Drug Metabolism and Disposition Fast Forward
First published on September 20, 2005; DOI: 10.1124/dmd.105.006593
0090-9556/05/3312-1765-1770$20.00
DMD 33:1765-1770, 2005
SHORT COMMUNICATION
TRANSAMINATION IN THE METABOLISM OF THE NEPHROTOXICANT N-(3,5-DICHLOROPHENYL)SUCCINIMIDE IN RATS
Donghui Cui,
Gary O. Rankin, and
Peter J. Harvison
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania (D.C., P.J.H.); Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania (D.C.); and Department of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia (G.O.R.)
(Received July 14, 2005;
Accepted September 14, 2005)
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Abstract
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The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Due to the involvement of NDPS metabolism in its mechanism of toxicity, the detailed biotransformation of 14C-NDPS in rats was previously evaluated using high-performance liquid chromatography-electrospray ionization-mass spectrometry. In the present report, we describe the identification of two novel amino metabolites of NDPS, which were present in significant amounts in rat kidney tissues. Using liquid chromatography-tandem mass spectrometry and synthetic standards, the two metabolites were identified as N-(3,5-dichlorophenyl)-2-aminosuccinamic acid (2-NDASA) and its N-acetylated derivative (N-acetyl-2-NDASA). The mechanism of formation of 2-NDASA was studied in vitro. Incubations were carried out in rat liver and kidney cytosols using the major oxidative metabolite of NDPS, N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid, as the substrate. Formation of 2-NDASA in vitro was confirmed using mass spectrometry. Inhibitors of alcohol dehydrogenase (4-methylpyrazole) and aldehyde dehydrogenase (disulfiram) reduced 2-NDASA formation by 40 to 50%. Menadione (an inhibitor of aldehyde oxidase) and quercetin (an inhibitor of carbonyl reductase) did not show any effects. (Aminooxy)acetic acid, an inhibitor of pyridoxal 5'-phosphate-containing enzymes such as aminotransferases, almost completely abolished the formation of 2-NDASA. Using liquid chromatography-mass spectrometry, the transamination mechanism was further supported by the incorporation of a 15N-amino group in 2-NDASA when 15N-glutamic acid was included in the incubation mixture. Results from these studies show that transamination is a metabolic pathway in the clearance of NDPS in rats, and that cytosolic dehydrogenases and aminotransferases may be involved in this process.
N-(3,5-Dichlorophenyl)succinimide (NDPS; Fig. 1) was originally synthesized as an agricultural antifungal agent (Fujinami et al., 1972
). In subsequent testing, NDPS was shown to be nephrotoxic in male rats at doses 
0.4 mmol/kg following acute administration (Rankin, 1982; Rankin et al., 1985). Although not widely used, NDPS remains on the market as an agricultural fungicide, and it has been studied extensively as a model compound for chemically induced kidney damage (Rankin, 2004).
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FIG. 1. Proposed metabolic scheme for the formation of the amino metabolites of NDPS. The  -keto acid intermediate (in brackets) was not monitored in the experiments.
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Studies in rats have shown that NDPS is well absorbed, widely distributed (highest in kidney), and rapidly eliminated, mainly as metabolites in urine (Ohkawa et al., 1974; Griffin and Harvison, 1998). The major in vivo metabolites of NDPS are N-(3,5-dichlorophenyl)succinamic acid (NDPSA), N-(3,5-dichlorophenyl)-2- and 3-hydroxysuccinamic acids (2- and 3-NDHSA), and N-(3,5-dichlorophenyl)malonamic acid (Ohkawa et al., 1974; Griffin and Harvison, 1998). Glucuronide/sulfate and glutathione-derived conjugates of 2-/3-NDHSA and NDPS/NDPSA, respectively, have also been reported (Cui et al., 2005). Both phase I and II metabolic pathways may be involved in the formation of a nephrotoxic species from NDPS (Rankin et al., 1987; Nyarko et al., 1997; Hong et al., 1999a,b; Cui et al., 2005). Using liquid chromatography-MS/MS (Cui et al., 2005), we tentatively identified two novel amino-derived metabolites of NDPS, N-(3,5-dichlorophenyl)-2-aminosuccinamic acid (2-NDASA) and its N-acetylated derivative (N-acetyl-2-NDASA). These two metabolites accounted for 34.5 ± 5.3% and 11.5 ± 2.0% of the total radioactivity in rat kidney and liver, respectively. A potential scheme for the formation of these two metabolites from 2-NDPSA is shown in Fig. 1. The experiments described in this report were conducted to further characterize the amino metabolites and investigate the mechanism of formation of 2-NDASA in vitro.
