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SHORT COMMUNICATION

LANSOPRAZOLE ENANTIOMER ACTIVATES HUMAN LIVER MICROSOMAL CYP2C9 CATALYTIC ACTIVITY IN A STEREOSPECIFIC AND SUBSTRATE-SPECIFIC MANNER

Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine and Clinical Pharmacology Center, Busan Paik Hospital, Busan, Korea

(Received July 12, 2004; accepted November 5, 2004)

	Abstract

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We recently proposed a possible stereoselective activation by lansoprazole of CYP2C9-catalyzed tolbutamide hydroxylation, as well as stereoselective inhibition of several cytochrome P450 (P450) isoforms. This study evaluated the effects of lansoprazole enantiomers on CYP2C9 activity in vitro, using several probe substrates. For tolbutamide 4-methylhydroxylation and phenytoin 4-hydroxylation, R-lansoprazole was an activator (140 and 550% of control at 100 µM R-lansoprazole, EC₅₀ values of 19.9 and 30.2 µM, respectively). R-Lansoprazole-mediated activation of the formation of 4-hydroxyphenytoin was also seen with recombinant human CYP2C9. R-Lansoprazole increased the Michaelis-Menten-derived V_max of phenytoin 4-hydroxylation from 0.024 to 0.121 pmol/min/pmol P450, and lowered its K_m from 20.5 to 15.0 µM, suggesting that R-lansoprazole activates CYP2C9-mediated phenytoin metabolism without displacing phenytoin from the active site. Kinetic parameters were also estimated using the two-site binding equation, with values <1 and ß values >1, indicative of activation. Additionally, phenytoin at 10 to 200 µM had no reciprocal effect on the hydroxylation of R-lansoprazole. Meanwhile, R-lansoprazole had no activation effect on diclofenac and S-warfarin metabolism in the incubation study using both recombinant CYP2C9 and human liver microsomes. These substrate-dependent activation effects suggest that phenytoin has a different binding orientation compared with diclofenac and S-warfarin. Overall, these results suggest that R-lansoprazole activates CYP2C9 in a stereospecific and substrate-specific manner, possibly by binding within the active site and inducing positive cooperativity. This is the first report to describe stereoselective activation of this cytochrome P450 isoform.

Although reactions involving atypical kinetics are most commonly associated with CYP3A4 (Shou et al., 1994; Galetin et al., 2002), they have also been noted with CYP2C9. CYP2C9 is prone to both activation and inhibition effects in drug-interaction studies. Substrate auto- and heteroactivation (Korzekwa et al., 1998; Hutzler et al., 2001b, 2002, 2003; Hummel et al., 2004), substrate inhibition (Lin et al., 2001), and biphasic kinetics (Korzekwa et al., 1998; Hutzler et al., 2001b) observed for CYP2C9 might be explained by different binding domains for substrates and modifiers within the enzyme-active site. The crystal structure indicates that multiple substrates/ligands may be bound to CYP2C9 simultaneously, which is consistent with reports that suggest a "two-site model" for CYP2C9 activity (Hutzler et al., 2001b; Williams et al., 2003).

Lansoprazole at therapeutic concentrations is metabolized, mainly by CYP2C19 and CYP3A4, to its hydroxy and sulfone metabolites, respectively, and is also metabolized by CYP2C9 to hydroxylansoprazole (Kim et al., 2002, 2003). Recently, we found that lansoprazole caused stereoselective inhibition of several P450 isoforms. Interestingly, R-lansoprazole activated CYP2C9-catalyzed tolbutamide 4-methylhydroxylation, but S-lansoprazole inhibited it. It appears that lansoprazole is also a substrate for the enzyme that it activates, suggesting that lansoprazole may cause activation by binding in the active site of CYP2C9. This scenario is analogous to that of dapsone and quinidine, which activate CYP2C9-mediated 4'-hydroxylation of flurbiprofen (Korzekwa et al., 1998) and CYP3A4-mediated 5'-methylhydroxylation of meloxicam (Ludwig et al., 1999), respectively.

A number of reports have addressed the activation of P450-catalyzed oxidative metabolism, but none has described enantioselectivity in P450 activation. The present study evaluated the selectivity of lansoprazole enantiomers on CYP2C9 activation, using different CYP2C9 probe substrates. We also characterized the enzyme kinetics of activation of CYP2C9-mediated metabolism and the effects of CYP2C9 substrates on lansoprazole metabolism.

