title: Glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites. pH stability and synthesis by human and dog liver.
abstract: Glucuronide conjugates of arylamines are thought to be important in the carcinogenic process. This study investigated the pH stability and synthesis of glucuronide conjugates of 4-aminobiphenyl and its N-hydroxy metabolites by human and dog liver. Both dog and human liver slices incubated with 0.06 mM [3H]-4-aminobiphenyl produced the N-glucuronide of 4-aminobiphenyl as the major product. After 2 hr of incubation, the N-glucuronide of 4-aminobiphenyl represented 52 and 27% of the total radioactivity recovered by HPLC in dog and human, respectively. When 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, or N-hydroxy-N-acetyl-4-aminobiphenyl was added to human microsomes containing [14C]UDP-glucuronic acid, a new product peak was detected by HPLC. At 0.5 mM, the rate of glucuronidation was N-hydroxy-N-acetyl-4-aminobiphenyl > N-hydroxy-4-aminobiphenyl > 4-aminobiphenyl. The rate of formation of the N-glucuronide of 4-aminobiphenyl was similar to that observed with benzidine and N-acetylbenzidine. The glucuronides of 4-aminobiphenyl and N-hydroxy-4-aminobiphenyl were both acid labile with T1/2 values of 10.5 and 32 min, respectively, at pH 5.5. The glucuronide of N-hydroxy-N-acetyl-4-aminobiphenyl was not acid labile with T1/2 values at pH 5.5 and 7.4 of 55 and 68 min, respectively. The glucuronide of 4-aminobiphenyl was the most acid labile conjugate examined. Thus, the glucuronide of 4-aminobiphenyl is a major product of dog and human liver slice metabolism and likely to play an important role in the carcinogenic process.
authors.affiliation: VA Medical Center, St. Louis, MO, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Babu
authors.forename: V M
authors.initials: VM
authors.lastname: Lakshmi
authors.forename: G P
authors.initials: GP
authors.lastname: Huang
authors.forename: T V
authors.initials: TV
authors.lastname: Zenser
authors.forename: B B
authors.initials: BB
authors.lastname: Davis
mesh_terms: D000611:Aminobiphenyl Compounds / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005965:Glucuronates / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism*; D008958:Models, Molecular
chemical_list: D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005965:Glucuronates; C006757:4-biphenylamine