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PubMed2000

Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae: role of the cytosolic Mg(2+) and mitochondrial K(+) acetaldehyde dehydrogenases Ald6p and Ald4p in acetate formation during alcoholic fermentation.

Acetic acid plays a crucial role in the organoleptic balance of many fermented products. We have investigated the factors controlling the production of acetate by Saccharomyces cerevisiae during alcoholic fermentation by metabolic engineering of the enzymatic steps involved in its formation and its utilization. The impact of reduced pyruvate decarboxylase (PDC), limited acetaldehyde dehydrogenase (ACDH), or increased acetoacetyl coenzyme A synthetase (ACS) levels in a strain derived from a wine yeast strain was studied during alcoholic fermentation. In the strain with the PDC1 gene deleted exhibiting 25% of the PDC activity of the wild type, no significant differences were observed in the acetate yield or in the amounts of secondary metabolites formed. A strain overexpressing ACS2 and displaying a four- to sevenfold increase in ACS activity did not produce reduced acetate levels. In contrast, strains with one or two disrupted copies of ALD6, encoding the cytosolic Mg(2+)-activated NADP-dependent ACDH and exhibiting 60 and 30% of wild-type ACDH activity, showed a substantial decrease in acetate yield (the acetate production was 75 and 40% of wild-type production, respectively). This decrease was associated with a rerouting of carbon flux towards the formation of glycerol, succinate, and butanediol. The deletion of ALD4, encoding the mitochondrial K(+)-activated NAD(P)-linked ACDH, had no effect on the amount of acetate formed. In contrast, a strain lacking both Ald6p and Ald4p exhibited a long delay in growth and acetate production, suggesting that Ald4p can partially replace the Ald6p isoform. Moreover, the ald6 ald4 double mutant was still able to ferment large amounts of sugar and to produce acetate, suggesting the contribution of another member(s) of the ALD family.

Acetates↗
PubMed2002

Decreasing the level of ethyl acetate in ethanolic fermentation broths of Escherichia coli KO11 by expression of Pseudomonas putida estZ esterase.

During the fermentation of sugars to ethanol relatively high levels of an undesirable coproduct, ethyl acetate, are also produced. With ethanologenic Escherichia coli strain KO11 as the biocatalyst, the level of ethyl acetate in beer containing 4.8% ethanol was 192 mg liter(-1). Although the E. coli genome encodes several proteins with esterase activity, neither wild-type strains nor KO11 contained significant ethyl acetate esterase activity. A simple method was developed to rapidly screen bacterial colonies for the presence of esterases which hydrolyze ethyl acetate based on pH change. This method allowed identification of Pseudomonas putida NRRL B-18435 as a source of this activity and the cloning of a new esterase gene, estZ. Recombinant EstZ esterase was purified to near homogeneity and characterized. It belongs to family IV of lipolytic enzymes and contains the conserved catalytic triad of serine, aspartic acid, and histidine. As expected, this serine esterase was inhibited by phenylmethylsulfonyl fluoride and the histidine reagent diethylpyrocarbonate. The native and subunit molecular weights of the recombinant protein were 36,000, indicating that the enzyme exists as a monomer. By using alpha-naphthyl acetate as a model substrate, optimal activity was observed at pH 7.5 and 40 degrees C. The Km and Vmax for alpha-naphthyl acetate were 18 microM and 48.1 micromol. min(-1). mg of protein(-1), respectively. Among the aliphatic esters tested, the highest activity was obtained with propyl acetate (96 micromol. min(-1). mg of protein(-1)), followed by ethyl acetate (66 micromol. min(-1). mg of protein(-1)). Expression of estZ in E. coli KO11 reduced the concentration of ethyl acetate in fermentation broth (4.8% ethanol) to less than 20 mg liter(-1).

Acetates↗
PubMed2003

Antimicrobial effects of mustard flour and acetic acid against Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella enterica serovar Typhimurium.

