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HERO ID
1012015
Reference Type
Journal Article
Title
Human interindividual variation in lymphocyte UDP-glucuronosyltransferases as a determinant of in vitro benzo[a]pyrene covalent binding and cytotoxicity
Author(s)
Hu, Z; Wells, PG
Year
2004
Is Peer Reviewed?
1
Journal
Toxicological Sciences
ISSN:
1096-6080
EISSN:
1096-0929
Volume
78
Issue
1
Page Numbers
32-40
Language
English
PMID
14600278
DOI
10.1093/toxsci/kfh010
Web of Science Id
WOS:000220076000005
Abstract
UDP-glucuronosyltransterases (UGTs) catalyse the glucuronidation and elimination of most xenobiotics and, thereby, may prevent their alternative bioactivation to carcinogenic and teratogenic reactive intermediates. Previous studies have shown that glucuronidation, bioactivation, and covalent binding of the carcinogen/teratogen benzo[a]pyrene (BP) in rat lymphocytes accurately reflected those processes in hepatic microsomes from the same animals. Accordingly, lymphocytes from 12 normal human volunteers were incubated with BP metabolites to determine UGT variability and its potential toxicological relevance. Over 200-fold interindividual variability was observed in both the glucuronidation and covalent binding of BP metabolites, with decreasing total glucuronidation among subjects correlating with a decreased UGT-modulated reduction in covalent binding (R(2) = 0.8272, p < 0.01) and, in six subjects, enhanced cytotoxicity (r = -0.9338, p < 0.001). Decreased glucuronidation of both BP diols (r = -0.9106, p < 0.001) and BP diones (r = -0.9625, p < 0.005), but not BP monophenols, correlated with enhanced cytotoxicity. These results provide the first evidence for substantial interindividual variability in UGT activities for BP metabolites among the normal population and suggest that UGT-deficient individuals may be at increased risk from the reactive intermediate-mediated effects of BP and related xenobiotics.
Keywords
glucuronidation; benzo[a]pyrene; cancer; birth defects; bioactivation; reactive intermediates
Tags
IRIS
•
Benzo(a)pyrene (BaP)
Considered
Cited
Toxicokinetics
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