Bioactivation of Heterocyclic Aromatic Amines by UDP Glucuronosyltransferases

2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAA) that arise during the burning of tobacco and cooking of meats. UDP-glucuronosyltransferases (UGT) detoxicate many procarcinogens and their metabolites. The genotoxic N-hydroxylated metabolite of AαC, 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AαC), undergoes glucuronidation to form the isomeric glucuronide (Gluc) conjugates N2-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HON2-Gluc) and O-(β-d-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN2-O-Gluc). AαC-HON2-Gluc is a stable metabolite but AαC-HN2-O-Gluc is a biologically reactive intermediate, which covalently adducts to DNA at levels that are 20-fold higher than HONH-AαC. We measured the rates of formation of AαC-HON2-Gluc and AαC-HN2-O-Gluc in human organs: highest activity occurred with liver and kidney microsomes, and lesser activity was found with colon and rectum micros...