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PubMed1986

New aspects of oestrogen/gestagen-induced growth and endocrine changes in individuals with Turner syndrome.

Patients with Turner syndrome (n = 33) were subjected to a sequential oestrogen/gestagen replacement therapy (21 days 2 mg oestradiol valerate plus 0.5 mg norgestrel for 10 days) for 1-4 years. In individuals aged 12-17 years, growth velocities before treatment ranged between 2.9 and 1.9 cm/year and increased to 6.8-3.8 cm/year following sex steroid substitution for 1 year. Thereafter a decrease was observed; depending on age, pre-treatment velocities were observed within 2-4 years of replacement therapy. On average, bone age advanced 1 year following 1 year of sex steroid administration and adult bone age was reached following 2-4 years of treatment. Approximately 70% of the individuals noted breast development to stage IV according to Tanner and experienced regular withdrawal bleedings. Oral administration of oestradiol valerate resulted in serum oestradiol levels normally seen during the early follicular phase; hypergonadotropic LH and FSH levels decreased slightly following 1 year of therapy. Growth ranged between 4 and 13 cm; in the oldest individuals the final height ranged between 149 and 156 cm. In summary, the oestrogen/gestagen replacement therapy chosen for this study achieved development of secondary sex characteristics, endocrine changes, growth velocities, bone age advancement and to a certain extent growth, which was almost comparable to that observed during puberty in healthy girls.

Adolescent↗
PubMed1979

Propionyl-CoA carboxylase deficiency with overflow of metabolites of isoleucine catabolism at all levels.

An 11-year old girl with spastic paraplegia and mental retardation has suffered from attacks of metabolic acidosis since the age of 18 months. "Ketotic hyperglycinemia" was diagnosed when she was 3 years old. Reinvestigation at 9 1/2 years included a two-day load with L-isoleucine, and propionyl-CoA carboxylase assay in cultured fibroblasts. The following compounds increased following the load: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric acid, 2-ethylhydracrylic acid, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, 2-oxo-3-methylvaleric acid, 2-methyl-3-oxovaleric acid, N-tiglylglycine, methylcitric acid and butanone. Small amounts of alloisoleucine appeared in plasma. Propionyl-CoA carboxylase deficiency was suggested by this metabolite pattern and demonstrated in cultured fibroblasts.

Acidosis↗
PubMed1978

Deranged isoleucine metabolism during ketotic attacks in patients with methylmalonic acidaemia.

Two patients with methylmalonic acidaemia due to methylmalonyl-CoA mutase deficiency were studied for several years. Both exhibited at least two attacks of severe ketoacidosis, during which they excreted, in addition to methylmalonic acid, a number of abnormal compounds: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, citraconic acid and N-tiglyglycine. These compounds represent partly intermediary metabolites from the isoleucine degradation pathway and partly secondary metabolites of propionyl-CoA and tiglyl-CoA.

Acidosis↗
PubMed1981

The coordinating properties of d-biotin.

The coenzyme d-biotin offers in its anionic form to metal ions 3 possible binding sites: the carboxylate group of the valerate side chain, the ureido residue of the 2-imidazolidone ring, and the thioether sulfur of the tetrahydrothiophene ring; the coordinating properties of these groups are summarized and compared. Hydrogen bond formation of the ureido group has also been observed, and hydrogen bonding may possibly be important in biotin-bicarbonate recognition. The aliphatic part of the valeric acid side chain can undergo hydrophobic interactions. Such interactions and/or the stereoselective sulfur-metal ion coordination could be the means for a correct 'fixation' of the biotinyl moiety at the surface of a protein, thus creating the active enzyme-substrate complex.

Binding Sites↗
PubMed2002

Effect of crystal form on in vivo topical anti-inflammatory activity of corticosteroids.

The aim of this study was to gain information on the effects of the crystal form of corticosteroids on the topical anti-inflammatory activity. Two different crystal forms, Form A and Form B, of the drugs of prednicarbate, hydrocortisone, betamethasone 17-valerate, prednisolone, and methyl prednisolone were prepared and their topical anti-inflammatory activities were measured using arachidonic acid induced ear edema assay in mice. Two crystal forms of the drugs showed differences in anti-inflammatory activity. Among the drugs examined, Form B of prednicarbate and betamethasone 17-valerate showed significantly more potent anti-inflammatory activities as compared to their Form A.

