Xenobiotics
Xenobiotics are foreign chemicals such as drugs and pesticides. The liver makes them water-soluble in two phases so the body can excrete them.
Sources of xenobiotics
| Source | Examples |
|---|---|
| Drugs | Paracetamol, antibiotics, sedatives; alcohol |
| Food additives | Preservatives (sodium benzoate), synthetic colours, flavours, artificial sweeteners |
| Pesticides | Insecticide residues (organophosphates, DDT) on vegetables, fruits and grains |
| Pollutants | Vehicle exhaust, industrial chemicals, polycyclic aromatic hydrocarbons such as benzpyrene |
| Natural toxins in food | Aflatoxin from mould on badly stored groundnuts and maize |
How the liver handles a xenobiotic
Most xenobiotics are fat-soluble, so they would stay in the body. The liver changes them in two phases so they dissolve in water and can leave.
- 1★Phase I: fat-soluble xenobiotic → more polar product (–OH, –COOH or –NH₂ added or exposed)Cytochrome P450 monooxygenases · RH + O₂ + NADPH + H⁺ → ROH + H₂O + NADP⁺
- 2★Phase II: product + glucuronic acid, sulphate, glutathione or acetyl group → conjugateTransferases (e.g., UDP-glucuronosyltransferase) · water-soluble and usually inactive
- 3Conjugate → excreted in urine (kidney) or bile (faeces)
★ one-way, controls the pace
Reactions in each phase
| Phase | Reaction | Example |
|---|---|---|
| I | Oxidation (hydroxylation) | Cytochrome P450 adds –OH to many drugs, steroids and pollutants |
| I | Reduction | Azo or nitro groups are reduced, e.g., prontosil → sulphanilamide |
| I | Hydrolysis | Esterases split esters, e.g., aspirin → salicylic acid |
| II | Glucuronidation (most common) | Glucuronic acid from UDP-glucuronic acid, e.g., bilirubin, paracetamol |
| II | Sulphation | Sulphate from PAPS (active sulphate), e.g., phenols, steroids |
| II | Glutathione conjugation | Glutathione S-transferase traps toxic reactive products, e.g., the toxic paracetamol metabolite |
| II | Acetylation | Acetyl group from acetyl-CoA, e.g., isoniazid, sulphonamides (people are fast or slow acetylators) |
Effects of xenobiotics
- Detoxification: most become harmless and are excreted.
- Toxic activation: in paracetamol overdose, the P450 product (NAPQI) uses up glutathione and damages liver cells.
- Cancer: benzpyrene (in tobacco smoke and charred or smoked food) is activated by P450 into a form that binds DNA.
- Allergy: some bind body proteins and act as antigens (haptens).
- Enzyme induction: alcohol, smoking and phenobarbitone raise P450 levels, so other drugs are cleared faster.
- Food–drug interaction: grapefruit juice blocks CYP3A4 in the intestine, so blood levels of drugs such as felodipine and some statins rise.
Detox depends on nutrition. Protein supplies the amino acids for the enzymes and for glutathione (glutamate, cysteine, glycine), and protein deficiency can slow drug metabolism. Cytochrome P450 is a haem (iron) protein, and Phase I needs NADPH. Grapefruit juice can raise blood levels of some drugs.
2 marks: “What are xenobiotics? Give two examples.” Foreign chemicals not made by the body, e.g., drugs, pesticides, food additives, pollutants.
5 marks: “Explain the role of cytochrome P450 in detoxification.” A liver microsomal haem enzyme that hydroxylates xenobiotics using O₂ and NADPH (Phase I), preparing them for conjugation.
10 marks: “Describe the metabolism of xenobiotics.” Define, list sources, explain Phase I and Phase II reactions with examples, then effects and the nutrition link.
Phase I adds a handle, Phase II adds a tag: P450 puts on an –OH handle, then glucuronic acid, sulphate, glutathione or an acetyl group is tagged on so the body can flush it out.