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Materials and Methods
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Chemicals. 2-NDHSA and NDPSA were prepared by the methods of Kellner-Weibel et al. (1997) and Fujinami et al. (1972), respectively. All reagents were of the highest purity commercially available and were purchased from Sigma-Aldrich (St. Louis, MO) unless otherwise noted. Protected aspartic acid analogs, Z-O-methyl-N-carbobenzoxyaspartic acid (Z-Asp-OMe) and Z-O-methyl-N-acetylaspartic acid (Ac-Asp-OMe), were obtained from Bachem Biosciences (King of Prussia, PA).
Animals. Male Fischer 344 rats (200–250 g) were obtained from Charles River Laboratories (Wilmington, MA) and were given a 1-week acclimation period before use. All experiments were approved by the Institutional Animal Care and Use Committee of the University of the Sciences in Philadelphia and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (U.S. National Institutes of Health).
In Vitro Formation of 2-NDASA. Rat liver and kidney cytosols were prepared using a standard method (Rodrigues et al., 1994). Final incubation mixtures (1 ml) contained 0.1 M (pH 7.4) potassium phosphate buffer, 2.5 mM MgCl2, 100 µM 2-NDHSA, and 2 mg/ml cytosolic proteins. Control incubations were performed with boiled cytosols or in the absence of cytosolic fractions. Mixtures were prewarmed at 37°C for 3 min and reactions were started with the addition of 2-NDHSA in DMSO (in 5 µl of DMSO to give the final concentration of 100 µM). The mixtures were incubated at 37°C for 60 min in a shaking water bath and were stopped with the addition of 2 ml of ice-cold acetonitrile containing NDPSA (2 µM) as the internal standard. The mixtures were then centrifuged and the supernatants were evaporated to dryness under vacuum. Residues were reconstituted into 30% acetonitrile in water for HPLC-MS/MS analysis.
The involvement of different enzymes in the formation of 2-NDASA was studied using a variety of enzyme inhibitors. 4-Methylpyrazole, disulfiram, menadione, quercetin, and aminooxyacetic acid (AOAA) were dissolved in acetonitrile and 5 µl was used (to give a final concentration of 100 µM for each inhibitor). Involvement of a transamination reaction was further evaluated using L-glutamic acid (a common amino group donor) and 15N-L-glutamic acid. The amino group donors were dissolved in water and 100 µl was used for a final concentration of 100 µM. Incubations in the absence of enzyme inhibitors (5 µl of acetonitrile only) were used as the no-inhibitor controls. After a 10-min preincubation, reactions were started with the addition of 2-NDHSA (in 5 µl of DMSO for a final concentration of 100 µM). Incubation conditions and sample treatments were the same as described above.
HPLC-MS/MS. Formation of 2-NDASA in rat liver and kidney cytosols was determined using an HPLC-MS/MS assay. The system consisted of an Agilent HP1100 HPLC apparatus coupled to a Finnigan TSQ7000 triple quadrupole mass spectrometer. Analytes were eluted on a Phenomenex Luna C18-2 column (2.0 x 50 mm, 5 µm; Phenomenex, Torrance, CA) using 25 mM ammonium formate, pH 3 (A) and 0.1% formic acid in acetonitrile (B) as mobile phase components. The HPLC was operated at a flow rate of 0.25 ml/min and the elution gradient was as follows: 0 to 10 min, 10% to 90% B; 10 to 11 min, 90% B; and 11 to 12 min, 90% to 10% B. The system was re-equilibrated at 10% B for 8 min before the next injection.
2-NDASA formation was monitored using positive electrospray ionization-MS. Single reaction monitoring scans with the precursor ion at m/z 277 and the product ion at m/z 162 were performed to detect 2-NDASA. The internal standard, NDPSA, was monitored under negative electrospray ionization, and single reaction monitoring scans from m/z 260 to m/z 160 were used. Under the HPLC conditions described, NDPSA and 2-NDASA had retention times of 7.2 min and 9.4 min, respectively. Collision energy at ±25 eV and collision gas (argon) at 1.7 mtorr were used in all scans. The assay exhibited a linear dynamic range of 0.05 to 64 µM for 2-NDASA.
