Glucuronic Acid Conjugates Research Articles

Metabolism of furametpyr. 2. (14)C excretion, (14)C concentrations in tissues, and amounts of metabolites in rats.

14C-Labeled furametpyr [N-(1,3-dihydro-1,1, 3-trimethylisobenzofuran-4-yl)-5-chloro-1, 3-dimethylpyrazole-4-carboxamide, Limber] was dosed to male and female rats at 1 (low dose) and 200 or 300 mg/kg (high dose). Elimination of furametpyr was rapid, and the dosed (14)C was substantially excreted within 7 days (45.5-53.3% in feces, 44.1-53. 8% in urine, and 0.01% in expired air). However, (14)C excretion rate showed sex- and dose-related differences, more rapid in males at low dose. (14)C concentrations in tissues decreased rapidly to generally low levels at 7 days (<0.004 ppm with the low dose and <1. 1 ppm with the high dose). Forty metabolites were detected, and 13 metabolites and 4 glucuronides were identified. A small amount of unchanged furametpyr was detected in feces (0.1-0.5% of the dose). The major metabolites in tissues were N-demethylated metabolites. In a bile study, 52.5-54.2% of the dosed (14)C was rapidly excreted into bile within 2 days. The absorption ratio was estimated to be >93.7% for the low dose (1 mg/kg). Major metabolites in bile were glucuronic acid conjugates of furametpyr hydroxides. On the basis of the results, furametpyr is substantially absorbed from the gastrointestinal tract after oral administration, rapidly distributed to tissues, extensively metabolized, and excreted into urine and bile or feces.

The pharmacokinetics and metabolism of sucralose in the dog

The pharmacokinetics and metabolism of sucralose were investigated in dogs following intravenous or oral administration. Oral doses of 14C-sucralose were rapidly absorbed, although there was some variation in the extent of absorption (range 18–48% of the dose). After intravenous or oral administration, radioactivity excreted in the urine was associated mainly with unchanged sucralose. One urinary metabolite was detected after both intravenous and oral doses and was identified by mass spectrometry as a glucuronic acid conjugate of sucralose. This metabolite accounted for about 15–20% of the intravenous dose but for only about 2–8% of the oral dose.

A novel Ser O-glucuronidation in acidic proline-rich proteins identified by tandem mass spectrometry

Human acidic proline-rich salivary protein PRP-1 and its C-terminally truncated form PRP-3 were analyzed by electrospray tandem mass spectrometry. Post-translational modifications were detected and characterized. A pyroglutamic acid residue was demonstrated at the N-terminus, Ser-8 and Ser-22 were shown to be phosphorylated and an O-linked glucuronic acid conjugation was identified. The latter modification was located to Ser-17 and found to be present in approximately 40% of the polypeptides.

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis, has been studied after mouth rinsing or an oral dose of 14C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and < 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (ω-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (ω-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.

Metabolism, excretion and distribution of the flame retardant tetrabromobisphenol-A in conventional and bile-duct cannulated rats

1. 14C-TBBP-A (2,2-bis(4-hydroxy-3,5-dibromophenyl)propane) was administered orally to the conventional and bile-duct cannulated male Sprague-Dawley rat (2.0 mg/kg body weight). Urine, bile and faeces were collected daily for 72 h, and selected tissues were removed for distribution studies. 2. Faeces was the major route of elimination of TBBP-A in the conventional rat (9.7% of dose), and urine was a minor elimination route (0.3%). Enterohepatic circulation was suggested by biliary excretion of 71.3% and faecal excretion of 26.7% of the administered radioactivity in the bile-duct cannulated rat. 3. 14C-labelled residues in tissues were 2% in the conventional rat, and <1% in the bile-duct cannulated rat. The large and small intestines contained the majority of the tissue 14C activity for both groups of rat. Levels of TBBP-A in liver were < 0.1%, and in fat were below the level of quantification. 4. Three metabolites were characterized in 0-24 h bile samples. Glucuronic acid and sulphate ester conjugates were characterized by mass spectrometry. More than 95% of the extractable faecal 14C was identified as parent TBBP-A. 5. Negligible amounts of TBBP-A-derived 14C were associated with carrier proteins he urine and bile.

Directly coupled liquid chromatography with inductively coupled plasma mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry for the identification of drug metabolites in urine: application to diclofenac using chlorine and sulfur detection.