Administration, Topical↗
PubMedDate not supplied

Demonstration of estrogen receptors in the skin.

The occurence of high affinity and limited capacity estrogen receptors in skin specimens was investigated and the concentrations of cytoplasmic and nuclear receptors were studied in 14 normal and 22 castrated women. The skin estrogen receptor levels were low in all cases examined, although they usually exceeded the limit value used for estrogen receptor levels in breast cancer tissue. The cytoplasmic and nuclear receptor concentrations in normal women varied from 2.4 to 9.0 and from 1.5 to 7.0 fmol/mg cytosol protein, respectively. The receptor was present as a very high affinity binding component (KD = 0.2- 1.6 x 10(-9)M). The estrogen receptor concentrations in the skin during estriol succinate and estriol valerate therapy were at roughly the same level as during the normal menstrual cycle. The patients who received no replacement therapy after castration displayed the lowest skin estrogen receptor levels. The share of nuclear receptors seemed to be smaller on average during the normal menstrual cycle and in castrated patients not given estrogen therapy than in women treated with estriol succinate or estradiol valerate.

Adult↗
PubMed2000

Thermophilic acidification of dairy wastewater.

Acidification of simulated dairy wastewater was conducted in an upflow reactor at 55 degrees C. Results showed that the degree of acidification decreased with the increase in chemical oxygen demand (COD) loading rate, from 60.8% at 4 g l(-1) day(-1) to 27.1% at 24 g l(-1) day(-1). Carbohydrate was readily degraded at all loading rates, but degradation of protein and lipid decreased with the increase in loading rate. Most carbohydrate degradation occurred at the reactor bottom, whereas protein was degraded mainly after the carbohydrate became depleted. The predominant acidification products were acetate, propionate, butyrate and ethanol, whereas formate, i-butyrate, valerate, i-valerate, caproate, lactate, methanol, propanol and butanol were present in lesser quantities. The increase in loading rate resulted in the increase of propionate and the decrease of acetate, but had little effect on ethanol and butyrate productions. Only 2.5-8.8% of influent COD was converted to hydrogen and methane. The biomass yield was 0.30-0.43 mg VSS mg(-1) COD.

Alcohols↗
PubMed2000

Effect of structural analogues of propionate and butyrate on colon cancer cell growth.

The aim of this study was to evaluate the effects of natural short-chain fatty acids (butyrate, propionate, valerate, acetate) and structural analogues of butyrate and propionate on cell growth and apoptosis in three human colonic adenocarcinoma cell lines (HT-29, Colo-320, and SW-948). We have previously shown that mercapto- and bromo-analogues of butyrate and propionate compete with natural short-chain fatty acids for uptake in the colonocyte. Among naturally occurring short-chain fatty acids, butyrate was the most potent inhibitor of proliferation in all three cell lines. Propionate exhibited a weaker antiproliferative effect, while other short-chain fatty acids (valerate, acetate) were ineffective. Bromo-analogues of butyrate and propionate were more potent proapoptotic agents than butyrate. In contrast to butyrate, the analogues induced strand breaks on isolated supercoiled DNA, the effect being completely reversed by a DNA-protecting agent, spermine. We conclude that bromo-analogues of butyrate and propionate are more potent proapoptotic agents than butyrate in colon cancer cells in culture. Their effect may be a result of direct DNA damage.

Adenocarcinoma↗
PubMed2005

Cytotoxicity of organic acids produced by anaerobic intestinal bacteria on cultured epithelial cells.

BACKGROUND: Anaerobic intestinal bacteria produce various organic acids. We identified the concentrations of various organic acids produced by intestinal bacteria needed to kill cultured cells. METHODS: Nine organic acids and their sodium salts were added to five epithelial cell lines and the cells were examined for cytotoxicity. To assess cytotoxicity, the colorimetric 3-(4,5-dimethyl-2-thiazoyl-2,5-diphenyl tetrazolium bromide (MTT) assay was performed. We calculated the lowest concentration that killed 50% of the cells by the MTT assay. Adherent and floating cells were collected 96 h after incubation for analysis of apoptosis by gel electrophoresis and flow cytometry. RESULTS: The minimum concentrations of the acids and sodium salts of n-butyric, propionic, isovaleric, and succinic acids capable of causing cytotoxicity were lower than the concentrations produced by intestinal bacteria. Apoptosis was found in all cell lines treated with the acids and the sodium salts of n-butyrate, isobutyrate, propionate, isovalerate, and n-valerate. However, no apoptosis was found in cells treated with the acid or sodium salts of formate and lactate. CONCLUSIONS: This study showed that acetate, butyrate, propionate, and valerate produced by intestinal bacteria could induce apoptosis at physiological concentrations. This cytotoxicity may contribute to the pathogenesis of colonic ulcers.

