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N-glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N_hydroxy-PhIP by specific human UDP-glucuronosyltransferases.

Abstract
Glucuronidation is a major metabolic pathway in the biotransformation of many xenobiotics. Recent studies have shown that in humans, UDP-glucuronosyltransferase (UGT)-mediated glucuronidation plays a critical role in the detoxification of food-borne carcinogenic heterocyclic amines. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant carcinogenic heterocyclic amine found in well-cooked meats, has been shown to be extensively glucuronidated in humans. To determine which UGT isozymes are involved in the biotransformation of PhIP and the cytochrome P4501A2-mediated reactive intermediate N-hydroxy-PhIP, microsomes expressing human UGT1A1, -1A4, -1A6 or -1A9 were incubated with PhIP and N-hydroxy-PhIP and the reaction products analyzed by HPLC and ESI-MS. Incubations containing N-hydroxy-PhIP and UGT1A1 expressing microsomes, with an apparent Km of 4.58 microM and a Vmax of 4.18 pmol/min/mg protein, had the highest capacity to convert N-hydroxy-PhIP to N-hydroxy-PhIP-N2-glucuronide. Microsomes expressing UGT1A9 produced N-hydroxy-PhIP-N3-glucuronide at the highest rate with an apparent Km and Vmax of 3.73 microM and 4.07 pmol/min/mg, respectively. A third previously undefined glucuronide accounted for 31% of the total glucuronides formed from the UGT1A4 expressing microsomes. No glucuronide conjugates were detected from microsomes expressing UGT1A6. Incubations containing PhIP as substrate formed direct PhIP-glucuronides in microsomes expressing UGT1A1, UGT1A4 and UGT1A9 but at levels averaging 53-fold lower than when N-hydroxy-PhIP was used as the substrate. Knowing the glucuronidation capacity of the specific UGT isozymes involved in PhIP and N-hydroxy-PhIP glucuronidation should help in determining the individual susceptibility to the potential cancer risk from exposure to PhIP.
AuthorsM A Malfatti, J S Felton
JournalCarcinogenesis (Carcinogenesis) Vol. 22 Issue 7 Pg. 1087-93 (Jul 2001) ISSN: 0143-3334 [Print] England
PMID11408353 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Carcinogens
  • Imidazoles
  • Pyridines
  • 2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • Glucuronosyltransferase
Topics
  • Biotransformation
  • Carcinogens (pharmacokinetics)
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Glucuronosyltransferase (metabolism)
  • Humans
  • Imidazoles (pharmacokinetics)
  • Microsomes (enzymology)
  • Pyridines (pharmacokinetics)
  • Spectrometry, Mass, Electrospray Ionization

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