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Activity of rat UGT1A1 towards benzo[a]pyrene phenols and dihydrodiols

Laura Webb1, Kristini Miles, Fay Kessler

  • 1Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Campus Box 980613, 1217 E. Marshall Room 536, Richmond, VA 23298-0613, USA.

Environmental Toxicology and Pharmacology
|July 26, 2011
PubMed

Insights

Multiple UDP-glucuronosyltransferases (UGTs) in rats metabolize benzo[a]pyrene (BaP) compounds. UGT1A1 and UGT1A7 show broad activity, with their contributions varying by tissue and environmental factors.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon found in environmental pollutants.
  • UDP-glucuronosyltransferases (UGTs) are crucial enzymes involved in the detoxification and elimination of xenobiotics, including BaP metabolites.
  • The UGT1A family in rats plays a significant role in metabolizing various xenobiotics.

Purpose of the Study:

  • To investigate the activity of specific rat UGT1A enzymes towards benzo[a]pyrene (BaP) metabolites.
  • To determine the tissue-specific expression and activity of UGT1A1 and UGT1A7 in relation to BaP metabolite glucuronidation.
  • To elucidate the contribution of different UGT1A enzymes to the overall metabolism of BaP-7,8-dihydrodiol (BPD).

Main Methods:

  • Enzyme activity assays using four rat UGT1A enzymes against BaP phenols and dihydrodiols.
  • Development and application of antisera for UGT1A1 and UGT1A7 to quantify UGT levels in rat tissues (liver, intestine, kidney).
  • Inhibition studies using bilirubin, a known UGT1A1 inhibitor, to assess enzyme contributions.

Main Results:

  • UGT1A1 and UGT1A7 exhibited broad activity towards BaP metabolites.
  • UGT activity towards BPD was highest in liver and intestine, with UGT1A1 predominantly in the liver and UGT1A7 in the intestine.
  • Phenobarbital and UGT1A7 inducers differentially modulated BPD glucuronidation activity, and bilirubin inhibition suggested UGT1A1 is not the primary enzyme for constitutive BPD glucuronidation in rat liver microsomes.

Conclusions:

  • Multiple UGT1A enzymes contribute to the glucuronidation of BPD and other BaP metabolites.
  • The relative importance of specific UGT1A enzymes is dependent on the tissue type and environmental influences.
  • Understanding these enzyme-specific contributions is vital for assessing the toxicological impact of BaP exposure.

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