This study was designed to investigate the individual and combined effects of mustard flour and acetic acid in the inactivation of food-borne pathogenic bacteria stored at 5 and 22 degrees C. Samples were prepared to achieve various concentrations by the addition of acetic acid (0, 0.5, or 1%) along with mustard flour (0, 10, or 20%) and 2% sodium chloride (fixed amount). Acid-adapted three-strain mixtures of Escherichia coli O157:H7, Listeria monocytogenes, and Salmonella enterica serovar Typhimurium strains (10(6) to 10(7) CFU/ml) were inoculated separately into prepared mustard samples stored at 5 and 22 degrees C, and samples were assayed periodically. The order of bacterial resistance, assessed by the time required for the nominated populations to be reduced to undetectable levels against prepared mustards at 5 degrees C, was S. enterica serovar Typhimurium (1 day) < E. coli O157:H7 (3 days) < L. monocytogenes (9 days). The food-borne pathogens tested were reduced much more rapidly at 22 degrees C than at 5 degrees C. There was no synergistic effect with regard to the killing of the pathogens tested with the addition of 0.5% acetic acid to the mustard flour (10 or 20%). Mustard in combination with 0.5% acetic acid had less bactericidal activity against the pathogens tested than did mustard alone. The reduction of E. coli O157:H7 and L. monocytogenes among the combined treatments on the same storage day was generally differentiated as follows: control < mustard in combination with 0.5% acetic acid < mustard alone < mustard in combination with 1% acetic acid < acetic acid alone. Our study indicates that acidic products may limit microbial growth or survival and that the addition of small amounts of acetic acid (0.5%) to mustard can retard the reduction of E. coli O157:H7 and L. monocytogenes. These antagonistic effects may be changed if mustard is used alone or in combination with >1% acetic acid.

Acetic Acid↗
PubMed2006

Putative ABC transporter responsible for acetic acid resistance in Acetobacter aceti.

Two-dimensional gel electrophoretic analysis of the membrane fraction of Acetobacter aceti revealed the presence of several proteins that were produced in response to acetic acid. A 60-kDa protein, named AatA, which was mostly induced by acetic acid, was prepared; aatA was cloned on the basis of its NH2-terminal amino acid sequence. AatA, consisting of 591 amino acids and containing ATP-binding cassette (ABC) sequences and ABC signature sequences, belonged to the ABC transporter superfamily. The aatA mutation with an insertion of the neomycin resistance gene within the aatA coding region showed reduced resistance to acetic acid, formic acid, propionic acid, and lactic acid, whereas the aatA mutation exerted no effects on resistance to various drugs, growth at low pH (adjusted with HCl), assimilation of acetic acid, or resistance to citric acid. Introduction of plasmid pABC101 containing aatA under the control of the Escherichia coli lac promoter into the aatA mutant restored the defect in acetic acid resistance. In addition, pABC101 conferred acetic acid resistance on E. coli. These findings showed that AatA was a putative ABC transporter conferring acetic acid resistance on the host cell. Southern blot analysis and subsequent nucleotide sequencing predicted the presence of aatA orthologues in a variety of acetic acid bacteria belonging to the genera Acetobacter and Gluconacetobacter. The fermentation with A. aceti containing aatA on a multicopy plasmid resulted in an increase in the final yield of acetic acid.

ATP-Binding Cassette Transporters↗
PubMed1966

Kinetics of acetate metabolism during sludge digestion.

The quantitative contribution of acetic acid to methane production was studied by use of C(14)-labeled acetic acid. Samples of domestic sewage sludge were incubated anaerobically in Warburg vessels. The rate of methane production in the vessels was 0.033 mumoles per ml per min. C(14)-labeled acetic acid was added, and the turnover rate was calculated. The pool size of acetic acid in the sludge was 4.7 mumoles/ml. The turnover rate was 0.0052 min(-1), giving a rate of formation of acetic acid of 0.024 mumoles per ml per min. Under these conditions, acetic acid would account for approximately 73% of the methane produced by the sludge. Acetic acid was found to exist primarily in an extracellular pool. The turnover rate of the extracellular pool was rapid, and it was concluded that most of the acetic acid must be metabolized to methane by a specialized microflora not involved in the formation of acetic acid.