Apoptosis↗
PubMed2006

Incorporation of polyethylene glycol in polyhydroxyalkanoic acids accumulated by Azotobacter chroococcum MAL-201.

Azotobacter chroococcum MAL-201 (MTCC 3853), a free-living nitrogen-fixing bacterium accumulates poly(3-hydroxybutyric acid) [PHB, 69% of cell dry weight (CDW)] when grown on glucose and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) [PHBV with 19.2 mol% 3HV] when grown on glucose and valerate. Use of ethylene glycol (EG) and/or polyethylene glycols (PEGs) of low molecular weight as sole carbon source were detrimental to A. chroococcum growth and polymer yields. PEG-200, however, in the presence of glucose was incorporated into the polyhydroxyalkanoate (PHA) polymer. Addition of PEG-200 (150 mM) to culture medium during mid-log phase growth favored increased incorporation of EG units (12.48 mol%) into the PHB polymer. In two-step culture experiments, where valerate and PEG simultaneously were used in fresh medium, EG was incorporated most effectively in the absence of glucose, leading to the formation of a copolymer containing 18.05 mol% 3HV and 14.78 mol% EG. The physico-mechanical properties of PEG-containing copolymer (PHBV-PEG) were compared with those of the PHB homopolymer and the PHBV copolymer. The PHBV-PEG copolymer appeared to have less crystallinity and greater flexibility than the short-chain-length (SCL) PHA polymers.

Azotobacter↗
PubMed1997

Energy state in HT-29 cells is linked to differentiation.

The relationship between the energy source used by HT-29 cells and their state of differentiation was determined. Short chain fatty acids and acetoacetate were applied to the cells for 9 d, after which the medium was replaced with conventional culture medium for a further 9 d so that the permanence of the changes could be assessed (18 d). Glucose utilization and lactic acid, acetoacetate, and beta-hydroxybutyrate production by the cells were determined. Differentiation was assessed by the presence of the enzymes sucrase-isomaltase and carbonic anhydrase 1, as well as morphological changes of the cells. By tracing carbon from acetate, propionate, and butyrate through the cells, it was found that the carbon from the short-chain fatty acids was fluxed into acetoacetate. Significant amounts of acetoacetate were released by the propionate-treated culture after 9 d and the acetate-, propionate-, valerate-, and caproate-treated cultures after 18 d. A significant positive correlation was found between acetoacetate synthesis and differentiation. Acetoacetate applied to HT-29 cells also induced their differentiation. The acetate-, butyrate-, valerate-, isovalerate-, and caproate-treated cells underwent terminal differentiation, while the propionate- and isocaproate-treated cultures underwent programming events. We, therefore, conclude that HT-29 cells utilize short chain fatty acids in preference to glucose, metabolize these to ketones, thereby raising the energy state and effecting the observed morphological and functional changes in the cells.

Acetoacetates↗
PubMed1980

The effect of estrogen priming on induction of labor with prostaglandins.

A double-blind, randomized study was designed to determine whether estrogen "priming" of the unripe cervix followed by prostaglandin induction of labor would have a synergistic effect on cervical ripening and improve the success rate of induction. One hundred near-term patients with Bishop scores less than or equal to 4 received an intramuscular injection of either 10 mg of estradiol valerate or a placebo 48 hours prior to induction of labor with oral prostaglandin E2. The serial changes in Bishop scores were very similar in both groups. The success rate of induction in the study group (69.8%) was not statistically different from that in the control group (61.9%). The duration of labor was 9.9 +/- 4.1 hours in the study group versus 9.1 +/- 3.7 hours in the control group (not significant). This study showed that 10 mg of estradiol valerate had no detectable effect on the unripe cervix near term and did not show a synergistic effect with prostaglandins during induction of labor.

Adult↗
PubMed1989

Pattern of human chorionic gonadotropin binding in the polycystic ovary.

