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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Laboratory of Pharmacology, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
Received September 4, 2004; accepted October 19, 2004.
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Abstract |
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; Wang et al., 1993). It has been widely reported that the NG-substituted arginine analogs exhibit a high degree of stereospecificity such that the L but not D enantiomers are capable of inhibiting NO synthase and increasing blood pressure (Moncada et al., 1991; Wang et al., 1993).
A number of unexpected observations have challenged this dogma. We and others have shown that NG-nitro-D-arginine (D-NNA) is as efficacious as L-NNA in increasing blood pressure in anesthetized rats (Wang and Pang, 1990; Raszkiewicz et al., 1992) and conscious rats (Wang et al., 1991, 1993), and in inhibiting endothelium-dependent relaxation ex vivo (Wang et al., 1993; Cheng et al., 1997). There are observations that support the notion that D-NNA is converted into an active compound in vivo. Pressor response to D-NNA is slower in onset than L-NNA (Wang et al., 1991). In addition, the potency of pressor response to D-NNA is one-half that of L-NNA, whereas the potency of D-NNA is only 3% that of L-NNA in vitro (Wang et al., 1993). Furthermore, pressor response to D-NNA, similar of that to L-NNA, is blocked by L-arginine but not D-arginine (Wang et al., 1991). These results lead to the hypothesis that D-NNA is converted in vivo to L-NNA (Wang et al., 1993). This postulation of in vivo conversion from D-NNA into L-NNA was later verified in another laboratory through the use of high-performance liquid chromatography (Wang et al., 1999). The enzymatic process and the organs responsible for the conversion remain unclear. There is, however, support that the kidney may play an important role in the chiral inversion of D-NNA into L-NNA. The in vitro inhibitory action of D-NNA on endothelium-dependent relaxation is negligible but is markedly increased following the incubation of D-NNA with homogenate of the kidney (Cheng et al., 1997). Furthermore, ligation of the kidney blocks the action of D-NNA on blood pressure (Wang et al., 1999).
The aim of this study was to examine the mechanism by which D-NNA is converted into L-NNA. The chiral separation of D-NNA and L-NNA was achieved via capillary electrochromatography (CEC), which is capable of separating D- and L-amino acids with high resolution and efficiency. We examined through bioassay and chemical analysis whether kidney ligation inhibited both pressor response to D-NNA and chiral inversion. Since D-amino acid oxidase (DAAO) has been reported to catalyze D-amino acid chiral inversion in mammals (Hasegawa et al., 2004), we also examined whether inhibition of the action of renal DAAO through administration of sodium benzoate would abolish chiral conversion and pressor response to naive D-NNA and D-NNA that was previously incubated with homogenate of the kidneys. Finally, we examined whether pure DAAO and tissue homogenates from various organs including the kidneys eliminated D-NNA as well as converted it into L-NNA.
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Materials and Methods |
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Animal Preparation. Male Sprague-Dawley rats (250–350 g; Fudan University Medical Animal Center, Shanghai, China) were anesthetized with sodium pentobarbital (65 mg/kg i.p.). Polyethylene cannulae (PE50; BD Biosciences, San Jose, CA) were inserted into the left femoral artery for the measurement of mean arterial pressure (MAP) by a pressure transducer (model YPJ01; Chengdu Instruments, Sichuan, China) and both femoral veins for the injection of drugs and the collection of blood samples. The body temperature was maintained at 37°C with a heating device connected to an electrical heated thermostat. In the kidney ligation studies, the anesthetized rats were given laparotomy followed by unilateral or bilateral ligation of the renal arteries and veins or sham-operation. In studies involving the use of conscious rats, the vascular cannulae were tunneled subcutaneously and exteriorized at the back of the neck. The rats were given >12 h of recovery from anesthesia and surgery before use.