Acetates↗
PubMed2003

Correlation of acetate catabolism and growth yield in Staphylococcus aureus: implications for host-pathogen interactions.

Recently, we reported that the prototypical Staphylococcus aureus strain RN6390 (a derivative of NCTC 8325) had significantly reduced aconitase activity relative to a diverse group of S. aureus isolates, leading to the hypothesis that strain RN6390 has impaired tricarboxylic acid (TCA) cycle-mediated acetate catabolism. Analysis of the culture supernatant from RN6390 confirmed that acetate was incompletely catabolized, suggesting that the ability to catabolize acetate can be lost by S. aureus. To test this hypothesis, we examined the carbon catabolism of the S. aureus strains whose genome sequences are publicly available. All strains catabolized glucose and excreted acetate into the culture medium. However, strains NCTC 8325 and N315 failed to catabolize acetate during the postexponential growth phase, resulting in significantly lower growth yields relative to strains that catabolized acetate. Strains NCTC 8325 and RN6390 contained an 11-bp deletion in rsbU, the gene encoding a positive regulator of the alternative sigma factor sigma(B) encoded by sigB. An isogenic derivative strain of RN6390 containing the wild-type rsbU gene had significantly increased acetate catabolism, demonstrating that sigma(B) is required for acetate catabolism. Taken together, the data suggest that naturally occurring mutations can alter the ability of S. aureus to catabolize acetate, a surprising discovery, as TCA cycle function has been demonstrated to be involved in the virulence, survival, and persistence of several pathogenic organisms. Additionally, these mutations decrease the fitness of S. aureus by reducing the number of progeny placed into subsequent generations, suggesting that in certain situations a decreased growth yield is advantageous.

Acetic Acid↗
PubMed2000

Global regulatory mutations in csrA and rpoS cause severe central carbon stress in Escherichia coli in the presence of acetate.

The csrA gene encodes a small RNA-binding protein, which acts as a global regulator in Escherichia coli and other bacteria (T. Romeo, Mol. Microbiol. 29:1321-1330, 1998). Its key regulatory role in central carbon metabolism, both as an activator of glycolysis and as a potent repressor of glycogen biosynthesis and gluconeogenesis, prompted us to examine the involvement of csrA in acetate metabolism and the tricarboxylic acid (TCA) cycle. We found that growth of csrA rpoS mutant strains was very poor on acetate as a sole carbon source. Surprisingly, growth also was inhibited specifically by the addition of modest amounts of acetate to rich media (e.g., tryptone broth). Cultures grown in the presence of >/=25 mM acetate consisted substantially of glycogen biosynthesis (glg) mutants, which were no longer inhibited by acetate. Several classes of glg mutations were mapped to known and novel loci. Several hypotheses were examined to provide further insight into the effects of acetate on growth and metabolism in these strains. We determined that csrA positively regulates acs (acetyl-coenzyme A synthetase; Acs) expression and isocitrate lyase activity without affecting key TCA cycle enzymes or phosphotransacetylase. TCA cycle intermediates or pyruvate, but not glucose, galactose, or glycerol, restored growth and prevented the glg mutations in the presence of acetate. Furthermore, amino acid uptake was inhibited by acetate specifically in the csrA rpoS strain. We conclude that central carbon flux imbalance, inhibition of amino acid uptake, and a deficiency in acetate metabolism apparently are combined to cause metabolic stress by depleting the TCA cycle.

Acetates↗
PubMed2001

Acetate and formate stress: opposite responses in the proteome of Escherichia coli.

