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Biomedical subjects

C K Kim

Publications and source records attributed to C K Kim.

At least 109 records · Page 6Linked to original sources
PubMed2000

Mammary gland tumor in transgenic mice expressing targeted beta-casein/HPV16E6 fusion gene.

The human papillomaviruses (HPV)-16 and HPV-18 referred to as high-risk HPVs are strongly associated with anogenital malignancies as well as benign epithelial cysts. It has been demonstrated that transgenic mice carrying HPV-16 E6-E7 under the control of the MMTV LTR developed malignant tumors including salivary gland carcinoma, lymphoma, skin histiocytomas and testicular tumors in a non-mammary gland specific manner. Another regulatory unit of rat beta-casein gene can confer the expression of fusion gene preferentially in the mammary glands of transgenic mice in a developmentally regulated manner. In order to generate mammary tumor formation in transgenic mice directing HPV16E6 gene alone into the mammary gland, this regulatory unit was fused to the E6 gene of HPV-16 type to constructing fusion gene. By screening 51 newborn founder transgenic mice, three mice carrying transgenes were identified. One line termed TG32 developed in a mammary gland tumor with large subcutaneous mass in the left rib region at 17 months of age. The levels of E6 transcript in the mass-tumor of TG32 line were lower than those in non-tumor mammary gland of identical TG32 and of TG250. In each tissue of TG32 line, high expression of E6 transcript was detected both in the mammary gland and brain. Histological analysis showed that cells from mammary gland tumor of the TG32 line had also hyperplasia appearance, with irregular or increased total number of mitotic rate. These observations suggest that developing phenotype and the level of E6 transcripts in the process of malignant transformation may have different mechanisms involving the capacity to bind and destabilize p53, although for confirmation it is necessary to investigate many more transgenic mice.

Animals↗
PubMed2000

Use of radioimmunoscintigraphy with indium-111-labeled CYT-356 (ProstaScint) scan for evaluation of patients for salvage brachytherapy.

PURPOSE: Indium 111 capromab pendetide radioimmunoscintigraphy (ProstaScint) has been used to detect occult recurrent carcinoma after radical prostatectomy. MATERIALS AND METHODS: We evaluated the role of ProstaScint in 24 men with rising prostate-specific antigen (PSA) level following definitive radiation therapy to differentiate between local and distant recurrence in this patient population. RESULTS: ProstaScint scan detected prostatic uptake only in 16 patients, extraprostatic uptake in 5, both prostatic and extraprostatic uptake in 1, and no uptake in 2. Ten of 21 patients with prostatic uptake had positive biopsies, 5 had negative biopsies, and 6 were not biopsied. Two of the three patients with negative scans had positive biopsies, and the third patient was not biopsied. Three patients had evidence of osseous metastasis on radionuclide bone scan, two corresponding to the sites detected on ProstaScint. All three patients had abnormal uptake beyond the prostatic fossa with (n =2) or without (n = 1) prostatic uptake. There were no positive bone scans in patients without extraprostatic uptake on ProstaScint. CONCLUSIONS: ProstaScint scan is useful in detecting occult recurrence outside the prostate in patients with rising PSA following radiation therapy. Compared to data from radical prostatectomy, ProstaScint scans in these patients reveal a higher prevalence of abnormal uptake in the prostate and less frequent extraprostatic uptake.

Aged↗
PubMed1999

Pharmacokinetics and organ distribution of cyclosporin A incorporated in liposomes and mixed micelles.

