1 Biopharmaceutical Division, SRI International, 333 Ravenswood Avenue, Menlo Park, California 94025
Received November 18, 2002; accepted February 15, 2003
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ABSTRACT |
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Key Words: estragole; 1'-hydroxyestragole; glucuronidation; UDP-glucuronosyltransferase; UGT2B7; UGT1A9.
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INTRODUCTION |
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Glucuronidation reactions involve the transfer of glucuronic acid to relatively nonpolar substrates by uridine diphosphate glucuronosyltransferases (UGTs), thereby generating hydrophilic glucuronides that are more easily eliminated (Parkinson, 1996). Two distinct families of UGTs have identified: UGT1 and UGT2, each of which has been further classified into individual isozymes (Clarke and Burchell, 1994
). In humans, the UGT1 locus encodes 13 UGT isoforms (UGT1A1 through UGT1A13p), of which four genes (UGT1A2p, UGT1A11p, UGT1A12p, and UGT1A13p) are pseudogenes (Gong et al., 2001
). Several human UGT2B isoforms have also been identified, such as UGT2B4, UGT2B7, UGT2B10, UGT2B11, UGT2B15, UGT2B17, and UGT2B28 (Levesque et al., 2001
; Mackenzie et al., 1997
; Turgeon et al., 2001
). The current investigation was performed to develop an in vitro glucuronidation assay method for 1'-HE in human liver microsomes and to identify the specific UGT isoform responsible for the glucuronidation of 1'-HE.
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MATERIALS AND METHODS |
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Synthesis of 1'-HE.
1'-HE was synthesized from 1'-acetoxyestragole, which was prepared by the allylic oxidation of estragole with t-butylperacetate in the presence of cuprous bromide at 100°C. The acetate ester was hydrolyzed with potassium carbonate in methanol at room temperature to give 1'-HE at a 60% overall yield from estragole. The identity of 1'-HE was confirmed using mass spectroscopy in APCI positive ion mode (m/z 147, M-H2O+H, 100% relative intensity), 1H NMR (CDCl3): 1.41 (1H, br s, -OH), 3.81 (3H, s, -OCH3), 4.30 (2H, m = CH2), 6.24 (1H, m = CH), 6.55 (1H, d, CHOH, J. = 15 Hz), 6.86 (2H, d, arom, J. = 6.6 Hz), 7.32 p.p.m. (2H, d, arom, J. = 6.6 Hz), and 13C NMR (CDCl3):
55.34, 63.94, 114.01, 126.20, 127.67, 129.41, 130.99, and 159.33 p.p.m.. Purity was determined by HPLC as 99.0% under the following conditions: Brownlee Spheri-5 RP-18, 4.6 x 100 mm column, isocratic mobile phase of 50% methanol/water, 1ml/min flow rate, and UV detection at 254 nm.
1'-HE glucuronidation assay.
Initially, optimal conditions for the in vitro formation of 1'-HEG were determined by varying incubation times (0 to 5 h) and final concentrations of microsomal protein (0 to 4 mg/ml), UDPGA (0 to 15 mM), and substrate (0 to 5 mM). The final conditions used in a typical incubation included the addition of UDPGA (7 mM) to a prewarmed mixture (37°C for 3 min) of microsomes (2 mg/ml) with 1'-HE (800 µM) and MgCl2 (10 mM) in PBS (1X, pH = 7.4) in a total volume of 200 µl. The reaction was stopped with the addition of chilled 0.2% acetic acid in acetonitrile (200 µl) after an incubation period of 4 h in a shaking water-bath (37°C). The samples were then centrifuged at 3,500 r.p.m. for 30 min at room temperature, and the supernatants (80 µl) were injected into a reverse-phase HPLC system with UV detection at 259 nm (Waters Corp, Milford, MA) and Luna C18 (4.6 x 250 mm, 5 µm particle size) column (Phenomenex Inc., Torrance, CA). The mobile phase consisted of 30% of 0.2% acetic acid in acetonitrile and 70% of 0.2% acetic acid in water, used at a flow rate of 1 ml/min. The retention times of 1'-HEG and 1'-HE were ~10 and 14 min, respectively. The formation of 1'-HEG was confirmed by incubation with ß-glucuronidase (3000 U) in 0.2 M sodium acetate buffer (pH = 5.0) for 24 h. Control samples without ß-glucuronidase (buffer alone) were included. Control experiments were performed in presence of a range (0.4 to 10%) of final concentrations of methanol (solvent for 1'-HE) to account for any effects of methanol on 1'-HE glucuronidation.
