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PubMed1986

Glucocorticoids: binding affinity and lipophilicity.

The relative binding affinity of 35 steroids for the glucocorticoid receptor was determined in experiments in which the competition of various unlabeled steroids with either [6,7-3H]dexamethasone or [1,2-3H]hydrocortisone for the cytosolic glucocorticoid receptor of cultured human keratinocytes was measured. The data obtained were correlated with steroid lipophilicity, measured as the partition coefficient of the steroid between 1-octanol and pH 7.4 aqueous buffer. The introduction of various substituents on the steroid molecule induced changes in the binding affinity and was associated in some cases with concomitant changes in steroid lipophilicity. The substitution by a 17 alpha-OH or 21-OH group leads in all cases to a decrease in steroid lipophilicity and to an increase in affinity. In contrast, 17 alpha-OAc and especially 21-OAc substitution on hydrocortisone and betamethasone causes a decrease in the steroid affinity for the receptor and an increase in steroid lipophilicity. The elongation of the ester chain from acetate to valerate in both position C-17 and C-21 leads to the increase in both the binding affinity for the receptor and the lipophilicity of steroids. However, all 21-esters showed lower binding affinity than the parent alcohol. The binding affinity of the highly lipophilic 17 alpha, 21-diester was found to be lower than that of the 17 alpha-ester but higher than that of the 21-ester or of the parent alcohol. Only in the series of 17 alpha- and 21-esters is there a correlation between the binding affinity of steroids for the glucocorticoid receptor and their lipophilicity.

Cells, Cultured↗
PubMed1989

High-pressure liquid chromatographic analysis of eflornithine in serum.

Eflornithine [2-(difluoromethyl)-DL-ornithine monohydrochloride, monohydrate; DFMO] is an ornithine decarboxylase inhibitor used to treat Pneumocystis carinii pneumonia (PCP) in AIDS patients unresponsive or intolerant to conventional drug therapy. A reversed-phase HPLC method utilizing precolumn dansylation is described which permits the analysis of DFMO in serum of AIDS patients in support of pharmacokinetic studies. Norvaline (2-amino valeric acid) was added as the internal standard and the sample was extracted with three portions of ice-cold 80% ethanol. The supernatants were evaporated in a vacuum oven at 50 degrees C, and the residue was dissolved in base and derivatized at 25 degrees C for 4 h in the dark using dansyl chloride in acetone. Dilute base was then added and 25 to 50 microL was injected into the HPLC. Chromatography was performed on a C-8, 15-cm column with a linear gradient from a 95:5 solution of 10 mM pH 4 acetate buffer and THF, to a 90:10 solution of acetonitrile and THF over a period of 28 min. Detection was by UV at 330 nm, and DFMO and norvaline eluted at 14.7 and 17.7 min, respectively. The method was linear over a range of 5 to 950 micrograms/mL, and replicate analyses of a 25-micrograms/mL control specimen produced a between-run coefficient of variation of 6%. No interferences were encountered in a variety of patient and normal serum blanks.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Submicron emulsion vehicle for enhanced transdermal delivery of steroidal and nonsteroidal antiinflammatory drugs.

Significant improvement is demonstrated for transdermal delivery of steroidal and nonsteroidal antiinflammatory drugs (NSAID), including betamethasone valerate and dipropionate, indomethacin, diclofenac, piroxicam, and naproxen, when formulated in a submicron Emulsion (SME) vehicle rather than in standard creams. SMEs comprise oil droplets, with mean size of approximately 100 nm (0.1 micron), dispersed in a continuous water phase. Hydrophobic drugs are incorporated into the oil phase of the SME, resulting in improved penetration and increased efficacy of the incorporated antiinflammatory drug. The performance of medicated topical SME was compared with that of regular topical cream formulations, as measured by the carrageenan-induced paw edema rat model. Indomethacin in SME topical vehicle was 50% more active than in regular cream base, Diclofenac in SME proved to be 40% more active than Voltaren Emulgel. Improvement of steroidal antiinflammatory drugs action in topical SME cream was even more pronounced; that is, up to 3-4-fold. Antiinflammatory drugs in SME also demonstrate noticeable systemic activity, but for regional edema treatment, local delivery is advantageous. The new SME delivery system was tested for primary irritation in humans in a 48-h trial. Low irritancy and excellent human acceptance for SME placebo or diclofenac-loaded SME cream make this novel transdermal/topical DDS attractive for further development.