The commercially available intravenous dosage form of cyclosporin A (C-CsA) contains a solubilizing agent, polyoxyethylated castor oil, which has been reported to be toxic. To replace the toxic solubilizing agent present in C-CsA, liposomal and mixed micellar preparations were made to solubilize CsA by the proliposome method and characterized. Furthermore, pharmacokinetics and organ distributions of these preparations were evaluated in comparison to C-CsA, which is micellar. The mean size of liposomal preparation (L-CsA) composed of DPPC/PA (molar ratio 3/1) and CsA was 43.6 nm and that of mixed micellar preparation (M-CsA) composed of DMPC/DSPE-PEG (molar ratio 95/5) and CsA was 6.5 nm. The solubilization of CsA was 2-fold greater in mixed micellar solution than in liposomes (0.06 vs 0.03 mg of CsA/mg of lipid). L-CsA, M-CsA and C-CsA were intravenously administered into rats via the femoral vein to analyze pharmacokinetics and organ distribution of CsA. M-CsA was not significantly different from C-CsA in every pharmacokinetic parameter studied. However, L-CsA resulted in 30% decrease in AUC and 55% increase in Cl(t) compared with C-CsA (P<0. 05), without any significant differences in MRT, V(dss) and t(1/2). In addition, the distributions of M-CsA and L-CsA in different organs were not significantly different from those of C-CsA (0.05), except for a 51% decrease of M-CsA in the spleen at 4 h and a 33% increase of L-CsA in the liver at 4 h (P<0.05). These findings demonstrate that the liposomal preparation composed of DPPC/PA and CsA shows slightly different pharmacokinetics and organ distribution patterns from C-CsA, whereas the mixed micellar preparation composed of DMPC/DSPE-PEG and CsA exhibits similar patterns to C-CsA, as expected. Furthermore, these results suggest that those mixed micellar and liposomal preparations can replace C-CsA containing the toxic solubilizing agent, thus providing useful alternative dosage forms for intravenous administration of CsA.

Animals↗
PubMed1999

Lad, an adapter protein interacting with the SH2 domain of p56lck, is required for T cell activation.

T cell-specific Src family tyrosine kinase, p56lck, plays crucial roles in T cell differentiation, activation, and proliferation. These multiple functions of p56lck are believed to be conducted through the protein-protein interactions with various cellular signaling proteins. To clarify the mechanisms through which p56lck contributes to T cell signaling, we identified the proteins binding to the Src homology 2 (SH2) domain of p56lck through a tyrosine phosphorylation-dependent yeast two-hybrid screening. Subsequent characterization of positive clones revealed the presence of a protein of 366 aa named Lad (Lck-associated adapter protein), which is a potential murine homologue of previously reported TSAd, a T cell-specific adapter protein. Lad contains several protein-protein interaction domains including a zinc-finger motif, an SH2 domain, a proline-rich SH3 binding motif, and several phosphotyrosine sites. Furthermore, Lad was tyrosine phosphorylated and associated with p56lck in vivo and redistributed from cytoplasm to the plasma membrane in a T cell activation-dependent manner. Moreover in T cells, IL-2 promoter activity was enhanced upon coexpression of Lad but was inhibited by the coexpression of antisense Lad RNA. These characteristics of Lad suggest that Lad play an essential role as an adapter protein in p56lck-mediated T cell signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Enhanced hepatocyte uptake and liver targeting of methotrexate using galactosylated albumin as a carrier.