We report the application of high-performance liquid chromatography (HPLC) linked to inductively coupled plasma mass spectrometry (ICPMS) and orthogonal acceleration time-of-flight mass spectrometry (oa-TOFMS) for the identification of phase I and II urinary metabolites of diclofenac. The metabolites were separated by reversed-phase HPLC monitored with a UV diode array detector (UV-DAD) after which 90% of the eluent was directed to an ICPMS source, with the remainder going to an oa-TOF mass spectrometer. Compounds containing (35)Cl, (37)Cl and (32)S were detected specifically using ICPMS and identified by oa-TOFMS. The metabolites detected and identified in this way included glucuronic acid and sulfate conjugates, mono- and dihydroxylated and free diclofenac. In addition a previously unreported in vivo metabolite, an N-acetylcysteinyl conjugate of diclofenac, was also characterised. This is the first application of the combination of HPLC/UV-DAD/ICPMS/oa-TOFMS for the investigation of the metabolic fate of chlorinated xenobiotics by direct biofluid analysis.

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

1. Z-7760 (S(−)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mgand 400 μCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routesof administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 μCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 μCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 μCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.

Metabolism of [14C]Flusilazole in the Goat

[Phenyl(U)-(14)C] and [triazole(3)-(14)C]flusilazole ([(bis 4-fluorophenyl)]methyl(1H-1,2,4-triazole-1-ylmethyl)silane; I) were extensively metabolized when fed to lactating goats (Capra hircus). The primary metabolites identified in goat tissues and milk were bis(4-fluorophenyl)(methyl)silanol (II) and 1H-1,2,4-triazole (III). Concentrations of total radiolabeled residues in the milk ranged from 0.09 to 0.74 microg/mL. Concentrations of radiolabeled residues found in tissues when the [(14)C] label was in the phenyl or triazole position, respectively, were 13.5 and 3.54 microg/g (liver), 8.74 and 0.75 microg/g (kidney), 0.41 and 0.52 microg/g (leg muscle), and 4.07 and 0.94 microg/g (back fat). Urine contained an additional major metabolite identified as [bis(4-fluorophenyl)](methyl)silylmethanol (IV) and its glucuronic acid conjugate (V). With either labeled form of flusilazole, the majority of the recovered radiolabel was excreted in urine or feces.

Mineralization of benzo[a]pyrene by Marasmiellus troyanus, a mushroom isolated from a toxic waste site

Mycelia from the mushroom Marasmiellus troyanus were grown in the presence of radiolabeled benzo[a]pyrene in liquid culture. After 15 days, 8.1% of the label from M. troyanus cultures was recovered in CO 2 as compared to 1.1% for Phanerochaete chrysosporium and 0.2% for Aspergillus niger. M. troyanus efficiently transformed B[a]P into water soluble metabolites with 64% of the label recovered in the water soluble fraction as compared to 11.7% for P. chrysosporium and 4.1% for A. niger. Glucuronic acid and sulfate conjugates of B[a]P were identified from the aqueous fraction of cultures of M. troyanus, after 17 days.

IDENTIFICATION OF A GENETIC DEFECT RESPONSIBLE FOR THE POLYMORPHISM OF PROPOFOL METABOLISM

S352 INTRODUCTION: Glucuronic acid conjugation is the major metabolism of propofol whereas both conjugation of its ringhydroxylated derivative with glucuronic acid and sulphate are minor metabolic pathways of propofol, which need preliminary hydroxylation at the C4 posotion. Although cytochrome (CYP)-dependent monooxygenases are responsible for this biotransformation, the major CYP isoforms has not been identified. In this paper we reported delayed emergence from propofol anesthesia in two patients, who exhibited genetic polymorphism of CYP2C19. CASES: A 35-yr-old man who underwent internal fixation of tibial fracture was anesthetized by continuous infusion of propofol under epidural anesthesia. It took 35 minutes for his emergence from propofol. A 38-yr-old man who underwent lower leg amputation due to osteosarcoma was anesthetized by propofol with nitrous oxide under epidural anesthesia. It took 33 minutes for his emergence from propofol. Both patients exhibited a guanine to adenine point mutation in exon5 of CYP2C19, which produced an aberrant splice site and a truncated nonfunctional protein. DISCUSSION AND CONCLUSION: Recently, Guitton et al showed that part of the propofol hydroxylase activity was mediated by CYP2C9 in vitro. However, propofol was likely to be metabolized by additional isoforms such as CYP2A6, 2C8, 2C18, 2C19 and 1A2. Although the activity of CYP2C9 and the expression rates of these specific isoforms in the microsomal fraction of two patients were unknown, genetic defect of CYP2C19 could be responsible for delayed emergence from propofol anesthesia.

