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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh010
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received August 8, 2003; accepted September 29, 2003
© 2003 Society of Toxicology

Carcinogenicity

Human Interindividual Variation in Lymphocyte UDP-Glucuronosyltransferases as a Determinant of in Vitro Benzo[a]pyrene Covalent Binding and Cytotoxicity

Zhuohan Hu 1 and Peter G. Wells 2*

1 Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
2 Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada; Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

* To whom correspondence should be addressed. E-mail: pg.wells{at}utoronto.ca.


  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 (R2 =0.8272, p<0.01), and, in 6 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.

Key Words: glucuronidation, benzo[a]pyrene, cancer, birth defects, bioactivation, reactive intermediates .


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