle: A balanced diet provides necessary components for enzyme function.

  • Altered Physiological State:

    • Pregnancy: Increases metabolism of many substances and alters drug transport and binding.

    • Hormonal Imbalance: Affects metabolism of substances.

    • Disease State: Example, liver diseases impair drug metabolism.

    • Temporal Factors: Circadian rhythms can affect metabolism, necessitating adjusted drug dosing.

Advantages of Biotransformation

  • Terminates the action of chemicals (drugs), reducing toxicity.

  • Enzymes have specificity, targeting specific functional groups.

  • Reduces lipophilicity of compounds, increasing renal and biliary excretion.

  • Applies in:

    • Pharmaceutical industry for synthesizing complex chemicals.

    • Agrochemical industry for producing specific pesticides.

    • Food preservation methods.

Phases of Biotransformation

Phase I Reactions

  • These reactions yield polar, water-soluble metabolites, often still active and can be referred to as functionalization reactions.

  • Involves activities such as:

    • Oxidation: Mainly done by cytochrome P450.

    • Reduction: Less common, often involved in activating substances.

    • Hydrolysis: Cleavage of a molecule in the presence of water causing significant chemical changes.

    • Hydroxylation: Adding an -OH group.

    • Demethylation: Removal of a methyl group.

    • Cyclization/De-cyclization: Ring formation and opening.

Phase II Reactions

  • Yield large, polar metabolites that are highly water-soluble and usually detoxify substances via conjugation reactions.

  • Reactions include:

    • Glucuronidation: Most common phase II reaction involving glucuronic acid.

    • Acetylation: Involves amino/hydrazine compounds.

    • Sulfation: Involves sulfating amino or -OH groups.

    • Methylation: Methylation of compounds with amino or phenolic groups.

    • Conjugation with Glutathione: Scavenges harmful electrophilic drugs and metabolites.

Phase III Reactions

  • Occurs after Phase II and involves further transformation for excretion.

    • Involves ATP-binding cassette (ABC) transporters (e.g., P-glycoprotein).

    • Conjugated substances are modified to be recognized and excreted by specific transporters.

Conclusion

  • Endobiotic and xenobiotic substances undergo biotransformation affected by several factors.

  • Biotransformation alters substances to active, inactive, or toxic forms based on their structural groups.

  • Phase II focuses on detoxification via conjugation, while microsomal enzymes act in Phase I and non-microsomal enzymes in Phase II.

  • Phase III represents the elimination stage, requiring ABC transporters for effective excretion.