Chemical Syntheses. N-(3,5-Dichlorophenyl)-2-aminosuccinamic Acid (2-NDASA). The protected aspartic acid, Z-Asp-OMe (281.3 mg, 1 mmol), was dissolved in 20 ml of dichloromethane containing 0.5% triethylamine. 3,5-Dichloroaniline (162.0 mg, 1 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (155.2 mg, 1 mmol) were then added into the solution and the resulting mixture was stirred at room temperature for 2 h. The mixture was cooled to –10°C and BBr3 (10 ml of a 1 M solution in hexane) was added dropwise while stirring. After stirring for another hour at room temperature, the reaction was stopped with the addition of water (50 ml, dropwise). The dichloromethane layer was washed three times with water (25 ml) and the combined water layers were dried under vacuum. Residues were then purified using a semipreparative HPLC system equipped with Agilent HP1100 pumps and a Zorbax Rx-C8 column (9.6 mm x 25 cm, 5 µm). Water along with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B) were used as the mobile phase components, and the flow rate was 2 ml/min. The gradient was as follows: 0 to 15 min, 10 to 40% B; 16 to 19 min, 80% B; 19 to 20 min, 80 to 10% B; and the column was re-equilibrated at 10% B for 6 min before the next injection. Structure of the isolated product was confirmed by 1H NMR (300 MHz) and liquid chromatography-MS/MS. 1H-NMR (d6-DMSO): 
2.99 (m, 2H, –CH2CONH–), 4.13 (m, 1H, –CHNH2), 7.33 and 7.65 (s, 3H, C6H3Cl2–). MS/MS [CID of (M – H)– at m/z 275]: 258 [(M – H)–-NH3], 214 [(M – H)–-NH3-CO2], 160 (dichloroaniline-H), 114 [(M – H)–-dichloroaniline].
N-(3,5-Dichlorophenyl)-2-N-Acetylaminosuccinamic Acid (N-acetyl-2-NDASA). N-acetyl-2-NDASA was synthesized using the same method as described above for the synthesis of 2-NDASA, except that Ac-Asp-OMe (189.2 mg, 1 mmol) was used as the starting protected aspartic acid. The reaction product was isolated using the same preparative HPLC system described above. 1H NMR and MS/MS characteristics of the N-acetyl-2-NDASA product were as follows: 1H NMR (d6-DMSO): 1.83 (s, 3H, CH3CO–), 2.73 (m, 2H, –CH2CONH–), 4.58 (m, 1H, –CHNHCOCH3), 7.27 and 7.64 (s, 3H, C6H3Cl2). MS/MS [CID of (M – H)– at m/z 317]: 299 [(M – H)–-H2O], 257 [(M – H)–-H2O-C2H2O), 160 (dichloroaniline-H), 156 [(M – H)–-dichloroaniline].
Statistical Analyses. Statistical tests were performed using the SigmaStat, version 2.03 (copyright Jandel Corporation, 1986–1992) software package. Analyses included descriptive statistics and comparisons of group means by a one-way ANOVA followed by the Student-Newman-Keuls test. A 5% level of significance was used for all analyses.
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Results and Discussion
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In a previous study (Cui et al., 2005), two amino-derived metabolites of NDPS were detected in male Fischer 344 rats and we numbered them M6 and M8. The two metabolites were detected in higher concentrations in rat kidney tissues than in liver (M6, 0.3 versus 0.1 µmol/g of tissue; M8, 0.2 versus 0.1 µmol/g of tissue) (Cui et al., 2005). The purpose of the current study was to further characterize these metabolites and investigate the mechanism of formation of M6 in vitro.
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FIG. 2. Mass spectral analysis of an incubate of 2-NDHSA (substrate) with rat liver cytosols. A, HPLC-extracted ion chromatograms of m/z 276 for 2-NDHSA; B, extracted ion chromatograms of m/z 275 showing the formation of 2-NDASA; C, negative CID product ion spectrum of m/z 275; and D, positive CID product ion spectrum of m/z 277.