Liver targeting of drugs has wide therapeutic implications due to numerous liver-related diseases. Using conjugates of methotrexate (MTX) to variously galactosylated bovine serum albumin (BSA), we studied whether we could enhance the liver targeting of MTX, a model drug, via galactose receptors selectively abundant on the hepatocytes. Here, we report that the galactosylation of the carrier protein BSA significantly enhanced the hepatocyte uptake and liver targetability of MTX. In vitro, the amount of MTX taken up by rat hepatocytes was positively correlated with the galactose content in BSA. MTX conjugates were relatively stable in plasma, but released MTX with time in liver homogenates. These results imply that the conjugates would exert low toxicity in the blood, but have therapeutic activity in the liver by liberating MTX. In vivo, MTX-galactosylated BSA conjugates (MTX-L(24)BSA) showed significantly different pharmacokinetics from free MTX or MTX-BSA conjugates. The plasma level of free MTX rapidly declined in a biexponential fashion with an apparent terminal half-life of 0.35 h. MTX-BSA conjugates showed the slowest decline with an apparent terminal half-life of 6 h, whereas MTX-L(24)BSA showed a biphasic pattern; a rapid distributive phase with a half-life of 0.567 h and a slow terminal phase. MTX-L(24)BSA showed the highest liver targetability, when evaluated in terms of two indices based on the area under the total amount of radioactivity-time curve (AUQ); Te*(liver), % AUQ(liver) to total AUQ, and te*, the ratio of AUQ(liver) to AUQ(kidney). Compared with free MTX and MTX-BSA, MTX-L(24)BSA showed about twofold higher Te*(liver) of 87.5%. The te* of MTX-L(24)BSA was 25- and fourfold higher than those of free MTX and MTX-BSA, respectively. Moreover, MTX-L(24)BSA showed a gradual increase in the therapeutically active intact form of MTX in the liver while showing the lowest level of intact MTX in the kidney. These results suggest that galactosylated BSA has a great potential as an hepatocyte-directed and more effective liver targeting carrier of drugs for liver diseases.

Animals↗
PubMed1999

Encapsulation of ethanol by spray drying technique: effects of sodium lauryl sulfate.

Microcapsules composed of ethanol, water and dextrin as a water-soluble polymer can be used to encapsulate poorly water-soluble drugs by spray drying technique. For the encapsulation of a high dose of poorly water-soluble drugs, large amounts of ethanol and consequently large quantities of dextrin are needed for the dissolution of drug and the encapsulation of ethanol, respectively. In order to increase the ethanol content with the decreased amount of dextrin, sodium lauryl sulfate (SLS) was employed in the preparation of microcapsules without drug by a spray drying method. Phase diagrams were prepared to determine the region of microcapsule formation with a three-component system of ethanol, dextrin and water. The homogeneous phase indicated in the phase diagram was used to prepare the alcoholic microcapsules since this phase was not separated rapidly and not too viscous to be spray-dried. Interestingly, SLS at concentrations below 2% remarkably increased both the ethanol content and the encapsulation efficiency of ethanol. The maximum ethanol content and encapsulation efficiency were observed with 0.5-1% of SLS (35.4 and 67.6%, respectively). Furthermore, the increase by SLS was more pronounced at the low dextrin/water ratios than at the high dextrin/water ratios. In particular, the ethanol content and the encapsulation efficiency with the dextrin/ethanol/water ratio of 0.4/1/1, which had relatively small amounts of dextrin, were about ten times higher in the presence of SLS than those without SLS. In conclusion, this study shows that small amounts of SLS can increase the ethanol content and the encapsulation efficiency of ethanol, and allow the reduction in the amount of dextrin required to encapsulate ethanol in the preparation of microcapsules. These findings suggest that the use of SLS may permit the effective encapsulation of high dose of water-insoluble drug into microcapsules.

Capsules↗
PubMed1999

Anthropogenic radionuclides in seawater of the Far Eastern Seas.

Large quantities of radioactive wastes have been dumped in the Far Eastern Seas by the former Soviet Union and the Russian Federation, and small amounts of radioactive wastes have been dumped by Japan and the Republic of Korea. In order to investigate the concentrations of anthropogenic radionuclides in the nine dumping areas, a second expedition was conducted in 1995 by Japan, the Republic of Korea, the Russian Federation and IAEA, following the first expedition in 1994. The results show that 137Cs, 90Sr and 239 + 240Pu concentrations in surface and bottom waters at dumping areas do not significantly differ from the values observed in background areas, and from historical values. There is no clear effect of possible contamination due to radioactive waste dumping. The concentrations and water column inventories of 137Cs, 90Sr and 239 + 240Pu in the Far Eastern seas are controlled by physical oceanic processes such as horizontal transport and biogeochemical processes such as scavenging.

Cesium Radioisotopes↗
PubMed1999

Nitric oxide stimulates ACTH secretion and the transcription of the genes encoding for NGFI-B, corticotropin-releasing factor, corticotropin-releasing factor receptor type 1, and vasopressin in the hypothalamus of the intact rat.

