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ToxSci Advance Access originally published online on March 25, 2003
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Toxicological Sciences 73, 36-43 (2003)
Copyright © 2003 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Glucuronidation of 1'-Hydroxyestragole (1'-HE) by Human UDP-Glucuronosyltransferases UGT2B7 and UGT1A9

Lalitha V. Iyer1, Mark N. Ho, Walter M. Shinn, Wallace W. Bradford, Mary J. Tanga, Shirley S. Nath and Carol E. Green

1 Biopharmaceutical Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025

Estragole (4-allyl-1-methoxybenzene) is a naturally occurring food flavoring agent found in basil, fennel, bay leaves, and other spices. Estragole and its metabolite, 1'-hydroxyestragole (1'-HE), are hepatocarcinogens in rodent models. Recent studies from our laboratory have shown that glucuronidation of 1'-HE is a major detoxification pathway for estragole and 1'-HE, accounting for as much as 30% of urinary metabolites of estragole in rodents. Therefore, this study was designed to investigate the glucuronidation of 1'-HE in human liver microsomes in vitro and identify the specific uridine diphosphate glucuronosyltransferase (UGT) isoforms responsible for 1'-HE glucuronidation. The formation of the glucuronide of 1'-HE (1'-HEG) followed atypical kinetics, and the data best fit to a Hill equation, resulting in apparent kinetic parameters of Km = 1.45 mM, Vmax = 164.5 pmoles/min/mg protein, and n = 1.4. There was a significant intersubject variation in 1'-HE glucuronidation in 27 human liver samples, with a CV of 42%. A screen of cDNA expressed UGT isoforms indicated that UGT2B7 (83.94 ± 0.188 pmols/min/mg), UGT1A9 (51.36 ± 0.72 pmoles/min/mg), and UGT2B15 (8.18 ± 0.037 pmoles/min/mg) were responsible for 1'-HEG formation. Glucuronidation of 1'-HE was not detected in cells expressing UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, and UGT1A10. 1'-HE glucuronidation in 27 individual human liver samples significantly (p < 0.05) correlated with the glucuronidation of other UGT2B7 substrates (morphine and ibuprofen). These results imply that concomitant chronic intake of therapeutic drugs and dietary components that are UGT2B7 and/or UGT1A9 substrates may interfere with estragole metabolism. Our results also have toxicogenetic significance, as UGT2B7 is polymorphic and could potentially result in genetic differences in glucuronidation of 1'-HE and, hence, toxicity of estragole.

Key Words: estragole; 1'-hydroxyestragole; glucuronidation; UDP-glucuronosyltransferase; UGT2B7; UGT1A9.


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