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INVOLVEMENT OF HUMAN HEPATIC UGT1A1, UGT2B4, AND UGT2B7 IN THE GLUCURONIDATION OF CARVEDILOL

Project Team for Pharmacogenetics (A.O., Y.S., N.H., H.J., M.S., S.O., J.S.), Division of Environmental Chemistry (A.O., N.H., H.J., M.A.), Division of Pharmacology (S.O.), and Division of Biochemistry and Immunochemistry (Y.S., J.S.), National Institute of Health Sciences, Tokyo, Japan

(Received July 28, 2003; accepted October 22, 2003)

	Abstract

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Carvedilol ((±)-1-carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol) is metabolized primarily into glucuronide conjugates. In the present study, we identified the human UDP-glucuronosyltransferase (UGT) isoforms involved in the glucuronidation of carvedilol by thin-layer chromatography using microsomes from human liver or insect cells expressing recombinant UGT isoforms. We observed two forms of carvedilol glucuronides, namely G1 and G2, in hepatic microsomes. The glucuronidation of carvedilol was catalyzed by at least three recombinant UGT isoforms: UGT1A1, UGT2B4, and UGT2B7. UGT2B4 formed both G1 and G2, whereas UGT1A1 and UGT2B7 were responsible for the formation of glucuronide G2 and G1, respectively. The enzyme kinetics for carvedilol glucuronidation by UGT1A1, UGT2B4, and UGT2B7 in addition to human liver microsomes were examined by Lineweaver-Burk analysis. The values of K_m and V_max for human liver microsomes were 26.6 µM and 106 pmol/min/mg protein for G1, and 46.0 µM and 44.5 pmol/min/mg protein for G2, respectively. The K_m values for UGT1A1, UGT2B4, and UGT2B7 for G1 and G2 (22.1-55.1 µM) were comparable to those of the liver microsomes, whereas the V_max values were in the range of 3.33 to 7.88 pmol/min/mg protein. The K_m and V_max/K_m values for UGT2B4 and UGT2B7 for G1 were similar, whereas UGT2B4 had lower Km and higher V_max/K_m values for G2 compared with those of UGT1A1. These results suggest that G1 formation is catalyzed by UGT2B4 and UGT2B7, whereas G2 is formed by UGT2B4 and UGT1A1. These three hepatic UGT isoforms may have important roles in carvedilol metabolism.

View larger version (8K): [in this window] [in a new window]   FIG. 1. Chemical structure of carvedilol. The asterisk indicates the chiral center position of the compound.

Carvedilol is administered orally as a racemic mixture of the R(+)- and S(-)-enantiomers. It is absorbed rapidly from the gastrointestinal tract and then undergoes extensive metabolism in the liver (Neugebauer et al., 1987). Previous studies in mammals, including humans, have shown that carvedilol is metabolized by both oxidation and conjugation pathways in the liver and then excreted predominantly into bile, mainly as glucuronide conjugates (Neugebauer et al., 1987; Fujimaki and Hakusui, 1990; Oldham and Clarke, 1997; Schaefer et al., 1998). However, some species differences have also been observed (Schaefer et al., 1998). In humans, oxidative biotransformation of carvedilol occurs primarily on its aromatic ring and oxidized side chains with the resulting metabolites being desmethyl, and 4'- and 5'-hydroxyphenyl carvedilols (0.3-6.4% in plasma and/or urine). Of the metabolites, 4'-hydroxyphenyl carvedilol has a greater ß-adrenoceptor blocking activity than the parent drug (Frishman, 1998). It has been reported that these pathways are mainly catalyzed by a hepatic cytochrome P450 enzyme, CYP2D6 (Zhou and Wood, 1995; Oldham and Clarke, 1997).

With regard to conjugation reactions, glucuronidation is the major metabolic pathway of carvedilol in humans, since the most predominant metabolite is the glucuronide conjugate of unchanged carvedilol (22% in plasma and 32% in urine) (Neugebauer et al., 1987; Neugebauer and Neubert, 1991). Taken together, these findings indicate that glucuronidation is the most important pathway for disposition of carvedilol. Glucuronidation is an important metabolic reaction for metabolic elimination of endogenous and exogenous compounds and is catalyzed by the UDP-glucuronosyltrasferases (UGTs¹), which are endoplasmic reticulum membrane-bound enzymes (Mackenzie et al., 1997). To date, 15 functional UGT isoforms have been identified in humans and classified on the basis of primary amino acid sequence into two families of protein termed UGT1 and UGT2 (Tukey and Strassburg, 2000). Human UGT isoforms have also been reported to be constitutively expressed in a tissue-specific manner in the liver, kidney, lung, small intestines, and brain (Strassburg et al., 1997, 2000; King et al., 2000; Tukey and Strassburg, 2000; Burchell et al., 2001).

