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At least 19 recordsLinked to original sources
PubMed1980

Metabolism of putrescine to 5-hydroxy-2-pyrrolidone via 2-pyrrolidone.

Incubation of 2-[14C]pyrrolidone with sliced rat liver and analysis of the incubation medium by silica gel chromatography revealed that 2-[14C]pyrrolidone is metabolized to an unknown. It was previously shown by Lundgren and Hankins ((Lundgren, D.W, and Hankins, J. (1978) J. Biol. Chem. 253, 7130-7133) that slices of rat liver readily synthesized 2-pyrrolidone from putrescine. The unknown metabolite was partially purified by methanol/chloroform extraction, activated charcoal column chromatography, and two-dimensional thin layer chromatography on silica gel plates. The 2-pyrrolidone metabolite was derivatized with bis(trimethylsilyl)trifluroacetamide and analyzed by gas chromatography-mass spectrometry. The mass of the molecular ion (245) and fragment ions suggests that the 2-pyrrolidone metabolite is 5-hydroxy-2-pyrrolidone. The mass spectrum of synthetic 5-hydroxy-2-pyrrolidone was identical to that of the unknown metabolite. Synthetic 5-hydroxy-2-[3H]pyrrolidone co-chromatographed on silica gel sheets with the unknown 2-[14C]pyrrolidone metabolite obtained directly from incubation media. Under appropriate conditions (pH 7.5, no acid treatment of medium), putrescine is metabolized to 5-hydroxy-2-pyrrolidone via 2-pyrrolidone. Several effector compounds, but not necessarily the same ones, inhibit or enhance, or both, the conversion of putrescine to 2-pyrrolidone and of 2-pyrrolidone to 5-hydroxy-2-pyrrolidone. This is the first demonstration of the biosynthesis of 5-hydroxy-2-pyrrolidone.

Animals↗
PubMed1975

Aqueous mixture of pyrrolidone-5-hydroxamic acid-iron (III) complexes: isolation and characterization of tris (pyrrolidone-5-hydroxamato) iron (III).

The published procedure for the synthesis of pyrrolidone-5-hydroxamic acid was improved. The acidity constant of the pyrrolidone-5-hydroxamic acid was determined as pKa = 8.65. In an aqueous solution of iron (III) ions, pyrrolidone-5-hydroxamic acid binds ferric ion, forming a mixture of mono-, bis-, and tris(pyrrolidone-5-hydroxamato)iron (III) complexes. These complexes were studied by potentiometric and spectrophotometric methods. The tris compound was isolated as dark orange-red crystals and identified according to elemental analysis and IR spectral data as C15H21FeN6O9.6H2O, having the magnetic moment of 5.67 B.M.

Chemical Phenomena↗
PubMed2003

Human experimental exposure to N-methyl-2-pyrrolidone (NMP): toxicokinetics of NMP, 5-hydroxy- N-methyl-2-pyrrolidone, N-methylsuccinimide and 2-hydroxy- N-methylsuccinimide (2-HMSI), and biological monitoring using 2-HMSI as a biomarker.

