Biochemistry · Topic
Xenobiotic biotransformation: phases I, II and III !
The body turns fat-soluble drugs and toxins into water-soluble molecules it can pass in urine or bile, in three phases.
Updated 2026-11-01
Key facts
- Phase I (functionalisation): oxidation, reduction or hydrolysis that exposes or adds an –OH, –NH₂ or –COOH group; mainly cytochromes P450.
- Phase II (conjugation): attaches a large polar molecule: glucuronic acid, sulfate, glutathione, acetyl, methyl or amino acids.
- Phase III (transport): ABC pumps such as P-glycoprotein (MDR1) and MRP2 push conjugates into bile or urine.
- Biotransformation does not always detoxify: it can activate prodrugs or create toxic metabolites (NAPQI, benzopyrene epoxides).
- The liver is the main organ; gut, kidney, lung and skin also take part.
In detail
- Entry: the fat-soluble xenobiotic crosses membranes easily and, unchanged, is reabsorbed by the kidney.
- Phase I: P450 (or esterases, amidases, monoamine oxidase, alcohol dehydrogenase) adds a reactive group.
- Phase II: a transferase joins it to an activated co-substrate: UDP-glucuronic acid (UGT), PAPS for sulfate (SULT), glutathione (GST), acetyl-CoA (NAT2), SAM for methyl (COMT, TPMT).
- The conjugate is large, polar and almost always inactive.
- Phase III: membrane transporters push it into bile (if large) or urine (if small).
- Some biliary conjugates are split in the gut and the drug is reabsorbed: enterohepatic circulation.
- Also called
- Drug metabolism, Detoxification
Clinical notes
- Slow acetylators (NAT2): more isoniazid neuropathy and more drug-induced lupus with hydralazine or procainamide.
- TPMT deficiency: severe bone marrow toxicity with azathioprine and mercaptopurine; genotyping can be done beforehand.
- Newborns have immature glucuronidation: grey baby syndrome with chloramphenicol and physiological jaundice.
- Advanced liver disease mainly reduces phase I; glucuronidation is preserved longer.
Related conditions
Related
- Cytochrome P450 system
- Glucuronidation
- Cytochrome P450 3A4 (CYP3A4)
- Cytochrome P450 2E1 (CYP2E1, MEOS)
- Glutathione (GSH)
- S-adenosylmethionine (SAM)
- Acetaminophen metabolism and NAPQI
- UGT1A1 (bilirubin UDP-glucuronosyltransferase)
Test yourself
Think of the answer, then tap the question to see it.
What is the final goal of biotransformation?
To make the molecule more polar and water-soluble so it is excreted in urine or bile.
What are three phase II reactions?
Glucuronidation, sulfation, glutathione conjugation, acetylation and methylation.
Why do slow acetylators get more neuropathy with isoniazid?
NAT2 clears it slowly and the drug accumulates, which depletes pyridoxine.
What is phase III?
The transport of conjugates out of the cell by ABC pumps such as P-glycoprotein and MRP2.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Biological oxidations (Reactome, 2026); Phase I - Functionalization of compounds (Reactome, 2026); Phase II - Conjugation of compounds (Reactome, 2026); What is pharmacogenomics?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.