The histologic evolution of polycystic ovaries in the estradiol valerate-treated rat coincides with the development of a unique plasma pattern of luteinizing hormone. To assess the role of luteinizing hormone in polycystic ovaries, it is necessary to evaluate the luteinizing hormone sensitivity of the specific tissues in the polycystic ovary. Therefore, we examined the pattern of luteinizing hormone binding sites in polycystic ovaries. Rats at 4 or 8 weeks after estradiol valerate treatment each received an intrajugular injection of iodine 125-labeled human chorionic gonadotropin. Some rats also received a 1000-fold excess of unlabeled human chorionic gonadotropin in the same injection. Ovaries were prepared for autoradiography. Dense accumulations of grains occurred over the theca of normal and atretic secondary follicles in all ovaries and over clusters of secondary interstitial cells. The iodine label was variable over the typically hypertrophied theca of precystic follicles. The theca of definitive cysts showed little or no label. These results indicate that cyst formation coincides with the loss of luteinizing hormone/human chorionic gonadotropin binding to the affected follicles.

Animals↗
PubMed1990

Spectrophotometric enzymatic assay for S-3-hydroxyisobutyrate.

An enzymatic spectrophotometric end-point assay has been developed for determination of S-3-hydroxyisobutyrate in biological fluids. The assay measures NADH production at 340 nm after initiation of the reaction with rabbit liver 3-hydroxyisobutyrate dehydrogenase (EC 1.1.1.31). The assay is not affected by R-3-hydroxyisobutyrate, lactate, malate, 3-hydroxybutyrate, 2-methyl-3-hydroxybutyrate, 3-hydroxyisovalerate, 3-hydroxy-n-valerate, 2-methyl-3-hydroxy-valerate, and 3-hydroxypropionate. The assay does measure 2-ethyl-3-hydroxypropionate, a minor metabolite produced by catabolism of alloisoleucine. Application of the method to measure S-3-hydroxyisobutyrate in plasma obtained from normal, 48-h starved, and mildly and severely diabetic rats gave levels of 28, 42, 112, and 155 microM, respectively.

Alcohol Oxidoreductases↗
PubMed1985

Calmodulin inhibitor trifluoperazine selectively enhances cytotoxic effects of strong vs weak DNA binding antitumor drugs in doxorubicin-resistant P388 mouse leukemia cells.

Doxorubicin-resistant P388 mouse leukemia cells are cross-resistant to anthracycline and non-anthracycline DNA intercalators as well as to natural and semisynthetic anthracyclines which bind weakly or not at all to DNA. In the presence of a non-lethal concentration of 5 microM trifluoperazine cytotoxic effects of the strong DNA binding drugs actinomycin-D, mitoxantrone and m-AMSA were enhanced less than 2 fold in doxorubicin-sensitive cells and up to 50 fold in doxorubicin-resistant cells. Additionally, trifluoperazine induced a greater than 2-fold enhancement in the cytotoxic effects (but not accumulation and retention) of the strong DNA binder N,N-dimethyladriamycin-14-valerate only in doxorubicin resistant cells. In contrast, cell kill, drug accumulation and retention in P388/S and P388/DOX cells treated with the weak DNA binders N-benzyl-adriamycin-14-valerate and 7(R)-O-methylnogarol, and DNA-nonbinding N,N-dibenzyldaunorubicin was similar with or without trifluoperazine treatment. The study demonstrates that the calmodulin inhibitor trifluoperazine induces a specific and marked enhancement in the cytotoxic effects of strong vs weak DNA binding antitumor drugs in doxorubicin-resistant cells.

Aminoacridines↗
PubMed1988

Anthracycline-induced DNA breaks and resealing in doxorubicin-resistant murine leukemic P388 cells.