	Materials and Methods

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Chemicals and Reagents. 4-Hydroxyphenytoin, lansoprazole, phenytoin, tolbutamide, ß-nicotinamide adenine dinucleotide phosphate (ß-NADP⁺), glucose 6-phosphate, and glucose-6-phosphate dehydrogenase were purchased from Sigma-Aldrich (St. Louis, MO). Diclofenac, 4-hydroxydiclofenac, 7-hydroxywarfarin, 4-methylhydroxytolbutamide, and S-warfarin were purchased from Ultrafine Chemical Co. (Manchester, UK). All reagents were of analytical or HPLC grade. Hydroxylansoprazole was the generous gift of Dr. Ichiro Ieiri (Department of Hospital Pharmacy, Faculty of Medicine, Tottori University). Individual R- and S-lansoprazole enantiomers were separated by chiral semipreparative HPLC on a Chiralpak AS column (10 µm, 4.6 x 250 mm; Daicel Chemical Co., Tokyo, Japan), as described by Katsuki et al. (1996).

Human Liver Microsomes and Recombinant P450. Human liver tissues (HL-10, HL-14, and HL-18) were obtained, with informed consent and with institutional review board approval, from patients undergoing partial hepatectomy for removal of metastatic tumors at the Department of General Surgery, Busan Paik Hospital (Busan, Korea). Microsomes were prepared by differential centrifugation of liver homogenates, as described previously (Shin et al., 1999). Human recombinant CYP2C9 (Supersomes) were purchased from BD Gentest (Woburn, MA).

P450 Reaction Conditions. Briefly, each incubation was performed with 0.5 mg/ml pooled human liver microsomes (HL-10, -14, and -18) in 50 mM phosphate buffer, pH 7.4, at a final volume of 0.25 ml. The incubation mixtures containing microsomes, CYP2C9 probe substrates, and effector (lansoprazole, 1–100 µM) were preincubated for 5 min at 37°C. Substrates were used at concentrations approximately equal to their respective K_m values: 15 µM for diclofenac, 50 µM for phenytoin, 50 µM for tolbutamide, and 5 µM for S-warfarin. After preincubation, reactions were initiated at 37°C by addition of the NADPH-generating system (3.3 mM glucose 6-phosphate, 1.3 mM ß-NADP⁺, 3.3 mM MgCl₂, and 1.0 unit/ml glucose-6-phosphate dehydrogenase) and stopped after the specified time by placing the incubation tubes on ice and adding 100 µl of either ice-cold acetonitrile or 10% perchloric acid, depending on the reaction, as described previously (Bourrie et al., 1996; Shin et al., 1999, Kim et al., 2003). Incubation mixtures were centrifuged at 20,000g for 10 min at 4°C, and aliquots of the supernatants were analyzed by HPLC.

Incubations using 20 pmol P450/ml isolated from baculovirus-infected insect cells expressing CYP2C9 were also performed using CYP2C9 probe substrates as above. In the experiments examining the effects of phenytoin on lansoprazole hydroxylation, the phenytoin concentrations ranged from 0 to 200 µM, and the lansoprazole concentrations ranged from 0 to 50 µM. Reactions were stopped by the addition of 0.1 ml of cold acetonitrile. All other conditions were as described above. All incubations were performed in duplicate, and the mean values were used for analysis.

Measurement of Reaction Products. HPLC assays similar to those previously described (Bourrie et al., 1996; Shin et al., 1999; Kim et al., 2003) were used to quantify products of CYP2C9-mediated reactions. The reactions investigated were diclofenac 4-hydroxylation, phenytoin 4-hydroxylation, tolbutamide 4-methylhydroxylation, S-warfarin 7-hydroxylation, and lansoprazole 5-hydroxylation. The HPLC system consisted of a model 307 pump, a model 234 autoinjector, and a model 118 UV/visible detector (Gilson Co., Villiers Le Bel, France). The Unipoint analysis system (Gilson Co.) was used to calculate analyte concentrations from peak area ratios.

Data Analysis. Kinetic parameters for phenytoin hydroxylation were estimated using the nonlinear least-squares regression function of WinNonlin software (Pharsight, Mountain View, CA), and the standard Michaelis-Menten equation:

(1)

where is the velocity of the reaction at substrate concentration S, V_max is the maximum velocity of the enzyme, and K_m is the substrate concentration at which the reaction velocity is 50% of V_max.

To quantify the activation of CYP2C9-catalyzed phenytoin 4-hydroxylation, we used a two-site binding model including an activator, as described previously by Korzekwa et al. (1998). The velocity of phenytoin hydroxylation in the presence of activator, R-lansoprazole, can be described by the following equation:

(2)

where S is the substrate (phenytoin), B is the effector (R-lansoprazole), V_max and K_m are kinetic constants for substrate metabolism, K_B is the binding constant for the effector, is the change in K_m resulting from effector binding, and ß is the change in V_max from effector binding. For activation, < 1 and/or ß > 1.