Although the primary metabolites of carvedilol are glucuronides, there have been no reports on the UGT isoforms involved in carvedilol glucuronidation. The purpose of this study was to identify the UGT isoforms responsible for carvedilol glucuronidation by kinetic analysis using microsomes from insect cells expressing human UGTs in addition to human liver microsomes.

	Materials and Methods

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Materials. (±)-Carvedilol was kindly supplied by Daiichi Pharmaceutical Co. (Tokyo, Japan). UDP-glucuronic acid, ß-glucuronidase from bovine liver, and alamethicin were purchased from Sigma-Aldrich (St. Louis, MO). [¹⁴C]UDP-glucuronic acid (326 mCi/mmol) was purchased from PerkinElmer Life and Analytical Sciences (Boston, MA). All other chemicals and organic solvents were of the highest quality commercially available. Pooled human liver microsomes (HLMs) from 8 male and 5 female donors (20-70 years old), 17 individual HLMs (6 males, 20-55 years old; 11 females, 2-78 years old), and the human recombinant UGT isoforms (control, 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) that are expressed in insect cell microsomes were purchased from BD Gentest (Woburn, MA). The microsomal protein levels were as described in the data sheets provided by the manufacturers. Thin-layer chromatography (TLC) plates (25 TLC aluminum sheets, 20 x 20 cm Silica gel 60 F254, with a concentration zone 20 x 2.5 cm) were purchased from Merck (Whitehouse Station, NJ).

Assay for Carvedilol Glucuronidation. Carvedilol glucuronidation activity was determined by TLC. The standard incubation mixture contained carvedilol (6.25-100 µM), microsomal proteins (1.0 mg/ml for livers and 3.0 mg/ml for recombinant UGTs), 10 mM MgCl₂, 2 mM UDP-glucuronic acid containing 0.2 µCi [¹⁴C]UDP-glucuronic acid, and alamethicin (25 µg/mg protein for liver microsomes and 8.3 µg/mg protein for recombinant UGTs) in 50 mM Tris-HCl buffer (pH 7.4) in a final volume of 100 µl. The alamethicin concentrations used were predetermined for optimal activity. Carvedilol was dissolved in dimethyl sulfoxide/0.05 N NaOH (50:50, v/v). The final concentration of dimethyl sulfoxide in the reaction mixture was 1.5% (v/v). After preincubation at 37°C for 5 min, the reaction was initiated by the addition of UDP-glucuronic acid. The mixture was incubated for 60 min at 37°C. For hydrolysis with ß-glucuronidase, the incubated mixture was centrifuged to remove the microsomes and then incubated with 26,000 units/ml of ß-glucuronidase for 12 h at 37°C. Then the reaction was terminated by the addition of 100 µl of methanol. After removal of the protein by centrifugation at 6000g for 20 min at 4°C, a 20-µl aliquot of the supernatant was spotted directly onto a TLC plate and subjected to chromatography in a solvent containing chloroform/methanol/ethanol/acetic acid/water (10:4:2:1:1, v/v). The dried plate was exposed for 48 to 96 h to a BAS imaging plate, and the glucuronides were quantified by scanning on a radioisotope imaging analyzer, BAS-1500 (Fuji-film, Tokyo, Japan). The counts measured were linear between 2 pmol and 2000 pmol of [¹⁴C]UDP-glucuronic acid. The intra- and interday variation coefficients did not exceed 7% in any of the assays. Blank samples contained all the components with the exception of UDP-glucuronic acid or carvedilol, which were added after termination of the reaction.

Data Analysis. The kinetic parameters (K_m and V_max) for carvedilol glucuronidation were estimated by analyzing Lineweaver-Burk plots using Prism v3.0 software (GraphPad Software Inc., San Diego, CA). All values are expressed as the mean ± S.D. of three separate experiments.

	Results

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General Properties of Carvedilol Glucuronidation. Microsomes from human liver and insect cells expressing human UGT isoforms (control, 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17) were used to examine carvedilol glucuronidation. Carvedilol glucuronidation was assayed by a TLC method using [¹⁴C]UDP-glucuronic acid as the substrate. A preliminary study showed that the formation of carvedilol glucuronides increased linearly during the 60-min incubation in the presence of 2.0 mg protein/ml for human liver microsomes or 3.0 mg protein/ml for recombinant human UGTs. The representative TLC patterns of pooled HLMs and recombinant human UGTs showing spots of glucuronidated carvedilol are shown in Figs. 2A and 3A, respectively.