Measurements of D-NNA and L-NNA. D-NNA and L-NNA were measured by CEC in the chiral ligand exchange mode (Wang et al., 1999). Plasma samples (100 µl) or incubation samples (100 µl) of D-NNA or L-NNA were deproteinated through mixing for 20 min with methanol/acetone (1000 µl; v/v = 1:1). After centrifugation at 10,000 rpm for 20 min, the organic layer was volatilized at –20°C, and the residue was dissolved in acetate buffer (pH 5.0, plasma in 100 µl, and incubation samples in 5 ml). After mixing for 1 min, an aliquot (10 nl) of the sample was injected into the CEC system (Unimicro Technologies Inc., Pleasanton, CA). Cupric acetate (1 mM) and aspartame (2 mM) were dissolved in the methanol/acetate buffer (pH 5.0, v/v = 1:20) to allow the formation of diastereomeric pairs with D-NNA or L-NNA. The diastereomeric pairs were separated on a reverse phase C18 column (75 µm x 20 cm; Unimicro Technologies, Co., Ltd., Shanghai, China) at detection wavelength of 280 nm. The retention times were 17 and 19 min for L-NNA and D-NNA, respectively. The samples were quantified against standard curves that ranged from 0.025 to 0.75 mM (r2 > 0.98). The between-day (n = 5) precision values measured by the time and area under the curve were 4.3 and 4.8% for L-NNA and L-NNA, respectively. The within-day precision of the quality control samples was 2% for both L-NNA and D-NNA.
Preparation of Tissue Homogenates. Male Sprague-Dawley rats were killed by a blow at the back of the neck. The kidneys, liver, lungs, heart, brain, and skeletal muscles were removed and washed with Tris-HCl buffer (4°C, 0.1 M, pH 8.2). Tissue samples (1 g each) were homogenized in Tris-HCl buffer (3 ml, pH 8.2) at 4°C with a homogenizer (Fluko Equipment Co., Shanghai, China). The homogenates were centrifuged at 1500 rpm for 10 min, and the supernatants were used for the determination of the activities of DAAO and conversions of D-NNA.
Tissue Homogenate Incubation with D-NNA. The effects of various homogenates from tissue (kidneys, liver, heart, lungs, brain, and skeletal muscle, n = 5 rats each group) on the conversion of D-NNA into L-NNA were determined. The supernatants (200 µl) of the tissue homogenate were incubated with D-NNA (200 µl, 50 mM) dissolved in Tris-HCl buffer plus additional Tris-HCl buffer (150 µl) in a shaking bath (700 rpm) at 37°C for 30 min. In some experiments, the homogenate was replaced with DAAO (200 µl of 13.5 units/ml, dissolved in Tris-HCl buffer, pH 8.2). The control samples were treated similarly, except that the buffer (100 µl) was replaced by sodium benzoate (100 µl of 100 mg/ml), and in some cases, supernatants from the homogenate were denatured through heating (10 min at 100°C). The blank control contained the same components but with saline in place of the D-NNA solution. The incubation mixtures were centrifuged at 10,000 rpm for 15 min and filtered through Millex-GP (0.22 µm x 33 mm; Nihon Millipore Ltd., Tokyo, Japan) before injection into rats. The incubation supernatants were used for in vivo functional studies or in vitro and ex vivo determination of D-NNA and L-NNA by CEC.
Determination of the Activity of DAAO. The activity of DAAO was determined according to the keto acid method (D'Aniello et al., 1993; Sarower et al., 2003). The supernatants (200 µl) of the homogenates were incubated with D-alanine (200 µl of 0.1 M dissolved in the above Tris-HCl buffer for 30 min in a shaking bath (700 rpm) at 37°C. Afterward, trichloroacetic acid (200 µl of 25%) was added to the incubated mixture, mixed again, and centrifuged at 12,000 rpm for 10 min. The supernatant (400 µl) was mixed with 2,4-dinitrophenylhydrazine (400 µl of 1 mM in 1 M HCl) and incubated at 37°C for 10 min. Subsequently, NaOH (800 µl of 1.5 M) was added and mixed. The mixture was kept at room temperature for 10 min, and the absorbance was read at 445 nm against a blank sample consisting of the same mixture without D-alanine. The activity of DAAO in the homogenates was quantified against the standard DAAO curves (from 3–54 units/ml, r2 > 0.97).