Acetate and formate are major fermentation products of Escherichia coli. Below pH 7, the balance shifts to lactate; an oversupply of acetate or formate retards growth. E. coli W3110 was grown with aeration in potassium-modified Luria broth buffered at pH 6.7 in the presence or absence of added acetate or formate, and the protein profiles were compared by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Acetate increased the steady-state expression levels of 37 proteins, including periplasmic transporters for amino acids and peptides (ArtI, FliY, OppA, and ProX), metabolic enzymes (YfiD and GatY), the RpoS growth phase regulon, and the autoinducer synthesis protein LuxS. Acetate repressed 17 proteins, among them phosphotransferase (Pta). An ackA-pta deletion, which nearly eliminates interconversion between acetate and acetyl-coenzyme A (acetyl-CoA), led to elevated basal levels of 16 of the acetate-inducible proteins, including the RpoS regulon. Consistent with RpoS activation, the ackA-pta strain also showed constitutive extreme-acid resistance. Formate, however, repressed 10 of the acetate-inducible proteins, including the RpoS regulon. Ten of the proteins with elevated basal levels in the ackA-pta strain were repressed by growth of the mutant with formate; thus, the formate response took precedence over the loss of the ackA-pta pathway. The similar effects of exogenous acetate and the ackA-pta deletion, and the opposite effect of formate, could have several causes; one possibility is that the excess buildup of acetyl-CoA upregulates stress proteins but excess formate depletes acetyl-CoA and downregulates these proteins.

Acetates↗
PubMed2003

Germination and adhesion of fungal conidia on polycarbonate membranes and on apple fruit exposed to mycoactive acetate esters.

The adhesion and germination of conidia of nine fungal species were assessed on polycarbonate membranes or on the skin of apple fruit in sealed glass bottles injected or not injected with acetate esters. Adhesion was determined after dislodging conidia from surfaces using a sonication probe. Adhesion and germination of conidia of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Penicillium citrinum, Penicillium claviforme, or Trichoderma sp. on membranes after 48 h were not increased in a 1.84 microg mL(-1) headspace of butyl acetate (BA), ethyl acetate, hexyl acetate, 2-methylbutyl acetate, pentyl acetate, or propyl acetate. Adhesion and germination of Botrytis cinerea, Penicillium expansum, and Penicillium roquefortii conidia were stimulated by all esters. Only conidia of B. cinerea and P. expansum exhibited increased adhesion and germination on the skin of apple fruit in bottles exposed to 0.92 microg mL(-1) of BA. Only conidia of B. cinerea and P. expansum produced decay in inoculated puncture wounds on fruit. Freshly made puncture wounds or 24-h-old puncture wounds in fruit were more adhesive than the unpunctured skin of fruit to conidia of B. cinerea or P. expansum. Fresh wounds were more adhesive to both fungi than 24-h-old puncture wounds. The skin and wounds of fruit were as adhesive to B. cinerea conidia as they were to P. expansum conidia. A 4-h exposure to 1.43 microg mL(-1) of BA increased adhesion of B. cinerea and P. expansum conidia in 24-h-old wounds. Results suggest that acetate-ester stimulation most likely is not a rare phenomenon in the fungi. For nutrient-dependent decay pathogens of apple fruit, acetate esters may be an alternative chemical cue used to maintain adhesion of conidia to wound surfaces.

Acetates↗
PubMed2003

Insulin effects on acetate metabolism.

Acetate metabolism was studied in patients with insulin resistance. To evaluate the interaction between glucose and acetate metabolism, we measured acetate and glucose turnover with a hyperinsulinemic euglycemic clamp (hot clamp) in obese and diabetic patients with insulin resistance (n = 8) and in a control group with normal insulin sensitivity (n = 6). At baseline, acetate turnover and plasma concentrations were similar between the two groups (group means: 4.3 +/- 0.4 micromol x kg-1 x min-1 and 128.2 +/- 11.1 micromol/l). Acetate concentrations decreased in both groups with hyperinsulinemia but were significantly lower in the insulin-resistant group (20% vs. 12%, P < 0.05). After the hot clamp treatment, acetate turnover increased for the two groups and was higher in the group with normal insulin sensitivity: 8.1 +/- 0.7 vs. 5.5 +/- 0.5 micromol x kg-1 x min-1 (P < 0.001). No change related to insulin action was observed in either group in the percentage of acetate oxidation. This was approximately 70% of overall utilization at baseline and during the clamp. No correlation between glucose and acetate utilization was observed. Our results support the hypothesis that, like glucose metabolism, acetate metabolism is sensitive to insulin.