View larger version (49K): [in this window] [in a new window]   FIG. 2. Representative TLC pattern (A) and the glucuronidation of carvedilol (B) by pooled HLMs with 100 µM carvedilol carried out under the experimental conditions described under Materials and Methods. In B, each bar represents the mean of three independent experiments.

View larger version (47K): [in this window] [in a new window]   FIG. 3. Representative TLC pattern (A) and the glucuronidation activity of carvedilol (B) by microsomes from insect cells expressing human UGT isoforms with 100 µM carvedilol under the experimental conditions described under Materials and Methods. In B, each bar represents the mean of three independent experiments. Closed bar, G1; hatched bar, G2.

With pooled HLMs, two distinct spots, namely G1 (R_f, 0.50) and G2 (R_f, 0.39), were detected. These spots were decomposed by treatment with ß-glucuronidase ("Hydrolysis" in Fig. 2A), indicating that G1 and G2 were glucuronides. When UDP-glucuronic acid or carvedilol was omitted from the incubation mixture, neither G1 nor G2 was formed. The formation rates of G1 and G2 by pooled HLMs at 100 µM carvedilol were 98 and 33 pmol/min/mg protein, respectively (Fig. 2B). Among the recombinant UGTs examined, three isoforms (1A1, 2B4, and 2B7) were capable of glucuronidating carvedilol (Fig. 3A). UGT2B4 formed both G1 and G2, whereas UGT1A1 and UGT2B7 catalyzed the formation of G2 or G1 only, respectively. The activities for G1 formation by UGT2B4 and UGT2B7 were 6.7 and 6.5 pmol/min/mg protein, respectively, whereas those for G2 by UGT1A1 and UGT2B4 were 2.6 and 2.9 pmol/min/mg protein, respectively (Fig. 3B). G1 or G2 formation activity was not detectable in the other recombinant UGT isoforms.

Since these three UGT isoforms are known to have genetic polymorphisms affecting their enzymatic activities, we then investigated interindividual differences in carvedilol glucuronidation activity among 17 individual HLM preparations (Fig. 4). Carvedilol was used at 50 µM for this analysis, which was comparable to the K_m values of pooled HLMs for G1 and G2 formation (27 and 46 µM, respectively, as described in the following section). Variabilities of 1.9- and 2.7-fold were observed for G1 and G2 formation, respectively.

View larger version (17K): [in this window] [in a new window]   FIG. 4. Interindividual variations of carvedilol glucuronide formation by HLMs prepared from 17 individuals. Carvedilol was used at 50 µM under the experimental conditions described under Materials and Methods. Closed bar, G1; hatched bar, G2.

Kinetic Analysis of Carvedilol Glucuronidation. Carvedilol glucuronidation with microsomes from human liver and insect cells expressing human UGTs (1A1, 2B4, and 2B7) followed Michaelis-Menten kinetics as demonstrated by the Lineweaver-Burk plots, in which all the curves were linear (r = 0.99-1.00) (Fig. 5). The apparent kinetic constants for carvedilol glucuronidation are summarized in Table 1. The K_m values of pooled HLMs and recombinant UGTs for G1 and G2 were 22 to 28 and 29 to 55 µM, respectively. The V_max of pooled HLMs for G1 was 106 pmol/min/mg protein, and V_max/K_m was 4.0 µl/min/mg protein. The glucuronidation activity of pooled HLMs for G2 was lower than that for G1, with the V_max being 45 pmol/min/mg protein and the V_max/K_m being 0.97 µl/min/mg protein. The V_max values of UGT2B4 for G1 and G2 were 7.2 and 3.3 pmol/min/mg protein, and the V_max/K_m values for G1 and G2 were 0.33 and 0.12 µl/min/mg protein, respectively. The respective V_max and V_max/K_m values for G2 production by UGT1A1 were 3.6 pmol/min/mg protein and 0.07 µl/min/mg protein, and 7.9 pmol/min/mg protein and 0.28 µl/min/mg protein for G1 production by UGT2B7.

View larger version (24K): [in this window] [in a new window]   FIG. 5. Lineweaver-Burk plots of carvedilol glucuronidation in microsomes from pooled HLMs and insect cells expressing human UGT1A1, UGT2B4, and UGT2B7. Each point represents the mean of three independent experiments carried out under the experimental conditions described under Materials and Methods. Closed circle, G1; open circle, G2.