Data Analyses. All results were expressed as means ± S.E.M. and analyzed by the analysis of variance followed by Duncan's multiple range test. A probability of error (P < 0.05) was selected as the criterion of statistical significance.
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Results |
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Baseline MAP was similar among the four groups of rats (92 ± 5, 92 ± 4, 92 ± 5, and 90 ± 4 mm Hg). In pentobarbital-anesthetized, sham-operated rats, the vehicle did not alter MAP, whereas D-NNA (32 mg/kg) gradually increased MAP to a sustained level of 20 mm Hg above baseline (Fig. 1A). D-NNA caused markedly less increase in MAP in the rats with unilateral renal ligation relative to the sham-operated rats, but MAP gradually increased to the same level as that attained in the sham-operated rats. Bilateral kidney ligation completely abolished the pressor response to D-NNA.
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Neither D-NNA nor L-NNA was detectable in the plasma prior to injection of D-NNA. Bolus injection (i.v.) of D-NNA was followed by a biphasic disposition curve in the sham-operated rats (Fig. 1B). Unilateral kidney ligation had negligible effects on the disposition of D-NNA. Bilateral kidney ligation nearly completely blocked the beta phase of D-NNA disposition without affecting the alpha phase. These results suggest that the kidneys are the primary organs responsible for the disposition of D-NNA.
Upon injection of D-NNA into the sham-operated rats, L-NNA was detected immediately, peak concentration (
30 µg/ml) was attained at 20 min, and it slowly declined to a plateau (13 µg/ml) at 40 min after injection (Fig. 1C). Unilateral kidney ligation significantly reduced the conversion of D-NNA into L-NNA; however, a similar plateau of concentration of L-NNA (13 µg/ml) was reached at 40 min after injection. Bilateral kidney ligation, on the other hand, nearly completely abolished the conversion of D-NNA into L-NNA, with approximately only 3 µg/ml of the peak plasma L-NNA level over the experiment period.
In a separate study, i.v. bolus injection of L-NNA (16 mg/kg) in the group of sham-operated, pentobarbital-anesthetized rats also elicited a pressor response (Fig. 2A). In contrast to D-NNA, pressor response to L-NNA was slightly potentiated (rather than abolished) in rats subjected to bilateral kidney ligation. Plasma L-NNA and D-NNA were measured, and no trace of D-NNA was detected after injection of L-NNA at any time point (results not shown). Plasma L-NNA exhibited a similar biphasic pattern of disposition in the sham-operated rats and rats with bilateral kidney ligation (Fig. 2B). These results show that L-NNA is metabolized through a pathway independent of the kidneys.
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The area under the curve (AUC) was estimated by the trapezoidal rule. The chiral inversion rate of D-NNA into L-NNA was calculated with the formula of Pang and Kwan (1993), where inversion rate = [AUC(L-NNA) after (D-NNA) x DOSE (L-NNA)]/[AUC (L-NNA) after (L-NNA) x DOSE (D-NNA)]. The calculated chiral inversion rate of D-NNA into L-NNA was 50 ± 3% in the sham-operated rats and 10 ± 1% in the bilateral kidney-ligated rats over the observation period. These results suggest that kidneys account for 80% of chiral inversion D-NNA in vivo.
Effects of Sodium Benzoate (the DAAO Inhibitor) on the Pressor Response to D-NNA in Conscious Rats. The conscious rats were divided into four groups (three to six in each group) under two treatments. One group was pretreated with i.v. bolus injection of the vehicle (5% glucose, 4 ml/kg), one group was given a low dose of sodium benzoate (80 mg/kg), and the remaining two groups were given a high dose of sodium benzoate (400 mg/kg). Sodium benzoate is a selective inhibitor of DAAO and was reported to effectively block DAAO activity at these doses in vivo (Moses et al., 1996). Twenty minutes later, the vehicle-pretreated group was i.v. bolus injected with D-NNA (32 mg/kg). The low dose benzoate-pretreated group was given D-NNA (32 mg/kg), and the two high-dose benzoate-pretreated groups were given the vehicle (5% glucose, 4 ml/kg) or D-NNA (32 mg/kg). Arterial pressure was monitored for 1 h.