We investigated the effect of the intracerebroventricular injection of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) on the release of adrenocorticotropin hormone (ACTH) and the neuronal response of hypothalamic neurons responsible for this release. Rats that were administered SIN-1 showed significant elevations in plasma ACTH levels, a response that was virtually abolished by antibodies against corticotropin-releasing factor (CRF) and significantly blunted by vasopressin (VP) antiserum. SIN-1 also upregulated heteronuclear (hn) transcripts for CRF and VP and messenger RNA (mRNA) levels for the immediate early gene NGFI-B and for CRF receptor type 1 (CRF-R(1)) in the parvocellular portion of the paraventricular nucleus (PVN) of the hypothalamus. Blockade of prostaglandin synthesis with ibuprofen did not alter the ACTH or the PVN response to SIN-1. The central nucleus of the amygdala and the supraoptic nucleus, regions that are involved in autonomic adjustments to altered cardiovascular activity, also responded to SIN-1 with elevated NGFI-B mRNA levels. However, the only change in mean arterial blood pressure caused by this NO donor was a transient and modest increase. To our knowledge, this is the first demonstration that in the intact rat NO stimulates the activity of PVN neurons that control the hypothalamic-pituitary-adrenal axis. It must be noted, however, that our results do not allow us to determine whether this effect was direct or mediated through PVN afferents. This study should help resolve the controversy generated by the use of isolated brain tissues to investigate the net effect of NO on hypothalamic peptide production.

Adrenocorticotropic Hormone↗
PubMed1999

Phospholipid-based microemulsions of flurbiprofen by the spontaneous emulsification process.

The purpose of this study was to investigate the possibility for parenteral delivery of flurbiprofen without chemical modification using a phospholipid-based microemulsion system. Microemulsions composed of ethyl oleate, lecithin and distearoylphosphatidyl-ethanolamine-N-poly(ethyleneglycol) 2000 (DSPE-PEG) were prepared using ethanol as a cosolvent. The effect of formulation variables on the particle size of the microemulsion was investigated. Flurbiprofen concentrations in plasma and various organs after the intravenous administration of flurbiprofen-loaded microemulsion were measured and compared with those after the intravenous administration of flurbiprofen axetil-entrapped emulsion (Lipfen(R), 50 mg/5 ml as flurbiprofen axetil) and flurbiprofen solution. Phospholipid-based microemulsions could solubilize more than 10 mg ml-1 of flurbiprofen at the ratio of vehicle to drug at least 10:1, if the oil contents (10 or 20%) of common parenteral emulsions were used. The half-life, AUC and MRT of flurbiprofen loaded in microemulsion (ethyl oleate:lecithin:DSPE-PEG:flurbiprofen=8:3:1:1.2) increased significantly. The biodistribution of flurbiprofen loaded in this microemulsion was quite different from others. Reticuloendothelial uptake of flurbiprofen loaded in microemulsion decreased compared with that in solution or Lipfen(R). It is concluded that the current microemulsion system might be applicable to formulate the parenteral dosage form of poorly water-soluble flurbiprofen without chemical modification.

Animals↗
PubMed1999

Development of dried liposomes containing beta-galactosidase for the digestion of lactose in milk.