Morphine glucuronidation assay.
Glucuronidation of morphine to M3G and M6G was studied in microsomes from 27 individual human liver microsomes by a method modified from Innocenti et al.,(2001). Briefly, individual liver microsomal preparations (2 mg/ml) were preincubated with morphine sulfate (0.5 mM) and MgCl2 (5 mM) in PBS-1X (pH = 7.4) for 5 min in a shaking water-bath at 37°C. Final incubation volume was set at 100 µl. The reaction was initiated with the addition of UDPGA (10 mM) and stopped with 400 µl cold ACN after 20 min. The samples were centrifuged at 14,000 r.p.m. for 20 min, after shaking for 20 min in a multitube vortexer (Henry Troemner LLC, Thorofare, NJ). The supernatants were evaporated to dryness under vacuum after addition of 20 µl of internal standard (10,11-dihydrocarbamazepine, 0.5 mg/ml), reconstituted with 100 µl PBS (1X) and centrifuged at 14,000 r.p.m. for 2 min. The resulting supernatant was injected (80 µl) into a reverse-phase HPLC system with fluorescence detection (Waters Corp, Milford, MA) at
ex = 210 nm and
em = 340 nm. The mobile phase consisted of 72% 10 mM sodium phosphate and 1 mM lauryl sulfate, pH = 2.1, and 28% acetonitrile used at a flow rate of 1ml/min through a Luna C18 (4.6 x 250 mm, 5 µm) column (Phenomenex Inc., Torrance, CA). Retention times for morphine, M3G, M6G, and internal standard were ~12, 7, 9, and 26 min. Incubations were performed in triplicate for each liver sample, and the rates of formation of M3G and M6G were expressed as pmols/min/mg microsomal protein, using standard curves of M3G and M6G.
Ibuprofen glucuronidation assay.
Individual microsomes (2 mg/ml), preincubated with Brij 58 (0.2 mg/ml) (4°C for 20 min), were incubated with saccharolactone (5 mM), MgCl2 (10 mM), ibuprofen (1 mM), and PBS (1X) (pH = 7.4) for 30 min at 37°C, in a total volume of 200 µl (Magdalou et al., 1990; Pritchard et al., 1993
). The reaction was started with the addition of UDPGA (10 mM) and stopped with 400 µl of 0.1% trifluoro-acetic acid (TFA) in acetonitrile, after which the samples were centrifuged at 3500 r.p.m. for 30 min. The resulting supernatants were injected (100 µl) into a reverse-phase HPLC system with UV detection at 226 nm (Waters Corp., Milford, MA) and a Luna C18 column (5 µm particle size, 4.6 x 250 mm, Phenomenex Inc., Torrance, CA). The mobile phase, consisting of 50% of 0.2% TFA in water and 50% of 0.2% TFA in acetonitrile, was run at a flow rate of 1 ml/min, with resulting retention times of ~6 and 22 min for ibuprofen acyl glucuronide (Ibu-AG) and ibuprofen, respectively.
PNP glucuronidation assay.
PNP glucuronidation was performed as a control for functional UGT activity in the microsomes, as PNP is a substrate for several UGT isoforms (Matsui and Watanabe, 1982; Rajaonarison et al., 1991
; Watanabe et al., 1986
). A preincubated mix (4°C for 30 min) of human liver microsomes (1 mg/ml) with Triton X-100 (0.025% v/v) was incubated with PNP (360 µM), EDTA (40 µM), MgCl2 (10 mM), and UDPGA (2 mM) in 0.1 M TrisHCl buffer (pH = 7.4), in a total volume of 500 µl. The reaction was stopped with the addition of 2.8 ml of 0.2 M glycine-NaOH buffer (pH = 10.4). Samples were centrifuged at 2500 r.p.m. for 30 min, and UGT activity in the supernatant was measured colorimetrically from the disappearance of substrate at
= 400 nm, using a spectrophotometer (Powerwave 200 Microplate Scanning Spectrophotometer, Winooski, UT).