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HPLC-extracted ion chromatograms of 2-NDHSA and its incubation product with rat liver cytosols are shown in Fig. 2, A and B, respectively. Under the HPLC conditions previously used for in vivo samples, the incubation product had a retention time and MS spectrum identical to those of M6 observed in rat urine and tissue homogenates (Cui et al., 2005). In negative Q1 scans the incubation product (M6) had an (M – H)– ion at m/z 275. The negative CID mass spectra of m/z 275 (Fig. 2C) for M6 and the synthetic standard of 2-NDASA (see Materials and Methods) exhibited major MS/MS fragments at m/z 258, 214, 160, and 114. Loss of ammonia in M6 (from m/z 275 to m/z 258, loss of 17 Da) and the subsequent loss of a carboxylic group (44 Da to m/z 214) suggested the structure of M6 as an amino derivative of NDPSA. To further characterize the position of the amino group, positive CID scans of m/z 277 for M6 were performed (Fig. 2D). Fragment ions at m/z 231 and m/z 74 provided evidence that the amino group was attached to the carbon at the 2-position of NDPSA. The fragment ion at m/z 116 also supported the notion that an amino group was added to the succinamic acid moiety. Since the HPLC retention times and MS/MS spectra of M6 formed in vitro (Fig. 2C) and in vivo (Cui et al., 2005) were identical to those obtained from synthetic 2-NDASA, M6 was identified as 2-NDASA.
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FIG. 3. Effect of various enzyme inhibitors on the formation of 2-NDASA in rat liver cytosols. Results are expressed as means ± S.D. (n = 6). *, values that are significantly different (p < 0.05) from the corresponding results in the complete incubations.
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Metabolite M8 was previously observed in rat urine and liver and kidney homogenates, and was tentatively identified as the N-acetyl derivative of M6 (Cui et al., 2005). In the current study, we used liquid chromatography-MS and a synthetic standard to confirm the proposed structure of M8 as N-acetyl-2-NDASA. Major MS/MS fragments at m/z 299, 257, and 160 were found in the negative CID mass spectrum of m/z 317 for synthetic N-acetyl-2-NDASA (see Materials and Methods) and M8 (Cui et al., 2005). Although M6 and M8 were detected in hepatic and renal homogenates prepared from rats that received NDPS (Cui et al., 2005), only M6 was produced by rat liver and kidney cytosols. This may be due to insufficient cofactor, i.e., acetyl coenzyme A, being present in the cytosolic preparations to support the acetylation of M6 to M8 in vitro. Fortifying acetyl coenzyme A in rat cytosolic incubations has been shown to produce acetylated metabolites that were absent without the cofactor (Martire et al., 1991). Alternatively, it is also possible that the acetylation reaction is not cytosolic. For example, evidence exists that aliphatic amines may be acetylated by liver and kidney microsomal enzymes in the presence of acetyl coenzyme A (Green and Elce, 1975).
A scheme depicting the metabolic pathways involved in the formation of 2-NDASA (M6) and its acetylated derivative (M8) is proposed in Fig. 1. To study the enzymes involved in the formation of M6, in vitro incubations were performed in the presence of a variety of chemical inhibitors. The -keto acid intermediate (Fig. 1) was not monitored because of its poor ionization potentials in mass spectrometry. Suppression of 2-NDASA formation in rat liver cytosol by various enzyme inhibitors is shown in Fig. 3. Only a minimal amount (just above the limit of quantitation of 50 nM) of 2-NDASA was produced when 2-NDHSA was incubated with boiled rat liver cytosol, which suggests the reaction was enzyme-catalyzed. Inhibitors of alcohol dehydrogenase (4-methylpyrazole) and aldehyde dehydrogenase (disulfiram) reduced 2-NDASA formation by 40 to 50%. Menadione (an inhibitor of aldehyde oxidase) and quercetin (an inhibitor of carbonyl reductase) did not show any effects. AOAA, an inhibitor of pyridoxal 5'-phosphate-containing enzymes such as aminotransferases, almost completely abolished the formation of 2-NDASA in vitro. These data suggest that oxidative enzymes, such as cytosolic alcohol and aldehyde dehydrogenases and aminotransferases, may be involved in the biotransformation of 2-NDHSA to 2-NDASA in rat liver cytosol. To further confirm that transamination is involved in the formation of 2-NDASA, 2-NDHSA was incubated with rat liver cytosol in the presence of a 15N-labeled amino group donor (15N-glutamic acid). A positive full-scan mass spectrum obtained from the incubation mixture with the addition of a nonlabeled glutamic acid is shown in Fig. 4A, while the corresponding MS spectrum in the presence of the 15N-glutamic acid is shown in Fig. 4B. A molecular ion at m/z 277 in Fig. 4A is consistent with the formation of 14N-2-NDASA. With the addition of 15N-glutamic acid, approximately half the (M + H)+ ion shifted from m/z 277 to m/z 278, and the chlorine isotope peak shifted from m/z 279 to m/z 280. CID product ion spectra of the 14N- and 15N-products were consistent with the incorporation of the amino group at the C-2 position of the succinamic acid ring (Fig. 4, C and D). These data suggest that an approximately 1:1 mixture of 14N-2-NDASA and 15N-2-NDASA was formed in the presence of 15N-glutamic acid. The partial incorporation of 15N can be explained by the presence of endogenous amino group donors in the liver cytosol preparations.