The hydrolyzed-lactose milk for lactase-deficient subjects has a sweeter taste than whole milk, and some subjects dislike its taste. In order to cope with this shortcoming, we examined whether beta-galactosidase, which hydrolyzes lactose, added to the whole milk in the form of dried liposomes, would be able to digest lactose in milk following the lysis of liposomes in the presence of bile salts. Dried liposomes containing beta-galactosidase were prepared in the presence of trehalose by the dehydration-rehydration vesicle method to overcome the instability of the conventional liposome suspension. The stability of liposomal membranes was evaluated by measuring the activity of entrapped beta-galactosidase under various storage conditions. By treating liposomes with trehalose, which was found to prevent the fusion of liposomes and the leakage of entrapped drug, the entrapping efficiency increased up to fourfold. Over 95% of dried liposomes which had been stored at 17 degrees C for 60 days were reconstituted to liposomes upon rehydration process. From the stability study, dried liposomes were found to retain 87% of beta-galactosidase activity at 17 degrees C after 60 days and to be more stable than the multilamellar vesicle suspension prepared without trehalose. The lysis study showed that dried liposomes were hardly lyzed in the simulated gastric fluid with pepsin, but lyzed immediately more than 90% in 0.01 M deoxycholic acid. Lactose hydrolysis in the presence of deoxycholic acid after the addition of dried liposome-entrapped beta-galactosidase to whole milk was proportional to the quantity of entrapped beta-galactosidase and the amount of dried liposomes added. These results demonstrate that beta-galactosidase entrapped in liposome is stable and reconstituted mostly upon rehydration, and can digest lactose in milk after the efficient lysis of liposomes in the presence of bile salts. This study implies that beta-galactosidase entrapped in liposome may be applied to whole milk for lactase-deficient subjects.

Animals↗
PubMed1999

Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum.

Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers (0.6%) to a formulation of thermally gelling suppositories that contained poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil and sodium alginate were examined as mucoadhesive polymers. The characteristics of the suppositories differed depending on the choice of mucoadhesive polymer. For example, the gelation temperature was between 30 and 36 degrees C, the mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h-1, the migration distance of the suppository in the rectum 4 h after administration was between 1 and 5 cm, and the bioavailability of propranolol was between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive force increased (r=0.984, p<0.0005), and the migration distance decreased (r=-0.951, p<0.005). No relationship was found between the bioavailability and the gelation temperature, drug release or irritation of the rectal mucosal membrane by the suppository. Therefore, retaining propranolol at the dosed site in the rectum by the addition of appropriate mucoadhesives to the formulation of liquid suppositories appears to be a very important factor in avoiding first-pass hepatic elimination and thereby increasing the bioavailability of the drug. Among the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited the largest mucoadhesive force and the smallest intrarectal migration resulting in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In contrast to other polymers, sodium alginate alone caused no irritation of the rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium alginate appears to be a preferred formulation for drugs that are sensitive to extensive first-pass metabolism.

Adhesiveness↗
PubMed1999

Preparation and evaluation of flurbiprofen-loaded microemulsion for parenteral delivery.

The purpose of this study was to improve the solubility of flurbiprofen, a poorly water-soluble drug, in an oil-in-water (o/w) microemulsion that is suitable for parenteral administration. Microemulsions with varying ratios of oil to surfactant were prepared with ethyl oleate, Tween 20 and isotonic solution. The effect of formulation variables on the particle size of microemulsion and solubility of flurbiprofen in microemulsion system was investigated. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion were compared with those of a solution of the drug. The mean droplet diameter of microemulsion containing less than 1% (w/w) of flurbiprofen was below 100 nm. The maximum solubility of flurbiprofen in the microemulsion system was found to be 10 mg/ml. However, the mean droplet diameters of flurbiprofen-loaded o/w microemulsions tend to be increased at room temperature. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion to rats were not significantly different from those of flurbiprofen in phosphate-buffered saline solution. It can be concluded that microemulsions of flurbiprofen prepared with ethyl oleate and Tween 20 can be used as a parenteral drug carrier for this and other poorly water-soluble drugs, provided that physical stability can be properly addressed.

Animals↗
PubMed1999

Cloning and sequencing of the fcbB gene encoding 4-chlorobenzoate-coenzyme A dehalogenase from Pseudomonas sp. DJ-12.