Urinary metabolites of a novel quinoxaline non-nucleoside reverse transcriptase inhibitor in dog, cynomolgus monkey and mini-pig

1. The metabolism of (S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) has been investigated following oral administration to dog, cynomolgus monkey and mini-pig. 2. The urinary metabolites were isolated and characterized using semi-preparative HPLC, NMR and LC-MS MS. The relative proportions of fluorine-containing metabolites were determined for each species by F-NMR signal integration. 3. The metabolite profiles for each species were similar, although the proportion of individual components varied, suggesting that similar metabolic pathways are involved in the biotransformation of GW420867X in the species studied. 4. The urinary metabolites indicated that the major routes of biotransformation included hydroxylation and subsequent glucuronic acid conjugation on the aromatic ring, and on the ethyl and isopropyl side chains. A component was observed in mini-pig urine that corresponded to hydroxylation and glucuronidation accompanied by loss of the fluorine atom.

Extensive metabolism of the flavonoid chrysin by human Caco-2 and Hep G2 cells

1. Chrysin is one of many bioflavonoids with chemopreventive properties in cardiovascular disease and cancer. In an effort better to understand factors that may affect the oral bioavailability of the bioflavonoids from dietary sources, the metabolism of chrysin by cultured intestinal Caco-2 cells and hepatic Hep G2 cells was studied, together modelling human presystemic metabolism. 2. At concentrations that may be achieved in the diet, chrysin was extensively metabolized to two conjugated metabolites, M1 and M2, with no CYP-mediated oxidation. M1 was identified as a glucuronide, and M2 as a sulphate conjugate by LC/MS and other spectroscopic and biochemical techniques. Sulphate conjugation occurred at a rate twice that of glucuronic acid conjugation in both cell types. 3. M1 was catalyzed by UGT1A6 with a Km=12 muM. M2 was catalyzed both by M- and P-form phenolsulphotransferases (SULT 1A3 and SULT 1A1) with very low Km of 3.1 and 0.05 muM respectively. 4. Pretreatment with 3-methylcholanthrene, interestingly, did not result in oxidation of chrysin but rather in increased glucuronidation. 5. Also, M1 and M2 were the only metabolites formed from chrysin in fresh rat hepatocytes. The metabolism of another flavonoid, apigenin, was very similar to that of chrysin. 6. These observations suggest that both sulphation and glucuronidation are critical determinants of the oral bioavailability of bioflavonoids in humans, although a contribution from CYP-mediated oxidation can not be excluded.

Separatory determination of diastereomeric ibuprofen glucuronides in human urine by liquid chromatography/electrospray ionization-mass spectrometry.

A method for the separatory determination of diastereomeric isomers of glucuronic acid conjugates of ibuprofen having a carboxyl group at the chiral center by liquid chromatography (LC)/electrospray ionization (ESI)-mass spectrometry (MS) has been developed. The authentic specimens of acyl glucuronides of R(-)- and S(+)-ibuprofen were chemically synthesized by the Mitsunobu reaction. In the ESI mode, the glucuronides were characterized by an abundant quasi-molecular ion [M-H]-, and the formation of the negative ion was markedly influenced by a drift voltage. The resolution of diastereomeric isomers was achieved on a Develosil ODS-HG-5 column with 20 mM ammonium acetate (pH 5.0):acetonitrile (5:2, v/v) as a mobile phase where diastereomers were monitored with a corresponding quasi-molecular ion. After oral administration of racemic ibuprofen, a preferential excretion of (S)-ibuprofen glucuronide into the urine was observed.

