Glucuronidation of carcinogen metabolites by complementary DNA-expressed uridine 5'-diphosphate

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Uracil-DNA Glycosylase Assay by Matrix-assisted Laser Desorption/Ionization Time-of-flight Mass Spectrometry Analysis
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Uracil-DNA Glycosylase Assay by Matrix-assisted Laser Desorption/Ionization Time-of-flight Mass Spectrometry Analysis

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P I Mackenzie1, L Rodbourn, T Iyanagi

  • 1Department of Clinical Pharmacology, Flinders University School of Medicine, Bedford Park South Australia.

Cancer Research
|April 1, 1993
PubMed

Insights

Three UDP glucuronosyltransferases (UGTs) mediate the glucuronidation of 2-acetylaminofluorene and benzo(a)pyrene metabolites. Each UGT form processes a distinct set of these carcinogenic compound metabolites.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • UDP glucuronosyltransferases (UGTs) are crucial enzymes in xenobiotic metabolism.
  • Metabolism of carcinogens like 2-acetylaminofluorene and benzo(a)pyrene involves complex pathways, including glucuronidation.
  • Understanding UGT activity is vital for assessing carcinogenic risk and drug interactions.

Purpose of the Study:

  • To characterize the substrate specificity of different UDP glucuronosyltransferase (UGT) forms.
  • To investigate the glucuronidation capacities of UGT1*06, UGT2B1, UGT2B2, UGT2B3, and UGT2B6 towards hydroxylated carcinogen metabolites.

Main Methods:

  • Synthesis of five UDP glucuronosyltransferase (UGT) forms via complementary DNA expression in COS 7 cells.
  • Incubation of UGTs with hydroxylated metabolites of 2-acetylaminofluorene and benzo(a)pyrene.
  • Analysis of glucuronidation activity using a range of carcinogen-derived substrates.

Main Results:

  • UGT1*06, UGT2B1, and UGT2B2 showed similar activity towards N-hydroxy-2-acetylaminofluorene.
  • UGT1*06 and UGT2B2 glucuronidated other 2-acetylaminofluorene metabolites, while UGT2B1 had limited activity.
  • Differential substrate specificities were observed for benzo(a)pyrene metabolites among UGT1*06, UGT2B1, and UGT2B2.
  • UGT2B3 and UGT2B6 were inactive towards tested carcinogen metabolites but glucuronidated testosterone.

Conclusions:

  • At least three UDP glucuronosyltransferase (UGT) forms (UGT1*06, UGT2B1, UGT2B2) are involved in the glucuronidation of 2-acetylaminofluorene and benzo(a)pyrene metabolites.
  • Each identified UGT isoform exhibits a unique substrate preference for these carcinogen metabolites.
  • UGT2B3 and UGT2B6 do not contribute to the glucuronidation of these specific carcinogen metabolites.

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