Administration, Cutaneous↗
PubMed1981

Influence of prostatic secretion protein on uptake of androgen-receptor complex in prostatic cell nuclei.

Prostatic secretion protein (PSP) is a major component of rat prostatic cytosol, and this protein is also found in the prostatic fluid. Purified PSP was found to inhibit the nuclear uptake of the [3H]methyltrienolone-receptor complex in vitro. Furthermore, purified PSP inhibited the binding of this androgen-receptor complex to DNA-cellulose. It is suggested that these effects of PSP may represent an intracellular control system regulating the concentration of PSP. Administration of estramustine, the dephosphorylated metabolite of the anti-cancer drug estramustine phosphate (Estracyt), to rats was found to decrease the weight of the prostate gland but to maintain the concentration of PSP, calculated as mg PSP/mg protein, at a constant level. In contrast, castration or administration of estradiol-17 beta valerate decreased the weight of the prostate gland as well as the concentration of PSP. These findings indicate that the mechanism of action of estramustine is at least partially different from that of estradiol-17 beta. Furthermore, it is suggested that estramustine may exert part of its action through its effects on the concentration of PSP.

Animals↗
PubMed2003

Synthesis and conformational investigation of cyclic dipeptides: 7-membered rings containing alpha- and beta-amino acids.

The synthesis of heterocyclic compounds containing the 7-membered ring system [1,4]diazepane-2,5-dione is described. The aim of this study was to elaborate the solid phase and solution synthesis of eight representatives of the cyclic scaffold and to investigate their chemical stability and their conformational properties. The solid phase synthesis was performed on aminomethyl polystyrene resin using 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid as a backbone linker system (BAL-linker). After attachment of the alpha- and beta-amino acid and deprotection of the amino function, the dipeptide ester was obtained. The molecule was cyclized on the solid support by treatment with NaOMe in MeOH/NMP. The product was cleaved from the resin by TFA. For the solution pathway the linear dipeptides were synthesized by coupling of the BOC-protected L-alpha-amino acid with the beta2-amino acid ester (EDC/HOBT). After N- and C-terminal deprotection of the dipeptide, the linear species was cyclized with EDC/HOBT at a concentration of 3 mM in DMF. The products showed high chemical stability after storage in DMSO at room temperature for weeks. The x-ray and two dimensional NMR investigations were performed to investigate the conformation of the molecules. Three types of configuration could be distinguished by NMR, depending on the substitution pattern of the cyclic compounds. The x-ray results confirmed the NMR observations. In general the 7-membered rings showed rigidity, thus they could represent optimal scaffolds for new receptor ligands.

Amino Acids↗
PubMed1994

Age-dependent appearance of synaptic currents in rat neocortical neurons in culture.

Rat neocortical neurons grown in dissociated cell culture were recorded with the whole-cell patch-clamp technique. Spontaneous inward currents were observed in cells that were held at a membrane potential of -80 mV in medium containing tetrodotoxin and Cd2+. These currents displayed amplitudes up to 140 pA and rise time of 1.8 +/- 0.2 ms (mean +/- SD, n = 15). They reversed near 0 mV and showed no voltage-dependent frequency of occurrence. Hence, they were presumably due to spontaneous release of transmitter. The inward currents appeared around day 10 in culture and were detected up to 4 weeks. When cells of different ages were compared, the maximal probability of recording these inward events occurred at around 3 weeks in culture. The inward currents were not reduced by application of bicuculline methiodide which is a competitive antagonist of the GABAA receptor, but were blocked by the broad-spectrum glutamate receptor antagonist kynurenic acid. Moreover, spontaneous inward events were not affected by DL-2-aminophosphono-valerate (NMDA receptor antagonist) but disappeared following application of the non-NMDA receptors antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Our observations indicate that the inward currents represent miniature synaptic events that are primarily mediated by non-NMDA excitatory amino acid receptor subtypes. Furthermore, our findings indicate that they develop over time and are not present in neurons that are grown in culture for less than 10 days.