The apparent enzyme inhibition or activation parameters of lansoprazole enantiomers [IC₅₀ or EC₅₀ (concentration effective in causing 50% of maximal activation)] were determined from a nonlinear least-squares regression analysis of the best-fit enzyme inhibition model and enzyme kinetic model (Segel, 1975) using WinNonlin software (Pharsight, Mountain View, CA). The following information provided by WinNonlin was used to evaluate the goodness of fit and the quality of parameter estimates: coefficients of variation of parameter estimates (CVs), parameter correlation matrix, sums of squares of residuals, visual examination of the distribution of residuals, and Akaike information criterion.

	Results and Discussion

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Although many studies have demonstrated activation of P450-catalyzed metabolism (e.g., Shou et al., 1994; Hutzler et al., 2002), none have demonstrated enantioselective activation of P450 isoforms. In this report, we describe the stereoselective activation of human liver microsomal CYP2C9 by lansoprazole. R-Lansoprazole (100 µM) activated CYP2C9-catalyzed tolbutamide 4-methylhydroxylation (140% of control, EC₅₀ of 19.9 µM) and phenytoin 4-hydroxylation (550% of control, EC₅₀ of 30.2 µM). S-Lansoprazole, however, inhibited tolbutamide hydroxylation (IC₅₀ 54.0 µM) and had no effect on phenytoin hydroxylation (Fig. 1, A and B). Stereoselectivity of activation has been reported for phase II enzyme activity; the R-isomer of zileuton competitively activates the glucuronidation of the S-isomer in vitro (Sweeny and Nellans, 1992). The activation of phenytoin hydroxylation by R-lansoprazole was also observed with recombinant human CYP2C9. R-Lansoprazole (100 µM) caused an 8-fold increase in phenytoin 4-hydroxylation, with an EC₅₀ of 16.2 µM (Fig. 2A), indicating that the CYP2C9 isoform is involved in the microsomal activation reaction. However, the activation of tolbutamide hydroxylation by R-lansoprazole was not observed in recombinant CYP2C9, confirming previous reports that many of these kinetic events are expression system-dependent (Ekins et al., 1998).

View larger version (25K): [in this window] [in a new window]   FIG. 1. Effect of racemic lansoprazole (), R-lansoprazole (), and S-lansoprazole () on CYP2C9-catalyzed phenytoin 4-hydroxylation (A), tolbutamide 4-methylhydroxylation (B), S-warfarin 7-hydroxylation (C), and diclofenac 4-hydroxylation (D) in pooled human liver microsomes. Microsomes were incubated with 50 µM phenytoin, 50 µM tolbutamide, 5 µM S-warfarin, or 15 µM diclofenac and various concentrations of lansoprazole. The corresponding control activities of phenytoin 4-hydroxylation, tolbutamide 4-methylhydroxylation, S-warfarin 7-hydroxylation, and diclofenac 4-hydroxylation were 0.011, 0.11, 0.012, and 10.1 nmol min-1 mg-1 protein, respectively. Data shown are averages of duplicate experiments.

View larger version (26K): [in this window] [in a new window]   FIG. 2. Effect of racemic lansoprazole (), R-lansoprazole (), and S-lansoprazole () on CYP2C9-catalyzed phenytoin 4-hydroxylation (A), tolbutamide 4-methylhydroxylation (B), S-warfarin 7-hydroxylation (C), and diclofenac 4-hydroxylation (D) in recombinant human CYP2C9. Microsomes were incubated with 50 µM phenytoin, 50 µM tolbutamide, 5 µM S-warfarin, or 15 µM diclofenac and various concentrations of lansoprazole. The corresponding control activities of phenytoin 4-hydroxylation, tolbutamide 4-methylhydroxylation, S-warfarin 7-hydroxylation, and diclofenac 4-hydroxylation were 0.016, 2.71, 0.040, and 22.5 pmol min-1 pmol-1 P450, respectively. Data shown are averages of duplicate experiments.

