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ToxSci Advance Access published online on March 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg066
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 18, 2002; accepted February 15, 2003
© 2003 Society of Toxicology

Biotransformation and Toxicokinetics

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

Lalitha V. Iyer 1*, Mark N. Ho 1, Walter M. Shinn 1, Wallace W. Bradford 1, Mary J. Tanga 1, Shirley S. Nath 1, Carol E. Green 1

1 Biopharmaceutical Division, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025

* To whom correspondence should be addressed. E-mail: lalitha.iyer{at}sri.com.


  Abstract

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 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 inter-subject 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 pmoles/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.

estragole, 1'-hydroxyestragole, glucuronidation, UDP-glucuronosyltransferase, UGT2B7, UGT1A9 .


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[Abstract] [Full Text] [PDF]


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