Bolus injection (i.v.) of benzoate caused a very small increase in MAP that returned to the baseline 10 min after administration (data not shown). As shown in Fig. 3A, i.v. bolus injection of D-NNA produced a pressor response in the vehicle-pretreated rats, with the slow onset (approximately 80% maximum effect at 30 min after injection). Pretreatment with benzoate (80 and 400 mg/kg) prevented the pressor response to D-NNA in a dose-dependent manner, where 400 mg/kg benzoate completely abolished the pressor response.
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The effect of benzoate on the pressor response to L-NNA was also tested in two groups of conscious rats (n = 3 in each group). As shown in Fig. 3B, i.v. bolus injection of L-NNA (16 mg/kg) in the vehicle-pretreated rats caused an increase in MAP that reached a similar maximum as did D-NNA, but with a faster onset (80% maximum after 10 min). Bolus injection i.v. of sodium benzoate (400 mg/kg) did not alter the pressor response to L-NNA (16 mg/kg).
To further confirm that endogenous renal DAAO plays an essential role in the pressor responses elicited by D-NNA, the effect of kidney homogenate-incubated D-NNA on MAP was studied in rats pretreated with benzoate. Two groups of conscious rats (n = 3–5 each group) received i.v. bolus injection of sodium benzoate (400 mg/kg). After 20 min, the rats received i.v. bolus injection of the supernatants (4 ml/kg) from kidney homogenates incubated for 30 min with either the vehicle or D-NNA (equivalent to 32 mg/kg). In benzoate-pretreated rats, injection of supernatants from kidney homogenate incubated with D-NNA produced a marked and sustained pressor response of similar magnitude (Fig. 4) as that in conscious rats without benzoate pretreatment (Fig. 3A). Bolus injection i.v. of supernatants from kidney homogenate incubated with the vehicle produced a much smaller increase in MAP that may be mediated by unknown vasoactive substances contained in the homogenates (Fig. 4).
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Correlation between D-NNA Chiral Inversion and DAAO Activity. The inhibitory effect of DAAO on D-NNA conversion was first tested in vitro without tissue homogenates. Following 30- and 60-min incubation with DAAO (4.9 units/ml), the concentration of D-NNA (18 mM) was reduced by 46 and 73%, respectively; however, no L-NNA was produced (n = 3 each treatment). The DAAO-mediated disappearance of D-NNA was blocked by the addition of sodium benzoate (0.13 M) (data not shown).
D-NNA conversion was measured in the homogenates of the kidneys, liver, heart, lungs, brain, and muscle (n = 5 in each group). Incubation of D-NNA (18.2 mM) for 30 min with homogenates of the kidneys, liver, and brain resulted in the disappearance of D-NNA by 50, 31, and 14%, respectively (Fig. 5A). In contrast, incubation of D-NNA with homogenates of the heart, lungs, and muscle did not significantly reduce the concentration of D-NNA. The reductions of the concentration of D-NNA concur with the increase in the concentration of L-NNA (Fig. 5B), and the two parameters were highly correlated (r = 0.92, P < 0.05; Fig. 5D).
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Neither D-NNA reduction nor L-NNA production was detected in benzoate-treated (1.3 x 10–5 M) or heat-denatured kidney homogenates (data not shown). The activity of DAAO was highly expressed in the kidneys followed by the liver and brain, with minimal activities detected in the heart, lungs, and muscle (Fig. 5C). High positive correlations were obtained between the activity of DAAO and the disappearance of D-NNA (Fig. 5E, r = 0.92, P < 0.05), as well as between DAAO activity and L-NNA production (Fig. 5F, r = 0.96, P < 0.05).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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) and by high-performance liquid chromatography (Wang et al., 1999). The present results and previous findings (Wang and Pang, 1990; Wang et al., 1991, 1993, 1999) indicate that D-NNA undergoes chiral inversion in vivo to form the active enantiomer L-NNA. Together with other reports of the conversion of D-phenylalanine (33%; Lehmann et al., 1983) and D-leucine (30%; Hasegawa et al., 2000) to the corresponding L-enantiomers, our results further suggest that chiral conversion of D-amino acids into L-amino acids is a common metabolic pathway in mammals.