Acetates↗
PubMed1982

Serum levels of acetate and TCA cycle intermediates during hemodialysis in relation to symptoms.

In order to study the metabolism of acetate transferred from dialysate, the plasma concentrations of organic acids including the tricarboxylic acid cycle (TCA cycle) intermediates were measured during hemodialysis in a comparative study between acetate dialysate and bicarbonate dialysate in 17 patients on maintenance hemodialysis treatment. Continuous measurements of serum concentrations of these organic acids during hemodialysis were performed using the filtrate obtained through an ultrafiltrate sampling device. The organic acids were measured by isotachophoresis. Serum acetate, malate and citrate concentration increased with time in acetate dialysis compared with bicarbonate dialysis. Correlations were found between these organic acids. Isocitrate became detectable when the serum acetate concentration was over 7 mmol/l which was correlated to the acetate concentration, and was accompanied by the development of symptoms. The above results suggest that an acetate overload on the patients during acetate dialysis affects acetate metabolism through the TCA cycle resulting in an accumulation of organic acids in the serum and the development of symptoms.

Acetates↗
PubMed1985

Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood.

There is now substantial evidence that some dietary polysaccharides, notably dietary fiber, escape absorption in the small bowel and are then broken down in the large intestine of man. The main end products of this colonic digestive process, which is anerobic, are short chain fatty acids (SCFA), and acetic, propionic, and butyric acids. Although these acids are known to be absorbed from the colon, their subsequent fate and significance is unknown. We have measured venous blood SCFA levels in healthy subjects after a 16-h fast, and then following oral doses of either 50 mmol SCFA, 5, 10, or 20 g doses of the fermentable carbohydrate lactulose, or 20 g of pectin. Fasting venous blood acetate was 53.8 +/- 4.4 mumol/liter (SEM) (n = 14). Fasting arterial blood acetate, taken simultaneously with venous blood in six subjects, was higher; 125.6 +/- 13.5 mumol/liter (arterial) vs. 61.1 +/- 6.9 mumol/liter (venous). Significant levels of propionate or butyrate were not detected in any blood samples. Following an oral dose of 50 mmol mixed SCFA, venous blood acetate reached a peak of 194.1 +/- 57.9 mumol/liter at 45 min and returned to fasting levels at 2 h. Blood acetate also rose in response to lactulose, peak levels occurring 2-4 h after the dose: 5 g, 98.6 +/- 23.1 mumol/liter; 10 g, 127.3 +/- 18.2 mumol/liter; and 20 g, 181.3 +/- 23.9 mumol/liter. Pectin fermentation was much slower, with blood acetate levels starting to rise after 6 h and remaining elevated at about twice fasting levels for the subsequent 18 h. However, areas under the blood acetate curves were closely related (r = 0.97; n = 5), whatever the source of acetate. These studies show that the large intestine makes an important contribution to blood acetate levels in man and that fermentation may influence metabolic processes well beyond the wall of this organ.

Acetates↗
PubMed2001

Risk-benefit assessment of glatiramer acetate in multiple sclerosis.