2-Amino-5-phosphonovalerate↗
PubMed1995

Oxidative cleavage of esters and amides to carbonyl products by cytochrome P450.

A series of esters and several amides were shown to undergo oxidative cleavage with the formation of carbonyl products in the presence of purified isoforms of liver microsomal cytochrome P450 (P450) in a reconstituted enzyme system. The reaction also requires NADPH and NADPH-cytochrome P450 reductase and is stimulated by phosphatidylcholine. Kinetic constants were determined in experiments in which the predicted aldehyde product was identified and quantitated by gas chromatography. A relationship was seen with P450 2E1 between the structures of the esters and the Vmax values, with the rates decreasing in the series of methyl formate to methyl valerate, and similarly in the series of methyl, ethyl, propyl, butyl, and amyl acetates. Furthermore, a clear correlation exists between the Km values of the ethyl esters examined and the log of the octanol/water partition coefficients of these substrates. With P450 2E1, the Km decreases significantly between one and four carbon atoms in the chain length of the acyl component of the ester but is unaffected by a further increase in length. However, no correlation was found between the Km value and the chain length of the alcohol moiety of the esters. Similarly, with P450 2B4 a large decrease in Km occurs between one and five carbons in the acyl component of the ethyl esters but is unaffected by a further increase in chain length. The observed correlation is presumed to arise from hydrophobic interactions between the access channel to the active site of P450 and the acyl side chain of the esters. P450 1A2 is also active in ester cleavage, and the three cytochromes examined with esters are active in the conversion of N-alkyl amides to aldehydes, as are P450s 2C3, 1A1, and 3A6. Studies on 2-butyl acetate oxidation by P450 2B4 in the presence of 18O2 showed 88% 18O incorporation into the product, 2-butanone. This is consistent with a mechanism that involves hydroxylation at the alpha-carbon of the alcohol component of the ester to yield an unstable geminal hydroxy ester, as proposed earlier by F. P. Guengerich et al. (1988, J. Biol. Chem. 263, 8176-8183) for several dihydropyridine carboxylic esters. Our results further indicate that such an intermediate decomposes by a nonhydrolytic mechanism and also rule out the possibility of transient ester hydrolysis with subsequent oxidation of the alcohol formed. In addition, they establish that oxidative cleavage is a widespread reaction among P450 cytochromes and commonly used esters and amides.

Amides↗
PubMed1995

New insights on the specificity of penicillin acylase.

In contrast with the general thought that penicillin G acylases (PGAs) were only able to hydrolyse amides or esters of higly hydrophobic acids, we have demonstrated that the PGA from Kluyvera citrophila catalysed the hydrolysis of 4-nitrophenyl esters of acetic, propionic, butyric and valeric acids. Values of kcat. and kcat./Km were greatest for the first compound and less than values for benzylpenicillin by factors of 30 and 7, respectively. 4-Nitrophenyl acetate was hydrolysed faster than 2-nitrophenyl acetate but slower than phenyl acetate. The pH dependence of the reaction was similar to that of benzylpenicillin. Several experiments showed that hydrolysis of 4-nitrophenyl acetate was not catalysed by contaminating esterase activity. The implications for the structural basis of substrate binding are discussed. These substrates open, for the first time, a way to investigate the kinetic parameters of PGA at the presteady-state and provides a new perspective about the role of PGA in nature.

Esters↗
PubMed2000

PPAR-gamma is selectively upregulated in Caco-2 cells by butyrate.

The peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear lipid-activable receptor controlling the expression of genes involved in lipid metabolism and adipocyte differentiation. In order to investigate the possible role of PPAR-gamma in the differentiation of intestinal epithelial cells, we examined its expression in the human colon carcinoma cell line Caco-2, which undergoes rapid cell differentiation in the presence of butyrate. PPARs were quantified on mRNA level by RT competitive multiplex PCR, the corresponding proteins were determined by Western blot. In contrast to PPAR-alpha and PPAR-beta, PPAR-gamma mRNA and protein increased significantly in butyrate-treated Caco-2 cells in a dose- and time-dependent manner. This effect was butyrate-specific, since no change in PPAR-gamma expression could be observed after incubation with propionate or valerate. Activation of PPAR-gamma by ciglitazone further increased butyrate-induced cell differentiation dose-dependently. These data demonstrate a role for PPAR-gamma in the regulation of cell differentiation in Caco-2 cells.