OBJECTIVE: N-methyl-2-pyrrolidone (NMP) is a strong and selective organic solvent with an extensive and increasing use. It has been reported to be a compound that is toxic to the reproductive system. The aim of this study was to evaluate toxicokinetics parameters for NMP and its metabolites, 5-hydroxy- N-methyl-2- pyrrolidone (5-HNMP), N-methylsuccinimide (MSI) and 2-hydroxy- N-methylsuccinimide (2-HMSI), and to develop a method for biological monitoring of NMP exposure that uses 2-HMSI as a biomarker. METHODS: Six healthy, male volunteers were exposed to NMP in an exposure chamber for 8 h at concentrations of 10, 25 and 50 mg/m(3). In addition, three of the subjects were exposed a second time at 50 mg/m(3). Air levels were monitored by Amberlite XAD-7 sampling and gas chromatography (GC) analysis. Levels of NMP and the metabolites in plasma and urine were analysed by GC or GC with mass spectrometry detection. RESULTS: The concentration of 2-HMSI in plasma and urine rose during exposure and reached a peak approximately 15 h after the end of exposure. It then decayed according to a one-compartment model with a half-time of about 18 h. There were very close correlations between the NMP air levels, on the one hand, and concentrations of 2-HMSI in plasma (r=0.98) and creatinine-adjusted urinary 2-HMSI levels (r=0.96), on the other. The renal clearances were 0.13, 1.4, 0.12 and 1.2 l/h for NMP, 5-HNMP, MSI and 2-HMSI, respectively. The total clearances were 11.4, 3.2, 8.5 and 1.1 l/h for NMP, 5-HNMP, MSI and 2-HMSI, respectively. The apparent volumes of distribution were 41, 28, 120 and 28 l for NMP, 5-HNMP, MSI and 2-HMSI, respectively. CONCLUSIONS: Toxicokinetics parameters for NMP, 5-HNMP, MSI and 2-HMSI have been estimated. Furthermore, 2-HMSI is applicable as a biomarker of exposure to NMP, and the levels in plasma and urine may be used to indicate an exposure over three days.

Administration, Inhalation↗
PubMed2000

Biological monitoring of N-methyl-2-pyrrolidone using 5-hydroxy-N-methyl-2-pyrrolidone in plasma and urine as the biomarker.

OBJECTIVES: The aims were to study the toxicokinetics of 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) in blood and urine after exposure to N-methyl-2-pyrrolidone (NMP) and to study the suitability of 5-HNMP as a biomarker for assessing NMP exposure. METHODS: Six male volunteers were exposed for 8 hours to NMP concentrations of 0, 10, 25, and 50 mg/m3. Blood and urine were sampled before, during, and up to 40 hours after exposure. Aliquots of urine and plasma were purified, derivatized, and analyzed for 5-HNMP on a gas chromatograph/mass spectrometer in the electron impact mode. RESULTS: The mean plasma concentration [P-(5-HNMP)] after 8-hour NMP exposure to 10, 25, and 50 mg/m3 was 8.0, 19.6, and 44.4 micromol/l, respectively. The mean urinary concentration [U-(5-HNMP)] for the 2 last hours of exposure was 17.7, 57.3, and 117.3 mmol/mol creatinine, respectively. The maximal P-(5-HNMP)and U-(5-HNMP) concentrations occurred 1 hour and 0-2 hours, respectively, after the exposure. The half-times of P-(5-HNMP) and U-(5-HNMP) were 6.3 and 7.3 hours, respectively. The 5-HNMP urinary concentrations were 58% of the calculated retained dose. There was a close correlation (r) between P-(5-HNMP) (r=0.98) and U-(5-HNMP) (r=0.97) with NMP exposure. CONCLUSIONS: 5-HNMP is an excellent biomarker for assessing exposure to NMP. Its plasma and urinary half-times (6-7 hours), the minimal risk for contamination during sampling in occupational settings, and the close correlation of P-(5-HNMP) and U-(5-HNMP) with NMP exposure makes 5-HNMP suitable for monitoring exposure to NMP. 5-HNMP in plasma is recommended.

Adult↗
PubMed2001

Water vapor absorption into amorphous sucrose-poly(vinyl pyrrolidone) and trehalose-poly(vinyl pyrrolidone) mixtures.