Pseudomonas sp. DJ-12 degrades 4-chlorobenzoate through hydrolytic dechlorination to produce 4-hydroxybenzoate and a chloride ion. The fcbB gene encoding the 4-chlorobenzoate-coenzyme A (4CBA-CoA) dehalogenase which catalyzes the nucleophilic substitution reaction to convert 4CBA-CoA to 4-hydroxybenzoate-coenzyme A (4HBA-CoA) in the consecutive steps of dechlorination was cloned from the chromosome of the organism. A nucleotide sequence analysis of the gene showed an open reading frame consisting of 810 nucleotides, which can encode for a polypeptide of molecular mass 30 kDa, containing 269 amino acid residues. A promoter-like sequence (-35 and -10 region) and a putative ribosome-binding sequence were identified. A deduced amino acid sequence of the 4CBA-CoA dehalogenase showed 86%, 50%, and 50% identity with those of corresponding enzymes in the Pseudomonas sp. CBS3, Arthrobacter sp. SU, and Arthrobacter sp. TM1, respectively.

Amino Acid Sequence↗
PubMed1999

Release of adriamycin from poly(gamma-benzyl-L-glutamate)/poly(ethylene oxide) nanoparticles.

Prolonged circulation of anticancer agent in blood is expected to decrease the host toxicity and enhance the anticancer activity. The purpose of this study is to develop and characterize the prolonged and sustained release formulation of anticancer agent using biodegradable poly(gamma-benzyl-L-glutamate)/poly(ethylene oxide) (PBLG/PEO) polymer nanoparticles. PBLG/PEO polymer is a hydrophilic/hydrophobic block copolymer and forms a micelle-like structure in solution. Spherical nanoparticles incorporating adriamycin were prepared by a dialysis method. The fluorescence intensity of adriamycin in the nanoparticles was increased when sodium dodecylsulfate was added. It is one of the evidences of entrapment of adriamycin in the polymer nanoparticles. Only 20% of entrapped drug was released in 24 h at 37 degrees C a and the release was dependent on the molecular weight of hydrophobic polymer. The endothermic peak of adriamycin at 197 degrees C disappeared in the nanoparticles system, suggesting the inhibition of a crystallization of adriamycin by polymer adsorption during the precipitation process. The mean residence time of adriamycin from the nanoparticles was more than threefold that from a free adriamycin. These results suggest usefulness of PBLG/PEO nanoparticles as a sustained and prolonged release carrier for adriamycin.

Animals↗
PubMed1999

Pharmacodynamics of insulin in polyethylene glycol-coated liposomes.

To reduce the injection frequency and toxicity of intravenously administered protein drugs, it is necessary to develop safe and sustained injectable delivery systems. In this study, to evaluate liposomes as safe and sustained injectable delivery systems of proteins, we chose insulin as a model protein drug and tested its incorporation efficiency and pharmacodynamics in various liposomes with and without polyethylene glycol (PEG)-derivatized phospholipid. The liposomes coated with PEG showed 3-fold higher efficiency of insulin incorporation than did the liposomes without PEG. Moreover, among the liposomes coated with PEG, dipalmitoylphosphocholine (DPPC) liposomes showed higher incorporation efficiency than did dimyristoylphosphocholine (DMPC) liposomes. For pharmacodynamic study, insulin (2 IU/kg) was administered in various formulations, such as insulin alone in phosphate-buffered saline and insulin in the DPPC liposomes with and without PEG, to streptozotocin-treated diabetic rats. The pharmacodynamics of insulin alone, however, could not be measured due to the immediate death of rats caused by hypoglycemic shock. In contrast, all the rats treated with liposomal insulin survived, probably by the sustained release of insulin from liposomes. Pharmacodynamics of liposomal insulin showed that PEG-coated liposomes induced the lowest level of blood glucose-the nadir-1 h later than did the liposomes without PEG. These results indicate that PEG-coated liposomes could be developed as a relatively safe and sustained injectable delivery system for insulin with improved incorporation efficiency. Moreover, it is suggested that the liposomes coated with PEG might have a potential as safe injectable delivery systems for other protein and peptide drugs.

