Biotransformation of endogenous and exogenous substances, types of biotransformation processes, toxic and carcinogenic substances in the environment.

Introduction

Biotransformation is the enzymatic modification of substances within the body to facilitate their elimination. This process applies to both endogenous compounds (e.g., hormones, bilirubin) and exogenous substances (e.g., drugs, environmental toxins). The liver plays a central role in detoxification, primarily through Phase I and Phase II reactions. Improper detoxification can lead to the accumulation of harmful metabolites, some of which are carcinogenic or cytotoxic.

Types of Biotransformation Processes

Phase I Reactions (Functionalization)

- Involve oxidation, reduction, and hydrolysis.

- Catalyzed mainly by cytochrome P450 monooxygenases (CYP450 enzymes).

- Introduce or expose polar functional groups (e.g., –OH, –NH₂).

- Example: Hydroxylation of steroids, oxidation of ethanol to acetaldehyde.

- May result in activation, inactivation, or conversion to toxic metabolites.

Phase II Reactions (Conjugation)

- Involve the addition of endogenous molecules to functional groups.

- Reactions include glucuronidation, sulfation, acetylation, methylation, glutathione conjugation.

- Increase solubility for renal or biliary excretion.

- Enzymes include UDP-glucuronosyltransferases, sulfotransferases, and glutathione-S-transferases.

Organs and Enzymes Involved

- **Liver** is the primary organ; enzymes localized in the smooth endoplasmic reticulum and cytosol.

- Other tissues include intestines, kidneys, lungs, and skin.

- Enzyme activity may be influenced by genetics, diet, disease, and drug interactions.

Toxic and Carcinogenic Substances in the Environment

- **Polycyclic aromatic hydrocarbons (PAHs)** from tobacco smoke: metabolized to epoxides → DNA adducts → mutagenesis.

- **Aflatoxins** (fungal toxins in food): activated by CYP450 to epoxides → hepatocarcinogenesis.

- **Benzo[a]pyrene**, **vinyl chloride**, **benzene**: known environmental carcinogens.

- **Heavy metals** (arsenic, cadmium, mercury): disrupt enzymatic systems, generate ROS.

- Detoxification failure may increase risk for cancer, neurodegeneration, or organ failure.

Clinical Relevance

- Pharmacokinetics and drug dosing depend on metabolic rate.

- Polymorphisms in CYP enzymes affect drug efficacy and toxicity.

- Acetaminophen overdose → glutathione depletion → hepatic necrosis.

- Inducers and inhibitors of liver enzymes alter detoxification capacity.

- Monitoring and managing toxin exposure is essential in public health and clinical medicine.

Conclusion

Biotransformation is a key protective mechanism allowing the body to neutralize and excrete potentially harmful compounds. Understanding these pathways is essential for drug development, personalized medicine, and the prevention of toxin-induced diseases.

References

1. Lippincott Illustrated Reviews: Biochemistry, 7th Edition

2. Guyton and Hall Textbook of Medical Physiology, 14th Edition

3. Lehninger Principles of Biochemistry, 7th Edition