Previous studies from this laboratory suggested that a solution model (Flory-Huggins equation) modified by a free volume model (Vrentas equation) could satisfactorily describe water absorption into an amorphous solid composed of a sugar or a polymer. This paper has extended the studies of single solutes to binary mixtures of trehalose-and sucrose-poly(vinyl pyrrolidone) (trehalose-PVP and sucrose-PVP, respectively) either co-lyophilized or individually lyophilized and then physically mixed. Water vapor absorption isotherms of the binary mixtures were determined at 30 degrees C. Co-lyophilized PVP-sugar mixtures take up essentially the same amount of water as predicted by the weight average of individual isotherms, whereas sugar crystallization is significant retarded in the molecular dispersions. The sugar-PVP interaction, as reflected in the Flory-Huggins chi interaction parameter, was estimated by fitting the high relative pressure (p/p(0)) region of the isotherm, at which the system is in a liquid state, with a three-component Flory-Huggins-type model. The estimated sugar-water PVP-water, and sugar-PVP interaction parameters suggest that the solute-water interactions are not significantly affected by the sugar-PVP interaction; that is, the solute-water interaction parameters in a binary solute system are similar to those in the corresponding single solute systems. Based on these interaction parameters, the sucrose-PVP interaction appears to be stronger than that of trehalose-PVP. Manipulation of the interaction parameters suggest that the water vapor absorption isotherm is not a sensitive indicator of possible sugar-PVP interactions. Density, glass transition temperature, T(g), and the heat capacity change, DeltaC(p), at T(g) were determined to estimate the excess water absorption energy due to the plasticizing effect of water using the structural relaxation model, as described by Vrentas. Results suggest that PVP is a better antiplasticizer for sucrose than for trehalose. Consequently, the excess free energy arising from structural relaxation was disproportionally reduced by the presence of PVP in these molecular dispersions. Finally, the entire isotherms of co-lyophilized sugar-PVP mixtures are reasonably described with an extended three-component Flory-Huggins model and Vrentas glass structural relaxation model.

Absorption↗
PubMed2004

Study of the characterization and crystallization of 4-hydroxy-2-pyrrolidone.

A systematic study of the characterization for racemic species of 4-hydroxy-2-pyrrolidone was undertaken. The melting point phase diagram of (R)- and (S)-4-hydroxy-2-pyrrolidone was determined by differential scanning calorimetry. The ternary phase diagram of (R)- and (S)-4-hydroxy-2-pyrrolidone with isopropanol was constructed at 15, 20, 25, and 35 degrees C. The crystalline nature of 4-hydroxy-2-pyrrolidone racemate was also characterized by means of comparison of solid-state FTIR spectra and powder X-ray diffraction patterns of the racemic mixture with those of one of the enantiomers. It is shown that (+/-)-4-hydroxy-2-pyrrolidone is a racemic conglomerate. The enthalpies of fusion of (R)-4-hydroxy-2-pyrrolidone and (+/-)-4-hydroxy-2-pyrrolidone and entropy of mixing of (R)- and (S)-4-hydroxy-2-pyrrolidone were calculated using the thermodynamic data. The solubility and supersolubility diagrams of (R)- and (S)-4-hydroxy-2-pyrrolidone in isopropanol were determined over a temperature range of 4-35 degrees C. The optical resolution of (+/-)-4-hydroxy-2-pyrrolidone was successfully achieved by preferential crystallization.

Journal Article↗
PubMed1985

Alternate putrescine metabolites: quantitative analysis of delta'-pyrroline oxidation to 2-pyrrolidone in tissue homogenates by high-pressure liquid chromatography.

A sensitive analytical procedure for following the oxidation of delta'-pyrroline to 2-pyrrolidone in tissue homogenates is described. Homogenates are extracted with chloroform/acetonitrile and fractionated by high-performance liquid chromatography, and 2-pyrrolidone is quantitated by monitoring the column effluent at 200 nm. The lower limit of 2-pyrrolidone that can be accurately (+/- 5%) quantitated is approximately 100 pmol. Phenazine methosulfate significantly enhances the rate of 2-pyrrolidone biosynthesis from delta'-pyrroline. Phenazine methosulfate and reduced glutathione are required to obtain proportionality between 2-pyrrolidone formation and incubation time. Formation of 2-pyrrolidone as a function of protein concentration is linear and 2-pyrrolidone biosynthesis as a function of delta'-pyrroline concentration is characterized by hyperbolic kinetics. Based on analysis of enzyme activity in different tissues, liver appears to play the dominant role in 2-pyrrolidone biosynthesis. The metabolic step from delta'-pyrroline to 2-pyrrolidone was localized in the cellular cytosol. These results demonstrate that the oxidation of delta'-pyrroline to 2-pyrrolidone is enzyme mediated and provide a useful method for further characterization of this metabolic step.