The effect of R-lansoprazole on the kinetics of phenytoin 4-hydroxylation by recombinant human CYP2C9 was further investigated (Fig. 3). In the absence of R-lansoprazole, K_m and V_max for phenytoin hydroxylation were 20.5 µM and 0.024 pmol/min/pmol P450, respectively. The V_max of phenytoin hydroxylation activity increased with increasing R-lansoprazole concentrations, and the K_m decreased (Table 1). Kinetic parameters for phenytoin metabolism were also estimated using a two-site enzyme kinetic model for activation (eq. 2). The results further support R-lansoprazole activation of phenytoin hydroxylation; the value was 0.59 ± 0.29, and the ß value was 7.05 ± 2.93, indicating activation (Korzekwa et al., 1998). As observed for quinidine (Ludwig et al., 1999) or 7,8-benzoflavone (Shou et al., 1994) metabolism by CYP3A4 and for dapsone metabolism by CYP2C9 (Korzekwa et al., 1998), R-lansoprazole is also a substrate for the enzyme that it activates. We investigated the effect of phenytoin on hydroxylansoprazole formation by CYP2C9; neither had a significant effect, generating velocity curves similar to that seen with R-lansoprazole alone (Fig. 4A). V_max values for lansoprazole hydroxylation ranged from 0.038 to 0.041 pmol/min/pmol P450, and K_m values ranged from 5.8 to 7.3 µM. These results suggest that both substrates (or substrate and activator) can be present simultaneously in the enzyme-active site (Shou et al., 1994; Hutzler et al., 2001b). Indeed, its crystal structure also indicates that CYP2C9 may have the capacity to bind multiple substrates simultaneously during catalysis (Williams et al., 2003). Meanwhile, hydroxylansoprazole formation from S-lansoprazole was somewhat inhibited by addition of phenytoin in a concentration-dependent manner (Fig. 4B), suggesting that S-lansoprazole and phenytoin could competitively bind in the same enzyme active site.

View larger version (31K): [in this window] [in a new window]   FIG. 3. Three-dimensional surface plot showing activation of phenytoin 4-hydroxylation by R-lansoprazole in recombinant human CYP2C9. The surface is the fit to eq. 2.

View larger version (22K): [in this window] [in a new window]   FIG. 4. Effect of phenytoin on R-lansoprazole (A) and S-lansoprazole (B) hydroxylation catalyzed by recombinant human CYP2C9. Recombinant CYP2C9 was incubated in the presence of 0, 10, 50, and 200 µM phenytoin. Data shown are averages of duplicate experiments.

In this study, additional R-lansoprazole effects on CYP2C9-mediated metabolism in human liver microsomes were substrate-specific. S-Warfarin hydroxylation was inhibited (IC₅₀ 67.9 µM), but diclofenac 4-hydroxylation was unaffected (Fig. 1, C and D). The substrate dependence of lansoprazole effects on CYP2C9-mediated metabolism was also observed with recombinant human CYP2C9. R-Lansoprazole did not show stereoselective activation on S-warfarin hydroxylation and diclofenac hydroxylation, in contrast to phenytoin hydroxylation (Fig. 2). Substrate-dependent effects have been extensively studied in CYP3A4 and have been attributed to action at multiple and cooperative binding sites within the active site (Korzekwa et al., 1998; Galetin et al., 2002; Egnell et al., 2003).

Whereas we have demonstrated the stimulation of phenytoin metabolism by R-lansoprazole in vitro, similar activations have been shown to occur in vivo. Tang et al. (1999) reported that the decrease in plasma concentrations of diclofenac observed when combined with quinidine treatment in the monkey reflected an increased hepatic clearance of the former drug, presumably resulting from the stimulation of CYP3A4-catalyzed oxidative metabolism. Additionally, Hutzler et al. (2001a) reported that apparent oral clearance of flurbiprofen was increased by 11% after 7 days of treatment with 100 mg of dapsone, consistent with the hypothesis that dapsone cooperatively enhances the metabolism of flurbiprofen in vivo. The in vivo activation potential of R-lansoprazole on phenytoin metabolism remains to be evaluated.

In conclusion, lansoprazole activates CYP2C9-mediated metabolism in a stereo- and substrate-specific manner, consistent with a model in which R-lansoprazole and substrate may fit into the active site simultaneously. In addition, our results show that lansoprazole enantiomers have different drug-interaction potentials for CYP2C9-mediated metabolism. In vitro drug-interaction studies with enantiomers, in addition to racemic mixtures, should be considered in the development of chiral drugs.

	Footnotes

 
This work was supported by a grant from the Ministry of Science and Technology, Korea (National Research Laboratory Program).

Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.104.001438.

ABBREVIATIONS: P450, cytochrome P450; HPLC, high-performance liquid chromatography.

Address correspondence to: Dr. Jae-Gook Shin, Associate Professor of Pharmacology, Director, PharmacoGenomics Research Center, Inje University College of Medicine, # 633-165, Gaegum-Dong, Jin-Gu, Busan 614-735, South Korea. E-mail: phshinjg{at}inje.ac.kr

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This Article Abstract Full Text (PDF) All Versions of this Article: dmd.104.001438v1 33/2/209    most recent 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 Liu, K.-H. Articles by Shin, J.-G. Search for Related Content PubMed PubMed Citation Articles by Liu, K.-H. Articles by Shin, J.-G.