Phase-2 conjugation

Category: drug_metabolism

Overview

Phase-2 conjugating enzymes attach polar groups to phase-1 oxidized metabolites (or directly to parent drugs), dramatically increasing water solubility for biliary or renal excretion. UGT (UDP-glucuronosyltransferase) — major; bilirubin + many drugs (UGT1A1 deficiency = Gilbert syndrome benign hyperbilirubinemia + atazanavir-induced jaundice; Crigler-Najjar severe form). SULT (sulfotransferase) — major for acetaminophen at therapeutic doses, hormones. GST (glutathione-S-transferase) — major for reactive metabolites (NAPQI from acetaminophen → GST → mercapturate excretion). NAT (N-acetyltransferase, NAT2) — isoniazid + sulfonamides; slow/fast acetylator phenotypes (NAT2 polymorphism affects INH toxicity). Methylation (COMT, HNMT) + acetylation (NAT) close the major phase-2 axes.

Organ Systems

Pathway Steps

  1. oxidized-or-parent-drug → glucuronide-conjugate — via UGT1A1 / 1A4 / 2B7 etc.. Glucuronidation (UGTs) is the highest-capacity phase-2 route, adding glucuronic acid for water-soluble excretion. UGT1A1 also conjugates bilirubin (Gilbert’s), and glucuronides can be recycled by gut β-glucuronidase (enterohepatic circulation).
  2. oxidized-or-parent-drug → sulfate-conjugate — via SULT1A1 / 1A3 / 2A1. Sulfotransferases are high-affinity but low-capacity (limited by the PAPS cosubstrate), so they saturate at higher doses — classically acetaminophen, where the sulfation route saturates and shifts metabolism toward the toxic CYP/NAPQI pathway.
  3. reactive-metabolite → glutathione-conjugate — via GST + γ-glutamyl-transpeptidase + mercapturate formation. Glutathione-S-transferases neutralize reactive electrophiles (forming mercapturates), the key defense against toxic CYP metabolites such as acetaminophen’s NAPQI. Depleting GSH (overdose, fasting) is what makes acetaminophen hepatotoxic; NAC replenishes it.
  4. arylamine-or-hydrazide → n-acetyl-conjugate — via NAT2 — INH; slow/fast acetylator phenotype. N-acetyltransferase 2 acetylates arylamines/hydrazides; its slow/fast-acetylator polymorphism alters isoniazid, hydralazine, and sulfonamide handling (slow acetylators risk drug-induced lupus and INH neuropathy) and modifies arylamine bladder-cancer risk.

References