Alkaline Phosphatase↗
PubMed1996

Identification and isolation of a 155-kDa protein with neuropathy target esterase activity.

A method is presented for the isolation of a 155-kDa protein that possesses phenyl valerate hydrolysis activity in the presence of paraoxon but is inhibited by mipafox; the functional definition of neuropathy target esterase (neurotoxic esterase; NTE). Microsomes, isolated from 18-day-old chicken embryos were treated with phospholipase A2 to solubilize the NTE activity. The extract was then combined with polyoxyethylene W1 detergent and resolved by gel filtration chromatography to yield an active fraction with an approximate mass of 200 kDa. This fraction was further purified by preparative isoelectric focusing and native electrophoresis to yield two separate bands possessing NTE activity. The slower migrating band was highly enriched in a 155-kDa protein that was identified as a source of the NTE activity by affinity chromatography using 3-(9'-mercaptononylthio)-1,1,1-trifluoro-propan-2-one bound to Sepharose CL6B. This represents the first report of the isolation of NTE in its active form and aids in the confirmation of the 155-kDa protein as the most likely candidate for NTE.

Animals↗
PubMed1996

Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies.

AD-32 (N-trifluoroacetyladriamycin-14-valerate), an analogue of doxorubicin, was examined for intraperitoneal (ip) administration in a phase 2 trial involving 25 patients with advanced gynecologic malignancies. At an AD-32 dose of 600 mg/m2, the limiting toxicity was grade 4 neutropenia (64% of patients), while severe abdominal pain was relatively uncommon (12%). Intraperitoneal AD-32 administration was associated with a 200-fold pharmacokinetic advantage for cavity exposure, compared to the systemic compartment. At the 600 mg/m2 dose level, 4 of 9 patients (44%) with ascites experienced control of malignant fluid reaccumulation. Based on the results of this phase 1 trial, further exploration of a possible role for the ip administration of AD-32 in individuals with gynecological malignancies appears indicated, particularly in patients with either small volume residual disease after initial systemic chemotherapy or in those with intractable ascites.

Aged↗
PubMed2002

Interaction of carboxylic acids with chitosan: effect of pK and hydrocarbon chain length.

Sorption of acetic, propionic, butyric, valeric, and isovaleric acid on chitosan and cross-linked chitosan was studied in aqueous solutions and water/ethanol mixtures. Langmuir, Freundlich, and Redlich-Peterson equations were used to fit experimental isotherms of sorption. Correlation between maximum sorption and the pK value of every carboxylic acid was found for sorption on chitosan in aqueous solutions, while sorption in water/ethanol mixtures was mainly determined by structure and the hydrocarbon chain length of the carboxylic acid. Slight molecular-sieves effect was found for carboxylic acids sorption on cross-linked chitosan.

Journal Article↗
PubMed2002

A rapid selective extraction procedure for the outer membrane protein (OmpF) from Escherichia coli.

Porins are essential pore-forming proteins found in the outer membrane of several gram-negative bacteria. Investigating the relationships between molecular structure and function involves an extremely time-consuming and labor-intensive purification procedure. We report a method for rapid extraction of the outer membrane protein, OmpF, from freeze-dried Escherichia coli cells using valeric acid, alleviating the effort and time in sample preparation. Extraction results in a highly enriched fraction containing OmpF as 76% of the total protein content. The apparent molecular mass determined by SDS-PAGE mobility was 38,900, similar to that of the monomeric form of OmpF. N-terminal sequencing yielded 23 amino acids with 100% identity to the published OmpF sequence. The trimeric form of OmpF was observed in unheated samples run on SDS-PAGE and analysis of these samples by periodic acid/silver staining revealed the presence of unbound lipopolysaccharides. Furthermore, this method should prove useful for isolating other outer membrane proteins.