Glatiramer acetate, formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids. Glatiramer acetate has been shown to be effective in preventing and suppressing experimental autoimmune encephalitis (EAE), the animal model of multiple sclerosis (MS). Therefore it was tested in several clinical studies, where it was found to slow the progression of disability and to reduce the relapse rate and the magnetic resonance imaging (MRI)-defined disease activity and burden in relapsing-remitting MS. As a daily standard dose, 20mg of glatiramer acetate is injected subcutaneously. After injection, glatiramer acetate undergoes rapid degradation to amino acids and shorter peptides; so it is not possible to measure any systemic plasma concentrations or excretion rates. Two major mechanisms have been proposed to explain the effects of glatiramer acetate in EAE and MS: the induction of glatiramer acetate-reactive T helper 2 (Th2)-like regulatory suppressive cells and the interference with T cell activation as an altered peptide ligand. The most common adverse effects were mild injection site reactions (erythema, inflammation and induration). The most remarkable adverse event is the acute and transient immediate postinjection reaction manifested by flushing, chest tightness, palpitations and dyspnoea. Other reported adverse effects are transient chest pain and lymphadenopathy. Antibodies to glatiramer acetate induced during treatment do not interfere with its clinical effects. In several controlled clinical studies, glatiramer acetate has been shown to provide consistent, reproducible clinical benefits in the target population of patients with relapsing-remitting MS. The safety profile and risk-benefit ratio are excellent. Overall, glatiramer acetate is very well tolerated and has an excellent risk-benefit profile in patients with relapsing-remitting MS.

Clinical Trials as Topic↗
PubMed1987

Lipogenesis in adipose tissue from ovariectomized and intact heifers immunized against estradiol and (or) implanted with trenbolone acetate.

Forty-two heifers were allotted randomly to six treatment groups: intact controls, intact heifers implanted with trenbolone acetate, ovariectomized heifers, ovariectomized heifers implanted with trenbolone acetate, intact heifers immunized against estradiol and intact heifers immunized against estradiol and implanted with trenbolone acetate. Blood titers of estradiol-17 beta were increased over 100-fold in heifers immunized against estradiol in Freund's complete adjuvant or saline:squalene/arlacel containing Mycobacterium. Lipogenic enzyme activities and acetate incorporation into fatty acids were increased in subcutaneous adipose tissue obtained at slaughter from heifers receiving immunization or the combination of immunization and trenbolone acetate. The increased lipogenic capacity was not reflected in either cell diameter or cells per gram adipose tissue. Ovariectomy in combination with trenbolone acetate caused the lowest activities for all enzymes measured. This treatments also caused the greatest decrease in cell diameter, which resulted in the largest number of cells per gram of adipose tissue. Trenbolone acetate alone had no detectable effect on lipogenesis in the intact heifer, but the combination of ovariectomy and trenbolone acetate caused substantial decreases in enzyme activities, in most cases a significant decrease as compared with ovariectomized heifers. The data suggest that trenbolone acetate is able to depress lipogenesis only when not competing with the effects of circulating estradiol.

Adipose Tissue↗
PubMed2000

Utilization and transport of acetic acid in Dekkera anomala and their implications on the survival of the yeast in acidic environments.

The yeast Dekkera anomala IGC 5153 exhibited a restricted ability to use weak acids as the only carbon and energy sources. Of the monocarboxylic, dicarboxylic, and tricarboxylic acids tested, only acetic acid was used in such a way. The cells were able to grow at acetic acid concentrations of 0.1 to 3% (vol/vol) over a pH range of 3.5 to 5.5, and the specific growth rates decreased exponentially with the increase of the undissociated acetic acid concentration in the culture medium. Transport assays carried out in cells that exhibited higher specific growth rates showed the presence of an acetate-proton symport associated with a simple diffusion component of the undissociated acetic acid, the weight of the latter increasing with the undissociated acid concentration in the culture media. The acetate carrier was shared by propionic, formic, and sorbic acids and was inducible and repressed by glucose and concentrations of undissociated acetic acid in the culture medium above 0.3% (vol/vol). In undissociated acetic acid repression conditions, the lowest values for the yeast specific growth rates were obtained, and the simple diffusion of the undissociated acid was the only mechanism involved in the acetic acid uptake by the cells. The results will be discussed in terms of the high tolerance of D. anomala to the acidic stress conditions present in wine.

Acetic Acid↗
PubMedDate not supplied

Acetate levels in human plasma.