However, pressor responses to L-NNA either i.v. bolus injected in a naive form or converted from D-NNA were not exactly parallel to plasma concentrations of L-NNA. For example, after bilateral kidney ligation, blood pressure did not increase in response to a small rise in plasma L-NNA levels (5 µg/ml) (Fig. 1), whereas blood pressure remained elevated after naive L-NNA administration in rats with plasma L-NNA levels dropped to below 5 µg/ml (Fig. 2). This discrepancy may be because L-NNA's pressor responses correlate with its cellular levels in the target cells/tissues rather than its plasma concentrations. Nitric oxide synthase is located in the endothelial cells, and L-NNA is a positive charged amino acid derivative and does not readily pass the cell membrane. It would be reasonable to postulate that L-NNA slowly enters endothelial cells and stays in the cells for a relatively long period leading to sustained pressor responses with slow onset. The hypothesis is supported the following: peak time for L-NNA-induced pressor response was obtained 30 min after L-NNA injection, although plasma concentration of L-NNA (10 µg/ml) was much below that at injection time (>300 µg/ml) (Fig. 2); and pressor response to converted L-NNA was sustained while plasma level of L-NNA dropped from 30 to 13 µg/ml (Fig. 1). Hence, production of small amount of L-NNA (3–5 µg/ml) from D-NNA in bilateral kidney-ligated rats would lead to trace of L-NNA entering endothelial cells and little effect in blood pressure (Fig. 1). On the other hand, once a high dose of L-NNA (16 mg/kg) was administered in both sham control and bilateral kidney-ligated rats, a large amount of L-NNA would presumably enter endothelial cells and subsequently produce long-lasting pressor responses when plasma level of L-NNA even dropped to as low as 3 µg/ml (Fig. 2).
The occurrence of D-amino acids and DAAO in mammals has been reported in recent years, although their physiological function is unclear (Pilone, 2000). It has been proposed that D-amino acids are converted to L-amino acids in two step that involve oxidation of the D-amino acids to the corresponding 
-keto acids by DAAO followed by amination to L-amino acids by the action of yet-unidentified transaminase(s) (Hasegawa et al., 2000). The existence of DAAO in microorganisms, mainly yeasts and bacterium, is related to the ability of yeasts to use D-amino acids for growth and bacterium to use them as constituents of the cell wall (Pilone, 2000). In this study, we have found that pure DAAO catalyzed the oxidation of D-NNA in vitro, leading to the elimination of D-NNA by 46 and 73% over 30 and 60 min, respectively, but not to production of L-NNA. The stereospecificity of DAAO is absolute and is restricted to the D-enantiomer even when both D- and L-amino acids are present. DAAO displays broad substrate specificity in vitro and is capable of deaminating neutral and basic D-amino acids; however, its most efficient substrates are amino acids with hydrophobic side chains (Pilone, 2000). Our results show that D-NNA is an excellent substrate for DAAO in vitro. Equally important is the fact that the selective inhibitor of DAAO sodium benzoate was effective in blocking the in vitro chiral inversion of D-NNA by homogenates of the kidneys, as well as completely blocking the pressor response of D-NNA in intact conscious rats. Moreover, there was a high correlation between the activity of DAAO and D-NNA conversion in tissues. Our results of the effectiveness of DAAO in chiral inversion of D-NNA is in agreement with the recent report of the conversion of D-leucine to L-leucine in DAAO-intact mice (ddY/DAAO+) but not in mutant mice that lack DAAO activity (ddY/DAAO–) (Hasegawa et al., 2004).