Amino Acid Sequence↗
PubMed1994

Dexamethasone, beta-estradiol, and 2,3,7,8-tetrachlorodibenzo-p-dioxin elicit thymic atrophy through different cellular targets.

The effects of single doses of dexamethasone (DEX), beta-estradiol-17-valerate (E2), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the kinetics of thymic atrophy and related bone marrow and thymocyte phenotype alterations were examined. The results imply differences in the mechanisms by which these compounds act. Of the three compounds, DEX induced maximal atrophy by 3 days with complete recovery by Day 12. At the point of maximal atrophy, the RAG-1+TdT+CD4+8+3int thymocyte population was proportionately the most depleted. In contrast, TCDD and E2 caused maximal thymic atrophy by Day 12. E2 treatment, like DEX, resulted in a preferential decrease in the RAG-1+TdT+CD4+8+3int population, but unlike DEX, this decrease persisted. TCDD-induced thymic atrophy resulted from a proportional loss of all classes of thymocytes. There was no significant relative reduction of TdT+RAG-1+ cells by TCDD in the thymus. A slow and persistent reduction of TdT and RAG-1 in bone marrow by both TCDD and E2 contrasted with the rapid reduction and quick recovery of these markers in marrow from DEX-treated animals. Additional studies showed that only DEX-induced atrophy was accompanied by the induction of thymocyte apoptosis, as detected by multiple nucleosomal length DNA fragments within the first 24 hr. The different kinetics and proportions of subsets in the atrophied thymuses, as well as the distinct patterns of alterations of RAG and TdT expression, and the presence or the absence of apoptosis provide evidence for different mechanisms of thymic atrophy by these agents. The slow induction and longer persistence of thymic atrophy induced by E2 and TCDD, as well as their effects on bone marrow stem cell markers, suggest that bone marrow thymocyte precursors are major targets for these agents.

Animals↗
PubMed2001

Production of microbial polyesters: fermentation and downstream processes.

Poly(3-hydroxyalkanoates) (PHAs) constitute a large and versatile family of polyesters produced by various bacteria. PHAs are receiving considerable attention because of their potential as renewable and biodegradable plastics, and as a source of chiral synthons since the monomers are chiral. Industrial PHA production processes have been developed for poly(3-hydroxybutyrate) (poly(3HB)) and poly(3-hydroxybutyrate-co-3-valerate) (poly(3HB-co-3HV). More than 100 other poly(3HAMCL)s, characterized by monomers of medium chain length, have been identified in the past two decades. These monomers typically contain 6-14 carbon atoms, are usually linked via-3-hydroxy ester linkages, but can occasionally also exhibit 2-, 4-, 5-, or 6-hydroxy ester linkages. Such polyesters are collectively referred to as medium chain length PHAs poly(3HAMCL)s. The vast majority of these interesting biopolyesters have been studied and produced only on the laboratory scale. However, there have been several attempts to develop pilot scale processes, and these provide some insight into the production economics of poly(3HAMCL)s other than poly(3HB) and poly(3HB-co-3HV). These processes utilize diverse fermentation strategies to control the monomer composition of the polymer, enabling the tailoring of polymer material properties to some extent. The best studied of these is poly(3-hydroxyoctanoate) (poly(3HO)), which contains about 90% 3-hydroxyoctanoate. This biopolyester has been produced on the pilot scale and is now being used in several experimental applications.

Chemical Engineering↗
PubMed1999

Polyhydroxybutyrate: plastic made and degraded by microorganisms.