Data analysis.
Each incubation in the various glucuronidation assays was performed in triplicate, and the results were expressed as mean ± SD. The data were fit to Michaelis-Menten (hyperbolic) and Hill (sigmoidal) models and further analyzed using Eadie-Hofstee plots. Standard parameters such as coefficient of determination (R2), Akaike Information Criterion (AIC), standard error of the parameter estimates, and visual inspection of Eadie-Hofstee plots were used to determine the quality of fit to a specific model. The apparent enzyme kinetic parameters of Km, Vmax, and n (for Hill model) for 1'-HE glucuronidation were calculated by nonlinear regression analysis (Enzyme Kinetics ModuleTM 1.1 of Sigma Plot® 2001, version 7.101, SPSS Inc., Chicago, IL). Catalytic efficiency was determined by calculating Vmax/Km ratio. Correlation analyses between glucuronidation of 1'-HE and other UGT2B7 substrates were performed using correlation coefficients (r2) (Primer of Biostatistics, version 4.02 by S.A. Glantz, McGraw Hill, 1996). P values < 0.05 were considered significant.
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RESULTS |
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1'-HE Glucuronidation by cDNA Expressed Human UGT Isoforms
The screening of microsomes from cells expressing specific UGT isoforms for 1'-HE glucuronidation indicated significant 1'-HEG formation (83.94 ± 0.188 pmols/min/mg protein) by the UGT2B7 isoform (Table 1). UGT1A9 was also capable of conjugating 1'-HE, with a mean 1'-HEG formation rate of 51.36 ± 0.72 pmols/min/mg protein. Minor 1'-HE glucuronidation was observed in microsomes expressing UGT2B15. The other UGT isoforms screened (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, and UGT1A10) did not exhibit detectable 1'-HE glucuronidating activity (Table 1
).
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DISCUSSION |
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Estragole is a component of several food-flavoring substances such as anise, star anise, fennel, basil, bay, tarragon, and marjoram, as well as fragrances, cosmetics, and terpentine oil, thereby resulting in a widespread exposure to humans. It is biotransformed to several metabolites (Figure 1), some of which are carcinogenic. Recent studies from our laboratory have shown that the glucuronidation of 1'-HE represents a major detoxification pathway for estragole and 1'-HE (Nath et al., 2001
, unpublished data). Hence, glucuronidation of 1'-HE may be a significant determinant of the toxicity and carcinogenic potential of estragole.
An assay method was developed to study the conversion of 1'-HE to 1'-HEG in human liver microsomes, by systematically varying each of the main incubation conditions. The formation of 1'-HEG decreased significantly at high substrate concentrations (4 and 5 mM), which is probably due to methanol concentrations 5%, used to dissolve 1'-HE at these high concentrations. Alternatively, impurities in the substrate might be responsible, although the high purity of the synthesized 1'-HE (99 %) makes this less likely. Product inhibition or a direct effect of 1'-HE on microsomal membrane fluidity or UGT enzyme activity at high concentrations are other possible reasons for this effect.
The atypical kinetic plot of 1'-HE glucuronidation suggests possible auto-activation, which has been reported with CYP3A4 substrates and more recently, with estradiol 3-glucuronidation by UGT1A1 and acetaminophen glucuronidation by UGT1A6 (Fisher et al., 2000). To our knowledge, this is the first report of activation kinetics with a UGT2B7 substrate.
The results from incubations of 1'-HE in cells expressing specific UGT isoforms clearly indicate that UGT2B7 and UGT1A9 are responsible for 1'-HE glucuronidation (Table 1). Correlation studies were performed with morphine 3- and 6-glucuronidation and ibuprofen glucuronidation, as these reactions are also known to be carried out by UGT2B7 (Coffman et al., 1997
, 1998
; Green et al., 1997
). The significant correlation results with morphine and ibuprofen glucuronidation further substantiate our finding on the role of UGT2B7 on glucuronidation of 1'-HE. Besides, the Km and Vmax values determined in this study are comparable to those reported in other studies (Innocenti et al., 2001
) for morphine 6-glucuronidation, which is carried out exclusively by UGT2B7 (Green et al., 1998
).