	Discussion

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In humans, orally administered carvedilol is absorbed rapidly and then undergoes extensive hepatic metabolism that involves oxidation and conjugation. It has been reported that oxidative metabolism of carvedilol is catalyzed generally by CYP2D6, which also metabolizes a number of other ß-blockers such as metoprolol, propranolol, and bufuralol (Madani et al., 1999; Johnson et al., 2000; Narimatsu et al., 2002). However, with the exception of propranolol, there are no reports on the human UGT isoforms involved in the glucuronidation of ß-blockers (Coffman et al., 1998; Li et al., 2001). Since glucuronidation is the predominant metabolic pathway of carvedilol, identification of the human liver UGT isoforms participating in this process is important for safe usage of this drug.

Carvedilol has three potential conjugation sites, the aliphatic secondary hydroxyl group at the chiral center, the aliphatic secondary amino group, and the carbazolyl amine moiety, and therefore, it can be glucuronidated to form N- and/or O-glucuronides (Fig. 1). In the present study, two types of carvedilol glucuronides (G1 and G2) were identified, although due to the limited quantity of the products, we could not determine the structures of these glucuronides.

A number of in vitro approaches have been developed for identifying the human UGT isoforms involved in the glucuronidation of endogenous and exogenous compounds (Ritter, 2000; Tukey and Strassburg, 2000). Using insect microsomes expressing human recombinant UGT isoforms, we first observed that at least three UGT isoforms, UGT1A1, UGT2B4, and UGT2B7, catalyzed carvedilol glucuronidation. Genetic polymorphisms of the three UGTs have been documented, some of which affect the enzymatic activities [e.g., UGT1A1^*28 and UGT2B4^*3 (http://som.flinders.edu.au/FUSA/Clin-Pharm/UGT/)]. In the present study, we observed approximately 2- to 3-fold interindividual differences for G1 and G2 formation among HLMs prepared from 17 individuals (Fig. 4). Thus, further studies are required to clarify whether genetic polymorphisms of these UGT isoforms lead to differences in the clinical response to carvedilol. Changes in the carvedilol glucuronidation activity of variant forms of the three UGTs also should be determined in vitro in the future.

To elucidate the affinity and activity of the UGT enzymes for carvedilol, kinetic analyses for carvedilol glucuronidation were carried out using Lineweaver-Burk plots. The K_m values for G1 were lower than those for G2 in microsomes from both human liver and insect cells expressing UGT2B4. In contrast, the V_max and V_max/K_m values for G1 were higher than those for G2. UGT2B7 formed G1 only, with K_m and V_max/K_m values comparable to those for UGT2B4. On the other hand, G2 formation by UGT1A1 had higher K_m and lower V_max/K_m values than those of UGT2B4. These results suggest that G1 formation is catalyzed by both UGT2B4 and UGT2B7, whereas G2 is formed by UGT2B4 and UGT1A1. The relative contributions of UGT1A1, UGT2B4, and UGT2B7 to carvedilol glucuronidation are not clear at present, since this also depends on their expression levels in the liver. UGT1A1 is known to glucuronidate bilirubin as well as many therapeutic drugs such as an active metabolite of irinotecan, SN-38 (7-ethyl-10-hydroxycamptothecin) (Iyer et al., 1998). UGT2B4 glucuronidates the bile acid and hyodeoxycholic acid (Pillot et al., 1993), whereas UGT2B7 catalyzes the glucuronidation of opioids such as morphine and naloxone (Coffman et al., 1998; Ritter, 2000). The present study suggests that the two UGT2B subfamily enzymes, UGT2B4 and UGT2B7, as well as UGT1A1, are responsible for the glucuronidation of carvedilol.

In conclusion, UGT1A1, UGT2B4, and UGT2B7 as well as human hepatic microsomes were capable of catalyzing carvedilol glucuronidation. Two glucuronides were differentially formed depending on the UGT isoforms. G1 was formed by UGT2B4 and UGT2B7, whereas UGT2B4 and UGT1A1 catalyzed G2 formation. These findings suggest that these three UGT isoforms are the main contributors to carvedilol glucuronidation in humans.

	Acknowledgments

 
We thank Daiichi Pharmaceutical Co. (Tokyo, Japan) for generously donating (±)-carvedilol. We also appreciate the generous support of Chie Knudsen.

	Footnotes

 
This study was supported by the Program for the Promotion of Fundamental Studies in Health Sciences (MPJ-6) of the Organization for Pharmaceutical Safety and Research of Japan.

¹ Abbreviations used are: UGT, UDP-glucuronosyltransferase; HLM, human liver microsomes; TLC, thin-layer chromatography; SN-38, 7-ethyl-10-hydroxycamptothecin.

Address correspondence to: Dr. Akiko Ohno, Division of Environmental Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: a-ohno{at}nihs.go.jp

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohno, A. Articles by Sawada, J.-i. Search for Related Content PubMed PubMed Citation Articles by Ohno, A. Articles by Sawada, J.-i.