Energy-dependent drug efflux is believed to be a major factor in cellular resistance to doxorubicin (DOX). However, recent studies have shown that decreased retention alone cannot account for anthracycline resistance, and possibly other factors, such as drug metabolism, free radical scavengers, and altered DNA damage/repair, may be involved. We have measured DOX-induced DNA damage and its repair in P388 cells sensitive (P388/S) and resistant (P388/R) to DOX. Our studies show 2- to 5-fold less DNA damage, measured as protein-associated single-strand DNA breaks, in P388/R cells when compared to similarly treated P388/S cells. The repair of DNA in whole cells, expressed as percent DNA rejoined, was complete in 4 hr in P388/R, whereas no repair was seen in P388/S cells until 20 hr. No difference in repair of DNA lesions was observed when nuclei were used in repair experiments. The absence of repair in sensitive whole cells may be due to high retention or slow drug efflux. Increase of cellular DOX retention by exposure of cells to trifluoperazine (TFP) or verapamil (VPL) did not result in the increase of DNA damage in P388/R cells. DOX analogs, N-trifluoroacetyladriamycin-14-valerate (AD 32), 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), and N-benzyladriamycin-14-valerate (AD 198), induced 2- to 4-fold more DNA damage than DOX in resistant cells. There was no difference in the poly(ADP-ribose) synthesis of P388/S and P388/R cells exposed to DOX or AD 32. Since ADP-ribose polymer synthesis is associated with free radical-induced DNA damage and is indicative of DNA repair by an excision-repair mechanism, data from these studies suggest that DNA breaks in anthracycline-exposed cells may not be due to free radical production but rather to other mechanisms, such as inhibition of DNA topoisomerase II activity. The present studies, in addition to emphasizing the role of DNA damage in resistance, also underscore the relative importance of DNA topoisomerase II function in anthracycline cytotoxicity.

Animals↗
PubMed1990

Inhibition of mitochondrial carnitine palmitoyltransferases by adriamycin and adriamycin analogues.

Adriamycin (ADR; doxorubicin) and its highly lipophilic, less toxic analogue N-benzyl-adriamycin-14-valerate (AD 198) were found to inhibit rat heart and liver carnitine palmitoyltransferases of both mitochondrial outer and inner membranes. The outer membrane enzyme was more sensitive to inhibition by these drugs than the inner membrane enzyme, and AD 198 was a more potent inhibitor of these enzymes than ADR. Other analogues of ADR, N-trifluoroacetyladriamycin-14-valerate (AD 32) and N-trifluoroacetyladriamycin-14-O-hemiadipate (AD 143), which are documented as being noncardiotoxic, were also more potent inhibitors of the mitochondrial carnitine palmitoyltransferases than ADR. Overall, the cardiac mitochondrial carnitine palmitoyltransferases seemed to be slightly more sensitive to the inhibitory effects of ADR and its analogues than the liver enzyme. ADR was an uncompetitive inhibitor with respect to palmitoyl-CoA and a noncompetitive inhibitor with respect to carnitine for both mitochondrial outer and inner membrane enzymes. Our data suggest that mitochondria can take up ADR and concentrate it within the matrix, as is known to happen with other positively-charged compounds. More ADR was found associated with the mitochondrial inner membrane than with the outer membrane; this could be due to the greater protein content of the inner membrane rather than drug binding to cardiolipin. Although inhibition of cardiac inner membrane carnitine palmitoyltransferase has been implicated previously as part of the cardiotoxicity mechanism of ADR, the present findings with ADR and its noncardiotoxic analogues do not support this view.

Animals↗
PubMed1991

Metabolism of glycyrrhetic acid by rat liver microsomes--III. Male-specific glycyrrhetinate dehydrogenase.

Glycyrrhetinate (GA) dehydrogenase localized in microsomes of rat liver catalyses the oxidation and reverse reduction of 18 beta-glycyrrhetic acid (GA), an aglycone of glycyrrhizin and a main component of liquorice, to 3-keto-18 beta-glycyrrhetic acid (3-ketoGA). The enzyme activity was detected in microsomes of adult males, but not in those of adult females. It was not observed in infant males but appeared 6 weeks after birth, increased gradually and reached the maximum level at 12 weeks after birth, whereas it was not detected in the hepatic microsomes of females of any age. The administration of estradiol valerate to intact adult males decreased GA dehydrogenase activity remarkably. Castration of male rats also caused a marked reduction of the activity, but the administration of testosterone proprionate to these rats restored it to close to the normal level. On the other hand, ovariectomy of female rats did not bring the activity into existence, but the injection of testosterone proprionate to the ovariectomized rats brought it into a slight existence, in spite of no appearance of the activity by the treatment of testosterone proprionate to intact adult females. The sex-related difference in the activity in adults was eliminated by hypophysectomy of male and female rats, their microsomal activities after the operation being the same, 20-40% of the activity in intact males. Moreover, the administration of estradiol valerate to the hypophysectomized rats did not affect the activity. These results indicate that GA dehydrogenase is male-specific and regulated by sex-hormones through the pituitary.

3-Hydroxysteroid Dehydrogenases↗