Synthesis and excretion profile of 1,4- [14C]phenylenebis(methylene)selenocyanate in the rat

1,4-Phenylenebis(methylene)selenocyanate (p-XSC) inhibits chemically induced tumors in several laboratory animal models. To understand its mode of action, we synthesized p-[14C]XSC, examined its excretion pattern in female CD rats and also the nature of its metabolites. p-[14C]XSC was synthesized from alpha,alpha-dibromo-p-[ring-14C]xylene in 80% yield. The excretion profile of p-[14C]XSC (15.8 mg/kg body wt, 200 microCi/rat, oral administration, in 1 ml corn oil) in vivo was monitored by measuring radioactivity and selenium content. On the basis of radioactivity, approximately 20% of the dose was excreted in the urine and 68% in the feces over 3 days. The cumulative percentages of the dose excreted over 7 days were 24% in urine and 75% in feces, similar to excretion rates of selenium. According to selenium measurement, <1% of the dose was detected in exhaled air; radioactivity was not detected. Only 15% of the dose was extractable from the feces with EtOAc and was identified as tetraselenocyclophane (TSC). Most of the radioactivity remained tightly bound to the feces. Approximately 10% of this bound material converted to TSC on reduction with NaBH4. Organic soluble metabolites in urine did not exceed 2% of the dose; sulfate (9 % of urinary metabolites) and glucuronic acid (19.5% of urinary metabolites) conjugates were observed but their structural identification is still underway. Co-chromatography with a synthetic standard led to the detection of terephthalic acid (1,4-benzenedicarboxylic acid) as a minor metabolite. The major urinary conjugates contained selenium. Despite the low levels of selenium in the exhaled air, the reductive metabolism of p-XSC to H2Se cannot be ruled out. Identification of TSC in vivo indicates that a selenol may be a key intermediate responsible for the chemopreventive action of p-XSC.

Disposition and metabolism of [ 3H]-4-n-nonylphenol in rainbow trout

In order to better understand the fate of nonylphenols consumed by aquatic vertebrates, the fate of low (6 μg kg −1) and high (25 mg kg −1) doses of [ 3H]4-n-nonylphenol was followed 48 h after a single oral dose. In the low dose experiments 7.6 and 7.2% of the dose was excreted into urine or bile whereas 46.5% was still present in other tissues of the fish. In the high dose experiment these compartments comprised 3.0, 5.5 and 11.0% of the dose respectively. Radioactivity was widely distributed in trout tissues and organs, the highest concentration being in the digestive tract, liver and kidney. No identification of the nature of residues was performed on these tissues. A radio-HPLC system was developed for the analysis of biliary metabolites. Based on this method, more than 10 metabolites were separated and tentatively identified by mass spectrometry. A major part of metabolites were glucuronic acid conjugates of nonylphenol and related hydroxylated compounds. Hydroxylation and oxidation occur on the alkyl chain whereas indirect evidence exists of an hydroxylation on the phenol ring of the molecule. No trace of unchanged nonylphenol was found in bile and urine.

Drug Glucuronidation by Human Renal UDP-Glucuronosyltransferases

The UDP-glucuronosyltransferases catalyse the conjugation of glucuronic acid to a wide variety of endobiotics and xenobiotics, representing one of the major conjugation reactions in the conversion of both exogenous (e.g. drugs and pesticides) and endogenous compounds (e.g. bilirubin and steroid hormones). The liver is the major site of glucuronidation, however a number of extrahepatic tissues exhibit particular UDP-glucuronosyltransferase activities. The present study was undertaken to assess the human renal UDP-glucuronosyltransferase system. Enzymatic analysis of human kidney showed that a limited number of UDP-glucuronosyltransferase isoforms were expressed in this tissue. However the level of renal UGT activity towards the anaesthetic propofol was higher compared with human liver. The glucuronidation of propofol is catalysed by UGT1A8/9 suggesting higher levels of this isoform in the kidney. Immunoblot analysis revealed two major UDP-glucuronosyltransferase immunopositive bands to be present in human kidney as compared to four major bands in human liver. The human kidney was capable of conjugating various structurally diverse drugs and xenobiotics.

Separation of the enantiomers of ibuprofen and its major phase I metabolites in urine using capillary electrophoresis.

A capillary electrophoresis method for determination of the enantiomers of ibuprofen and its major phase I metabolites: 2'-hydroxyibuprofen and 2'-carboxyibuprofen in urine samples have been developed. Cyclodextrins and linear dextrins have been investigated as chiral selectors. Simultaneous chiral separation of the enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen was obtained using a mixture of dextrin 10 and heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin in a 2-[N-morpholino]ethanesulphonic acid buffer, pH 5.26. The electroosmotic flow was reversed using hexadimethrine bromide as a buffer additive. The method can be used for the determination of the free enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen as well as for the indirect determination of their glucuronic acid conjugates in urine samples.