Animals↗
PubMed1999

The phnIJ genes encoding acetaldehyde dehydrogenase (acylating) and 4-hydroxy-2-oxovalerate aldolase in Pseudomonas sp. DJ77 and their evolutionary implications.

The two final steps of meta-cleavage pathway for catechol degradation involve conversion of 4-hydroxy-2-oxovalerate, via acetaldehyde, to acetyl coenzyme A. We report here the complete nucleotide sequences and overexpression of the phnIJ genes for an acetaldehyde dehydrogenase (acylating) (ADA) and a 4-hydroxy-2-oxovalerate aldolase (HOA) from the meta-pathway operon of the phenanthrene-degrading bacterium, Pseudomonas sp. strain DJ77. Additional partial sequence analysis of adjacent DNA shows the gene order within the operon to be phnHIJ, identical to the order found for the isofunctional genes in the other meta-pathway operons. The deduced amino acid sequences of the PhnI (312 amino acids) and PhnJ (343 amino acids) have identities of 51-71% with the corresponding genes of dmp, xyl, nah, bph_LB400, bph_KKS102, tod, cum, cmt, and MTCY03C7 operons. The phylogenetic analyses reveal the evolutionary relationships of HOA and ADA.

Acetaldehyde↗
PubMed1999

Chronic intermittent stress does not differentially alter brain corticosteroid receptor densities in rats prenatally exposed to ethanol.

Prenatal ethanol exposure produces hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stressors. The present study tested the hypothesis that decreased corticosteroid receptor densities at HPA feedback sites may play a role in deficient feedback inhibition and the resultant HPA hyperresponsiveness that is observed following prenatal ethanol exposure. Brains of adult Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum-fed control (C) treatment groups were examined for both mineralocorticoid receptor (MR; Type I) and glucocorticoid receptor (GR; Type II) densities using a cytosolic binding assay. Experiment 1 compared the effects of chronic intermittent stress (Stress Regimen I) and corticosterone (CORT) pellet implants on hippocampal corticosteroid receptor densities in control rats. Experiment 2 determined whether exposure to Stress Regimen I would differentially downregulate and whether adrenalectomy (ADX) would differentially upregulate hippocampal corticosteroid receptors in E compared with PF and C animals. Experiment 3 examined the effects of a modified chronic intermittent stress regimen (Stress Regimen II) on corticosteroid receptor densities at several HPA feedback sites (hippocampus, prefrontal cortex, hypothalamus, and anterior pituitary) in E compared with PF and C animals. CORT pellet implants significantly downregulated hippocampal GR and MR densities in control males and females. Exposure to Stress Regimen I produced downregulation of hippocampal GRs and MRs in males comparable with that produced with CORT pellet implants, and significant downregulation of hippocampal GRs in females across all prenatal treatment groups. This stress regimen also elevated basal plasma CORT levels without concurrent changes in plasma CBG levels, and increased relative adrenal weights in both males and females. In addition, upregulation of hippocampal GRs occurred at 7 days compared with 24 h following ADX in females that had previously been exposed to this stress regimen. Following exposure to Stress Regimen II, both the downregulation of hippocampal corticosteroid receptors and the increase in basal CORT levels in males and females appear to have been abolished by the changes in housing condition during the period of chronic stress. Importantly, prenatal ethanol exposure did not differentially alter GR or MR densities at any feedback site under non-stressed conditions. Exposure to Stress Regimen II, revealed subtle effects of prenatal treatments on hippocampal GRs however it is unlikely that these changes in corticosteroid receptor densities mediated the feedback inhibition deficits observed in E animals. Together, these data demonstrate that: (1) a relatively mild intermittent stress regimen can increase basal CORT levels and downregulate hippocampal corticosteroid receptor densities (2) a seemingly small change in housing conditions during stress appears to eliminate both receptor downregulation and increase in basal CORT levels and (3) decreased corticosteroid receptor densities at HPA feedback sites in the brain do not appear to underlie the HPA hyperresponsiveness observed in E animals.

Animals↗