Animals↗
PubMed1975

Intermediates of the gamma-glutamyl cycle in mouse tissues. Influence of administration of amino acids on pyrrolidone carboxylate and gamma-glutamyl amino acids.

GAMMA-Glutamyl transpeptidase, gamma-glutamyl cyclotransferase, L-pyrrolidone carboxylate hydrolase, gamma-glutamylcysteine synthetase and glutathione synthetase, the enzymes of the gamma-glutamyl cycle, were found in mouse brain, liver and kidney. The activity of L-pyrrolidone carboxylate hydrolase was many times lower than the activities of the other enzymes, and thus the conversion of L-pyrrolidone carboxylate to L-glutamate is likely to be the rate-limiting step of the cycle. The specificity of gamma-glutamyl cyclotransferase from mouse tissues was similar to that from rat tissues. The concentration of pyrrolidone carboxylate and gamma-glutamyl amino acids, intermediates of the gamma-glutamyl cycle, was determined by a gas chromatographic procedure coupled with electron capture detection. Administration of L-2-aminobutyrate, an amino acid that is utilized as substrate in the reaction catalyzed by gamma-glutamylcysteine synthetase, led to a large accumulation of gamma-glutamyl-2-aminobutyrate and pyrrolidone carboxylate in mouse tissues. L-Methionine-RS-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, abolished the increase in concentration of pyrrolidone carboxylate. No accumulation of pyrrolidone carboxylate was observed after L-cysteine. The separate administration of several protein amino acids had little effect on the concentration of pyrrolidone carboxylate; however formation of small amounts of the corresponding gamma-glutamyl derivatives (e.g. gamma-glutamylmethionine and gamma-glutamylphenylalanine) was detected. These intermediates are probably formed by transpeptidation between glutathione and the corresponding amino acid, catalyzed by gamma-glutamyl transpeptidase. The concentration of pyrrolidone carboxylate increased significantly after administration of a mixture containing all protein amino acids, the highest increase occurring in the kidney. The results suggest that two separate pathways for the formation of gamma-glutamyl amino acids and pyrrolidone carboxylate exist in vivo. One of these results from the function of gamma-glutamylcysteine synthetase in glutathione synthesis. The other pathway involves the amino-acid-dependent degradation of glutathione, mediatedby gamma-glutamyl transpeptidase. Only very small amounts of free intermediates are apparently derived from the latter pathway, suggesting that the gamma-glutamyl amino acids formed in this pathway are either enzyme-bound or are directly hydrolyzed to glutamate and free amino acid.

Amino Acids↗
PubMed2004

Effects of orchidectomy and testosterone replacement on mouse pyrrolidone carboxypeptidase activity in the HPA axis.

Pyrrolidone carboxypeptidase, also known as pyroglutamyl aminopeptidase, removes pyroglutamyl terminal residues from biologically active peptides such as thyrotropin-releasing hormone. The aim of the present work was to study the influence of orchidectomy and testosterone replacement on soluble (pyrrolidone carboxypeptidase type I) and membrane-bound (pyrrolidone carboxypeptidase type II) activities in the hypothalamus-pituitary-adrenal axis. Forty male mice (Balb/C) were distributed into five groups: sham-operated controls, orchidectomized, and orchidectomized treated with increasing doses of testosterone in each group (3, 6 and 12 mg/kg). In the hypothalamus, orchidectomy increased pyrrolidone carboxypeptidase type I, whereas the highest dose of testosterone returned this activity to control levels. In the pituitary, neither pyrrolidone carboxypeptidase type I nor type II activities changed after orchidectomy, although both activities increased after administration of testosterone in both cases. On the other hand, orchidectomy increased pyrrolidone carboxypeptidase type I and type II activities in adrenal glands, while testosterone replacement returned it to control levels. These results suggest that testosterone differentially modulates pyrrolidone carboxypeptidase type I and type II activities, and therefore also their endogenous substrate regulation. Thus, the influence of sex hormones in the physiology of the HPA axis through the modulation of the Pyrrolidone carboxypeptidase type I and type II activities is of great importance on stress and neuropathology associated with HPA dysfunction

Androgens↗
PubMed2005

Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

Animals↗
PubMed1988

Effect of 2-pyrrolidone on the concentration of GABA in rat tissues.