Endosulfan Elevates Testosterone Biotransformation and Clearance in CD-1 Mice

Toxicant-mediated induction of hepatic biotransformation enzymes is a mechanism by which endogenous steroid hormone metabolism and elimination may be altered. Endosulfan, an organochlorine insecticide that has been demonstrated to induce hepatic P450 biotransformation enzymes, was examined for its ability to alter the rate of steroid hormone metabolism in CD-1 mice. Our objective was to evaluate whether endosulfan-induced changes in the rate of testosterone metabolism were reflected in the rate of testosterone clearance and if those alterations were sufficient to disrupt steroid hormone homeostasis within the animal. Major pathways for testosterone metabolism in the liver, including hydroxylation, conjugation to glucuronic acid or sulfate, and reduction/dehydrogenation, were examined for changes due to endosulfan exposure. In female mice, endosulfan treatment elicited a dose-dependent increase in the rate of total testosterone hydroxyl metabolite formation by selectively increasing the rate of production of 16β-, 6α-, and 16α-hydroxytestosterone metabolites. The hydroxylation of testosterone in the 16β position was most sensitive to endosulfan with a 3.3-fold increase in the rate of production of this metabolite observed following exposure to 7.5 mg/kg/day for 7 days. The rate of testosterone dehydrogenation to androstenedione was increased by 7.5 mg/kg/day of endosulfan, but the rate of direct glucuronic acid or sulfate conjugation to testosterone was not affected by any of the dosages investigated. Endosulfan was generally more toxic to male mice and did not significantly alter the rate of total hydroxytestosterone metabolite formation or glucuronic acid or sulfate conjugation. The ability of endosulfan to enhance the elimination of testosterone was, therefore, investigated in female mice. Exposure of mice to 7.5 mg/kg/day of endosulfan resulted in an ∼3.6-fold increase in the rate of urinary elimination of [14C]androgen, but had no significant effect on the fecal elimination of [14C]androgen. The increase in androgen clearance was associated only with a small, nonsignificant decrease in serum testosterone levels. Results indicate that increases in testosterone biotransformation from endosulfan exposure can result in increases in the elimination of the steroid. However, homeostatic processes apparently compensate for the effect and minimize any consequences on serum hormone levels.

Characterization of biliary metabolites of 4-n-nonylphenol in rainbow trout (Oncorhynchus mykiss)

1. [R-2,6-3H]-4-n-nonylphenol was synthesized and a single dose (5 mg, 1850 KBq) orally administered to rainbow trout. After 48 h, the radioactivity present in the bile amounted 5.5%. More than ten biliary metabolites were separated by hplc and collected for subsequent mass spectrometry analysis. The metabolic profile was totally modified by β-glucuronidase hydrolysis, showing that most of the metabolites were glucuronic acid conjugates. 2. Conjugated metabolites were identified by lc-ms analysis and their aglycones were analysed by gc-ms analysis as TMS and acetyl derivatives. 3. The major metabolite accounted for 52 ± 11% of the biliary radioactivity and was identified as nonylphenol-glucuronide. 4. Nonylphenol was hydroxylated at both ω and ω-1 positions of the alkyl chain, giving 9-hydroxynonylphenol and 8-hydroxynonylphenol. 5. 9-Hydroxynonylphenolwasoxidized to the corresponding acid,and subsequently β-oxidized, yielding 7-(4-hydroxyphenyl)heptanoic acid, 5-(4-hydroxyphenyl)pentanoic acid, 3-(4-hydroxyphenyl)propionic acid and 3-(4-hydroxyphenyl)-2-propenoic acid.

Stereoselective Metabolism of New Oral Anti-diabetic Agent Troglitazone Stereoisomers in Liver.

Troglitazoneの4種類の立体異性体についてKKマウス，RFVLマウス，雌雄F344ラット，カニクイザルおよびヒト肝ミクロソームおよびサイトゾルによる硫酸ならびにグルクロソ酸抱合反応について検討した．Thiazolidinedione環5位は抱合反応においてこの部位の立体異性体間で差が見られなかったので，2位での立体異性体2S(5R/S)体，2R(5R/S)体間について比較した． その結果，1．硫酸抱合反応速度には大きな種差は認められなかった．立体異性体の基質選択性は2S>2R体であった．ラットについては性差があり，雄は雌の約2倍であった． 2．グルクロン酸抱合反応速度はマウスおよびサルでは速く種差が認められた．立体異性体間の基質選択性は，KKマウスでは2R>2S体であったが，他の動物およびヒトでは2S>2R体であった．