Second phase of hepatic xenobiotic metabolism where Phase I metabolites are conjugated with endogenous molecules (glucuronide, sulfate, glutathione, glycine, acetyl groups) to increase water solubility for excretion. Phase II enzymes are primarily cytoplasmic and include UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), and N-acetyltransferases (NATs).
Phase II reactions attach polar molecules to Phase I metabolites: (1) Glucuronidation (UGTs) uses UDP-glucuronic acid to conjugate metabolites for biliary/urinary excretion. (2) Sulfation (SULTs) uses PAPS (3'-phosphoadenosine-5'-phosphosulfate) for phenols, alcohols, hormones. (3) Glutathione conjugation (GSTs) neutralizes electrophilic compounds and free radicals. (4) Acetylation (NATs) and glycination add small molecules. These reactions require adequate cofactor supply.
Phase II capacity limits overall detoxification—if Phase I operates faster than Phase II, reactive intermediates accumulate causing oxidative damage. Many patients have impaired Phase II due to genetic polymorphisms (e.g., GSTM1 null), nutrient deficiencies (sulfur amino acids, glutathione precursors, B vitamins, magnesium), or excessive toxic burden. Supporting Phase II with cruciferous vegetables (sulforaphane), NAC, glycine, magnesium, and B vitamins prevents accumulation of damaging intermediates.
- Six main conjugation pathways: glucuronidation, sulfation, glutathione, acetylation, methylation, glycination
- Increases water solubility of toxins for excretion
- Rate-limiting step in detoxification when cofactors depleted
- Requires: glutathione, glycine, sulfur amino acids, B vitamins, magnesium
- UGTs glucuronidate hormones, drugs, bilirubin, environmental toxins
- GSTs neutralize reactive oxygen species and electrophiles
- Genetic polymorphisms (GSTM1 null ~50% population) reduce capacity
- Cruciferous vegetables (sulforaphane) upregulate Phase II enzymes via Nrf2
- Imbalanced Phase I/Phase II ratio causes accumulation of toxic intermediates
- Phase I — Phase II conjugates reactive metabolites from Phase I oxidation
- liver — Phase II enzymes predominantly expressed in hepatocytes
- glutathione — glutathione is essential cofactor for GST conjugation reactions
- sulfur amino acids — cysteine and methionine provide sulfur for sulfation and glutathione
- glycine — glycine used for conjugation of bile acids and xenobiotics
- B vitamins — B vitamins (B2, B3, B6, B12, folate) cofactors for Phase II pathways
- magnesium — magnesium required for sulfation (PAPS synthesis)
- cruciferous vegetables — sulforaphane from cruciferous vegetables induces Phase II enzymes
- Nrf2 — Nrf2 transcription factor upregulates Phase II enzyme expression
- NAC — N-acetylcysteine provides cysteine for glutathione synthesis
- sulforaphane — potent Nrf2 activator inducing Phase II enzyme expression
- oxidative stress — impaired Phase II allows accumulation of pro-oxidant intermediates
- CYP enzymes — Phase I CYP enzymes create substrates for Phase II conjugation
- bile acids — Phase II conjugates bile acids for intestinal secretion
- estrogen metabolism — Phase II glucuronidates and sulfates estrogen metabolites
- polymorphisms — GSTM1, GSTT1, NAT2 polymorphisms affect Phase II capacity
- methylation — methylation is Phase II pathway using SAMe as cofactor
- toxins — Phase II detoxifies environmental toxins and endogenous metabolites
- ginger — ginger supports liver detoxification including Phase II pathways
- olive oil — fat-soluble nutrients in olive oil support Phase II cofactor absorption