We have developed a gas liquid chromatographic assay for plasma acetate which detects 0.01 mM and has a standard deviation of less than 16% of the mean at 0.05 mM. The acetate concentration of venous blood obtained from normal subjects was 0.025 +/- 0.002 mM. The value was not significantly different from the venous acetate concentration of dialysis patients, prior to a dialysis treatment. The acetate concentration of arterial plasma obtained from dialysis patients prior to a hemodialysis treatment was 0.048 +/- 0.006 mM. This was significantly greater than the venous concentration of 0.027 +/- 0.002 (p less than 0.01). This arteriovenous difference suggests that acetate is utilized peripherally. At the onset of hemodialysis, acetate concentrations rapidly rose and, in all but one case, reached a steady state value in the range of 1.5-5.1 mM. At the termination of dialysis, acetate concentrations fell rapidly, usually achieving baseline values within one hr. The rate of decrease was not a simple logarithmic function, suggesting that acetate metabolism is not solely a first order function. Furthermore, acetate disappearance was more rapid in the dialysis patients than in the normal subjects. We wish to emphasize that the present data, which were obtained on a small number of subjects are preliminary and should be interpreted with caution.

Acetates↗
PubMed2001

Cyproterone acetate: a genotoxic carcinogen?

Cyproterone acetate, a widely used synthetic progestagen with antiandrogenic activity, is known for years to produce liver tumours in rats, with a higher incidence in females. This effect was attributed to a rodent-specific tumour promoting mode of action based on the detection of a strong hepato-mitogenic activity of cyproterone acetate. However, more recent studies have demonstrated that cyproterone acetate is sex-specifically activated to (a) DNA-damaging intermediate(s) in the liver of female rats which result in the formation of DNA adducts, induction of DNA repair, and increased levels of micronuclei and gene mutations. Consistent with a sex-specific genotoxicity, cyproterone acetate showed a tumour-initiating potential in a liver foci assay with female rats but not with male rats. Most important, cyproterone acetate was found to induce formation of DNA adducts in primary cultures of human hepatocytes indicating that human liver cells have the capacity to activate cyproterone acetate to genotoxic intermediates. However, the overall assessment of the preclinical data presented in this review suggests that induction of liver tumours in female rats most probably depends on both, genotoxic and mitogenic effects which would suggest a non-linear mode of action with regard to tumour formation. With the exception of DNA adduct formation all other adverse effects induced by cyproterone acetate in rat liver, including gene mutations and liver tumours, can be detected at very high dose levels only. Hence, a cancer risk estimate based on a simple linear extrapolation from high dose to low exposure conditions of recommended clinical use would be questionable. Human data from pharmacoepidemiological studies that specifically addressed the question of possible liver cancer risk in patients treated with cyproterone acetate do in principle support this interpretation. In agreement with these considerations the regulatory authorities of the European Union came to the common conclusion that a possible cancer risk associated with the clinical use of cyproterone acetate, if any, appears to be low and the risk-benefit ratios for the currently authorised indications remain favourable.

Androgen Antagonists↗
PubMed1979

Sodium acetate as a preservative in protein hydrolysate solutions.

The inhibitory effect of sodium acetate on microorganism growth in protein hydrolysate solutions was studied. Solutions of 5% protein hydrolysate and 5% dextrose in water (seven parts) and 50% dextose in water (three parts) containing 0, 30, 50 and 90 mEq/liter of sodium acetate were inoculated with Staphylococcus aureus, Escherichia coli, Candida albicans and Pseudomonas aeruginosa. The number of colony-forming units in the solutions after inoculation was compared with that after incubation for 24 hours at 37 C. Sodium acetate inhibited growth of S aureus and E coli. Growth of P aeruginosa was inhibited in protein hydrolysate solutions with and without sodium acetate; inhibition could not be attributed solely to sodium acetate and may have been releated to pH of the solutions (4.7 to 5.4). Growth of C albicans was not inhibited by sodium acetate. Sodium acetate reduced growth of some common contaminants of protein hydrolysates. Sodium acetate is known to reduce metabolic acidosis, a reported complication of parenteral nutrient therapy and a possible predisposing factor in C albicans sepsis. Addition of sodium acetate to protein hydrolysate solutions should be considered seriously.

Acetates↗