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FIG. 4. Mass spectra of the 2-NDHSA incubation products in rat liver cytosol in the presence of either 14N-glutamic acid or 15N-glutamic acid. Positive full-scan MS spectra of 14N-2-NDASA (A) and a mixture of 14N-and 15N-2-NDASA (B). C, positive CID product ion spectrum of m/z 277 for 14N-2-NDASA; and D, CID product ion spectrum of m/z 278 for 15N-2-NDASA.
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Formation of 2-NDASA in rat kidney was also evaluated using 2-NDHSA as the substrate. Under the same incubation conditions, formation of 2-NDASA was significantly higher in rat kidney than in liver (2.9 ± 0.2 versus 1.0 ± 0.2 nmol/mg protein/h, respectively). As in liver cytosol, N-acetyl-2-NDASA was not produced by the renal preparations. In rat kidney cytosol fractions, the involvement of alcohol and aldehyde dehydrogenases and aminotransferases in the formation of 2-NDASA was indicated by the inhibitory effects of 4-methylpyrazole (39.0 ± 8.8% inhibition), disulfiram (36.9 ± 6.7% inhibition), and AOAA (88.3 ± 2.3% inhibition).
The identification of 2-NDASA and its acetylated product suggested that a transamination reaction is involved in the metabolism of NDPS in rats. Similar metabolic pathways involving oxidation and transamination have been proposed in the metabolism of several xenobiotics. Examples include the formation of an amino metabolite of 3-(phenylamino)-1,2-propanediol in human liver preparations in studies of its involvement in Spanish toxic oil syndrome (Mayeno et al., 1995), and identification of an N-acetylated metabolite of phenyl glycidyl ether in rat urine in studies of phenyl glycidyl ether-induced dermatitis (de Rooij et al., 1998). The observation that formation of 2-NDASA was significantly higher in rat kidney compared to liver may be partially explained by the presence of two different isozymes of glutamine transaminases (L and K) in the two tissues. Kidney glutamine transaminase (glutamine transaminase K, also known as cysteine conjugate ß-lyase) was shown to have higher activity than glutamine transaminase L, and has high affinity toward aromatic -keto acids (Cooper and Meister, 1981). Although 2-NDASA was detected in higher amounts in kidney homogenates than in liver (Cui et al., 2005), its role in NDPS-induced nephrotoxicity, if any, remains to be determined. Recently, we found that 2-NDASA (up to 1 mM) was not toxic to isolated renal cortical cells (unpublished results). However, the in vivo effects of 2-NDASA in rats have not been studied.
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Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.105.006593.
ABBREVIATIONS: NDPS, N-(3,5-dichlorophenyl)succinimide; AOAA, (aminooxy)acetic acid hemihydrochloride; CID, collision-induced dissociation; 2-NDASA, N-(3,5-dichlorophenyl)-2-aminosuccinamic acid; N-acetyl-2-NDASA, N-(3,5-dichlorophenyl)-2-N-acetylaminosuccinamic acid; 2- and 3-NDHSA, N-(3,5-dichlorophenyl)-2- and -3-hydroxysuccinamic acid; NDPSA, N-(3,5-dichlorophenyl)succinamic acid; Z-Asp-OMe, O-methyl-N-carbobenzoxyaspartic acid; Ac-Asp-OMe, O-methyl-N-acetylaspartic acid; DMSO, dimethyl sulfoxide; HPLC, high-performance liquid chromatography; MS/MS, tandem mass spectrometry; MS, mass spectrometry.
Address correspondence to: Dr. Peter J. Harvison, Professor of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA 19104-4495. E-mail: p.harvis{at}usip.edu
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References
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Abstract
Materials and Methods