The importance of the kidneys on chiral conversion of D-NNA was shown by the following observations. Bilateral kidney ligation caused greater inhibition of pressor response to D-NNA than unilateral ligation of the kidneys, as well as less disappearance of D-NNA and greater appearance of L-NNA. These findings provide the first chemical evidence for the importance of the kidneys in chiral inversion of D-NNA. Sodium benzoate abolished pressor response to naive D-NNA but not to D-NNA preincubated with kidney homogenates, thereby showing the involvement of renal DAAO in the conversion of D-NNA. Incubations of D-NNA with homogenates of the kidneys caused markedly greater disposition of D-NNA and production of L-NNA than homogenates of the liver, which, in turn, has greater activity than homogenates of the brain, heart, lungs, and skeletal muscle. The activity of DAAO is highest in the kidneys followed by the liver and brain, in accordance with reports of greater expression of DAAO in the kidneys (Konno et al., 1997; Pilone, 2000; Hasegawa et al., 2004). Taken together, it is concluded that the renal DAAO plays an essential role in the chiral inversion of D-amino acids and accounts for approximately 80% D-NNA conversion in the body. The kidney has also been shown to be the principle organ for the chiral inversion of D-leucine (Hasegawa et al., 2004).
With the recent advent of chromatographic chiral separation and detection, it has become clear that many chiral pharmaceuticals undergo chiral inversion in the body. Such drugs include 2-arylpropionic acid analogs (Drummond et al., 1990), the new quinoxaline toposomerase poison 2-[4-(7-chloro-2-quinoxaliny)oxy] phenoxy propionic acid (Zheng et al., 2002), and thalidomide (Eriksson et al., 1998). The metabolic chiral inversion of 2-arylpropionic acids such as ibuprofen and ketoprofen (nonsteroidal anti-inflammatory agents) has been well characterized. Chiral inversion is normally unidirectional in various species including humans, e.g., from R to S inversion for profens, whereas S to R inversion is rare (Jamali et al., 1997). The long-chain acyl-CoA synthetase and 2-arylpropionyl-CoA epimerase have been identified as key enzymes involved in the chiral inversion of 2-arylpropionic acids (Reichel et al., 1995, 1997; Brugger et al., 1996). Epimerase mRNA and protein are strongly expressed in the rat liver and kidneys and weakly expressed in heart and brain (Reichel et al., 1995, 1997). Thus, the chiral inversion process for D-amino acids to L-enantiomers is distinctly different from that for 2-arylpropionic acids.
In conclusion, L-NNA was detected, and pressor response is observed soon after injection of D-NNA. Chiral inversion and pressor responses to D-NNA were blocked by kidney ligation (80%) and following injection of the selective DAAO blocker benzoate (completely). However, benzoate did not block pressor response to D-NNA that had been preincubated with homogenate of the kidneys. The pure DAAO disposed D-NNA but did not produce L-NNA, whereas homogenates of the kidneys, liver (lesser degree), and brain (much lesser degree) disposed of D-NNA while producing L-NNA at the same time. Moreover, D-NNA chiral inversion correlates with the activity of DAAO. Thus, renal DAAO plays an essential but not sufficient role in chiral inversion of D-amino acids.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: NO, nitric oxide; L-NNA, NG-nitro-L-arginine; D-NNA, NG-nitro-D-arginine; CEC, capillary electrochromatography; DAAO, D-amino acid oxidase; MAP, mean arterial pressure; AUC, area under the curve.
Address correspondence to: Dr. Yong-Xiang Wang, Laboratory of Pharmacology, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, China. E-mail: yxwang{at}sjtu.edu.cn
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, vehicle response in sham-operated rats; 
, D-NNA in sham-operated rats; 
, D-NNA in unilateral kidney-ligated rats; 
, D-NNA in bilateral kidney-ligated rats. *, significantly different (P < 0.05) from respective values in the sham-operated group given D-NNA.
, L-NNA in sham-operated rats; 
, L-NNA in bilateral kidney-ligated rats. *, significantly different (P < 0.05) from respective values in the sham-operated group given L-NNA.