Polyhydroxybutyrate (PHB) offers many advantages over traditional petrochemically derived plastics. In addition to its complete biodegradability, PHB is formed from renewable resources. It possesses better physical properties than polypropylene for food packaging applications and is completely nontoxic. The poor low-impact strength of PHB is solved by incorporation of hydroxyvalerate monomers into the polymer to produce polyhydroxybutyrate-co-valerate (PHBV), which is commercially marketed under the trade name Biopol. Like PHB, PHBV completely degrades into carbon dioxide and water under aerobic conditions. Microbial synthesis of PHB is the best method for industrial production because it ensures the proper stereochemistry for biodegradation. Microorganisms synthesize and store PHB under nutrient-limited conditions and degrade and metabolize it when the limitation is removed. Current production employs Alcaligenes eutrophus because it grows efficiently on glucose as a carbon source, accumulates PHB up to 80% of its dry weight, and is able to synthesize PHBV when propionic acid is added to the feedstock. PHBV is currently 16 times the price of polypropylene. However, the development of transgenic PHA-producing organisms is expected to greatly reduce its cost. Benefits of using transgenic systems include lack of a depolymerase system, ability to use faster-growing organisms, production of highly purified polymers, and ability to utilize inexpensive carbon sources. Because transgenic plants may someday result in the evolution of plastic crops that could lower the price of PHA to a competitive level, future research will surely focus on such recombinant DNA techniques.

Bacteria↗
PubMed1993

The growth of preneoplastic lesions by 1,2-dimethylhydrazine in rat colon is inhibited by dietary starch.

The effect of dietary starch and sucrose on colon proliferation and the growth of foci of dysplastic crypts in the colon (FDC) were studied in female Sprague-Dawley rats, treated p.o. with 1,2-dimethylhydrazine (DMH). The animals were fed for 30 and 105 days with high fat (23% w/w corn oil) diets in which carbohydrates were represented by corn starch (starch diet) or sucrose (sucrose diet) (46% w/w). After 105 days of feeding, proliferation was markedly reduced in animals fed the starch diet. The number of FDC was not significantly affected by dietary treatments. However, after 30 and 105 days the percent of small FDC (formed by one-two dysplastic crypts) was higher in the animals fed the starch diet when compared to the sucrose diet. In the cecum of the animals fed the starch diet the percent of butyrate, propionic, isovaleric, and valeric over total short-chain fatty acids (SCFA) was increased, whereas the percent of acetic acid was decreased. Cecal pH was also decreased in the animals fed starch. The results suggest that starch diets have a protective role against DMH-colon carcinogenesis in the rat, mediated by a drop in cecal pH and an increased concentration of some SCFA.

1,2-Dimethylhydrazine↗
PubMed1987

Animal models for study of polycystic ovaries and ovarian atresia.

In the human, polycystic ovaries are generally accompanied by normal or elevated levels of serum LH, normal or slightly depressed FSH and by high levels of circulating estrogens and androgens. If the excess androgen secretion is reduced by one of several methods, ovulatory cycles are usually restored. Several animal model systems have been proposed for the study of the pathophysiology of the polycystic ovarian syndrome. These include neonatal androgenization, hCG administration to hypothyroid rats, injection of estradiol valerate and maintaining animals in constant light. In a model developed in this laboratory, pubertal or adult rats were treated with the weak androgen, dehydroepiandrosterone (DHA), to induce polycystic ovaries. This treatment also altered the blood levels of LH and FSH but the effect on gonadotropins and on the formation of the degenerative follicles was fully reversed following discontinuation of the androgen injections. The polycystic ovaries of the DHA-treated animals were steroidogenically more active than controls raising the possibility that the DHA was acting directly on the ovary in addition to an action on the pituitary-hypothalamus axis. In order to study the direct effect of androgens on the ovary, another animal model was developed in which immature, hypophysectomized rats were injected with pregnant mare serum gonadotropin (PMSG) to initiate follicular growth followed by a single injection of dihydrotestosterone (DHT). The androgen caused follicular atresia and decreased the number of ova shed in response to ovulation induction with hCG. The suppressive effects of DHT were entirely prevented by concomitant treatment with estradiol. The studies with DHT were continued using another batch of PMSG, but the DHT-induced increase in the rat of atresia and suppression of induced ovulation were no longer seen. However, when this same batch of PMSG was given with estrogen or with the antiandrogen flutamide, there was less atresia and the growth of follicles was actually enhanced. Based on these studies, it was postulated that the second batch of PMSG had greater LH activity than the first preparation and that the LH has stimulated endogenous androgen production. The ovarian follicles which appeared to be most susceptible to this DHT effect were small to medium in size and had a low capacity to synthesize estrogen. This possibility was confirmed in another animal model system in which immature rats were injected with PMSG and 4 separate injections of DHT and then sacrificed at several time points over the next 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