The finding that UGT2B7 and UGT1A9 are involved in 1'-HE glucuronidation raises important questions on the interaction between estragole and other dietary components and therapeutic drugs. UGT2B7 and UGT1A9 are both expressed in the gastrointestinal and liver tissues (Czernik et al., 2000; Strassburg et al., 1998
) and hence, interactions between dietary estragole and other compounds can occur at both these sites. UGT2B7 is a major human UGT2B isoform that has been shown to conjugate many endogenous compounds and xenobiotics (Radominska-Pandya et al., 2001
). It is known to conjugate compounds of various therapeutic categories, such as the opioid analgesics (morphine, dihydrocodeine) (Coffman et al., 1997
; Kirkwood et al., 1998
), nonsteroidal anti-inflammatory agents (ibuprofen, ketoprofen) (Coffman et al., 1998
; Jin et al., 1993a
), benzodiazepines (R-oxazepam) (Court et al., 2002
), immunosuppressants (cyclosporine, tacrolimus) (Strassburg et al., 2001
), chemotherapeutic agents (epirubicin) (Innocenti et al., 2001
) and anti-HIV compounds (zidovudine) (Barbier et al., 2000
). UGT2B7 is also responsible for the glucuronidation of fatty acids such as linoleic acid, linoleic acid diols, 13-hydroxyoctadecadienoic acid, and 13-oxooctadecadienoic acid (Jude et al., 2001a
,b
) and carcinogens such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (Ren et al., 1999
). UGT1A9 is also involved in the glucuronidation of several compounds such as R-oxazepam (Court et al., 2002
), acetaminophen (Court et al., 2001
), flavopiridol (Ramirez et al., 2002
) and dietary flavonoids (Oliveira and Watson, 2000
).
The carcinogenicity of 1'-HE is clearly dependent on the balance between formation of the active metabolites, (1'-sulfoöxyestragole) and epoxides, and detoxification by glucuronidation. Our data demonstrate marked interindividual differences in the rate of 1'-HE glucuronidation, which may have toxicogenetic implications. The screen of 1'-HE glucuronidation in liver samples from 27 individuals indicates a significant intersubject variability, with a CV of 42%. UGT2B7 is a polymorphic enzyme, with a histidine to tyrosine substitution at codon 268, resulting in two variant formsUGT2B7(Y) and UGT2B7(H)of the enzyme (Bhasker et al., 2000; Jin et al., 1993b
). No significant phenotypic significance has been associated with this polymorphism (Bhasker et al., 2000
; Gall et al., 1999
). However, there is recent evidence of a single nucleotide polymorphism (C to T) at position 161 in the UGT2B7 promoter, which is in complete linkage disequilibrium with the polymorphism in codon 268 and is associated with low glucuronidation rates of morphine in humans (Sawyer et al., 2002
). Furthermore, UGT2B7 expression is regulated by transcription factors such as hepatic nuclear factor-1a (HNF1a) and octamer transcription factor-1 (Oct-1) (Ishii et al., 2000
; Toide et al., 2002
) and hence, genetic and environmental factors and concomitant medications affecting HNF1a and Oct-1 may influence glucuronidation of 1'-HE by UGT2B7.
To date, no polymorphisms have been reported for UGT1A9 (Gagne et al., 2002). The lack of a role of UGT1A1 in 1'-HEG formation suggests that 1'-HE glucuronidation will be unaffected in Gilberts syndrome, a common genetic hyperbilirubinemic syndrome that is associated with reduced UGT1A1 activity and is prevalent up to about 20% in Caucasian subjects (Bosma et al., 1995
; Monaghan et al., 1996
).
The presence of polymorphic UGT2B7 with low enzyme activity implies that certain individuals could be "low glucuronidators" of 1'-HE and may have a greater susceptibility to estragole and 1'-HE induced carcinogenesis, as its metabolism may be shunted toward formation of the carcinogenic metabolites (Fig. 1). Environmental and dietary factors and concomitant chronic drug administration can influence the regulation of UGT2B7 expression. Our future studies will address this issue of genetic influences on estragole metabolism and carcinogenesis, as well as interactions of estragole with other dietary components, natural compounds, and therapeutic drugs.
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NOTES |
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1 To whom correspondence should be addressed. Tel: (650) 859-2232. Fax: (650) 859-2889. E-mail: lalitha.iyer{at}sri.com.
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