[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Xenobiotic biotransformation: phases I, II and III

[Biochemistry](https://durgical.com/en/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

- [Acetaminophen toxicity](https://durgical.com/en/conditions/acetaminophen-toxicity/)
- [Neonatal jaundice](https://durgical.com/en/conditions/neonatal-jaundice/)
- [Tuberculosis](https://durgical.com/en/conditions/tuberculosis/)

## Related

- [Cytochrome P450 system](https://durgical.com/en/biochemistry/topics/cytochrome-p450-system/)
- [Glucuronidation](https://durgical.com/en/biochemistry/topics/glucuronidation/)
- [Cytochrome P450 3A4 (CYP3A4)](https://durgical.com/en/biochemistry/enzymes/cytochrome-p450-3a4/)
- [Cytochrome P450 2E1 (CYP2E1, MEOS)](https://durgical.com/en/biochemistry/enzymes/cytochrome-p450-2e1/)
- [Glutathione (GSH)](https://durgical.com/en/biochemistry/molecules/glutathione/)
- [S-adenosylmethionine (SAM)](https://durgical.com/en/biochemistry/molecules/s-adenosylmethionine/)
- [Acetaminophen metabolism and NAPQI](https://durgical.com/en/biochemistry/topics/acetaminophen-metabolism-and-napqi/)
- [UGT1A1 (bilirubin UDP-glucuronosyltransferase)](https://durgical.com/en/biochemistry/enzymes/ugt1a1/)

## 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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Biological oxidations](https://reactome.org/PathwayBrowser/#/R-HSA-211859) (Reactome, 2026); [Phase I - Functionalization of compounds](https://reactome.org/PathwayBrowser/#/R-HSA-211945) (Reactome, 2026); [Phase II - Conjugation of compounds](https://reactome.org/PathwayBrowser/#/R-HSA-156580) (Reactome, 2026); [What is pharmacogenomics?: MedlinePlus Genetics](https://medlineplus.gov/genetics/understanding/genomicresearch/pharmacogenomics/) (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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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/topics/xenobiotic-biotransformation-phases-i-ii-and-iii/