The effects of 2-pyrrolidone, a cyclic lactam of GABA, were studied on blood and organ levels of 2-pyrrolidone, GABA, glutamic acid, glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T). When administered i.p., the only significant effects observed were increases of brain and liver 2-pyrrolidone. In contrast, regular oral administration for 7 months produced significant increases of GABA and glutamic acid in brain and of glutamic acid alone in liver while GAD decreased in brain and increased in liver; GABA-T was unchanged. A new method for the synthesis of radioactive 2-pyrrolidone was set up and the enzymatic conversion of 2-pyrrolidone to GABA was measured by an original procedure. The results obtained in vitro by this method on the conversion of 2-pyrrolidone to GABA catalyzed by tissue slices, together with the observed inhibition of the GABA-dependent oxygen consumption by 2-pyrrolidone, partially explain the effects of the oral administration.

4-Aminobutyrate Transaminase↗
PubMed1991

Enhancing effect of pyrrolidone derivatives on transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen.

The enhancing effects of pyrrolidone derivatives on the transdermal penetration of 5-fluorouracil, triamcinolone acetonide, indomethacin, and flurbiprofen were studied by using an in vitro technique and full-thickness rat skin. The enhancers included 1-methyl (1), 1-hexyl (2), and 1-lauryl-2-pyrrolidone (3). Penetrants with various physicochemical properties were used. Flurbiprofen penetrated through skin rapidly after application alone. 5-Fluorouracil, triamcinolone acetonide, and indomethacin showed little penetration. Pyrrolidone derivatives enhanced the penetration of penetrants, especially the lipophilic compounds 2 and 3, which showed a great enhancing effect on the penetration of 5-fluorouracil and indomethacin. Pyrrolidone derivatives also enhanced the solubility of these penetrants in isopropyl myristate. Compounds 2 and 3 showed greater enhancing effects on the solubility and penetration of hydrophilic penetrants than those of lipophilic penetrants. These results suggest that the pyrrolidone derivatives enhance the flux of penetrants in skin by increasing the solubility of penetrants in the stratum corneum. Compounds 1 and 2 were detected in the receptor phase. All enhancers accumulated to a great extent in the skin. These derivatives also enhanced the skin retention of drug. It is concluded that these pyrrolidone derivatives are useful for transdermal drug delivery, although further studies are necessary before they could be used clinically.

Administration, Topical↗
PubMed1990

Enhancing effect of pyrrolidone derivatives on the transdermal penetration of sulfaguanidine, aminopyrine and Sudan III.

The enhancing effect of pyrrolidone derivatives on the percutaneous penetration of sulfaguanidine, aminopyrine and sudan III was investigated using in vitro technique and excised rat skin. 1-Methyl (MP), 1-hexyl (HP) and 1-lauryl-2-pyrrolidone (LP) were used as penetration enhancers. Aminopyrine showed high penetration through skin although sulfaguanidine and sudan III showed little penetration. Pyrrolidone derivatives enhanced their penetrations. Especially HP and LP enhanced the penetration of sulfaguanidine to a high extent. Sudan III was not detected in the receptor phase regardless of the presence of enhancer. Pyrrolidone derivatives significantly increased the skin accumulation of sulfaguanidine, aminopyrine and sudan III. Penetration of pyrrolidone derivatives was also determined. MP and HP showed high penetrations. LP was not detectable in the receptor phase. MP, HP and LP showed high skin accumulations. These results suggested the usefulness of pyrrolidone derivatives as percutaneous penetration enhancers.

Administration, Cutaneous↗