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PubMed2003

A phenylacetate derivative, SCK6, inhibits cell proliferation via G1 cell cycle arrest and apoptosis.

Phenylacetate is a differentiation agent and has anticancer activity with relatively low toxicity. In the present study, we examined the anticancer effect of six synthetic phenylacetate derivatives in human lung cancer cells in our search for more effective phenylacetate analogous. Results showed that the antiproliferative effects of these synthetic compounds were stronger than those of phenylacetate, and that N-butyl-2-(2-fluorolphenyl)acetamide (SCK6) is the most potent compound. To address the mechanism of the antiproliferative effect of SCK6, cell cycle analysis was performed. Result showed that SCK6 (1 mM) induced G(1) arrest in CH27 cells. Western blot analysis of G(1) phase regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase 2 (Cdk2), Cdk4, Cyclin E and Cyclin D3 were decreased after treatment with SCK6 but not those of Cdk6, Cyclin D1 and D2. In contrast, SCK6 increased the protein levels of p53 and p21(CIP1/WAF1). Data from in situ terminal transferase-mediated dUTP-fluorescensin nick end-labeling (TUNEL) assay and DNA fragmentation analysis demonstrated that SCK6 induced apoptotic cell death in CH27 cells. This SCK6-induced apoptosis was accompanied by a downregulation of Bcl-2 protein and activation of the caspase-9 cascade. Overexpression of Bcl-2 by adeno-Bcl-2 vector infection significantly inhibited SCK6-induced apoptosis. Moreover, treatment with caspase inhibitors also markedly reduced cell death induced by SCK6. Taken together, these results suggest that downregulation of G(1)-associated Cdks and cyclins and upregulation of p53 and p21(CIP1/WAF1) may contribute to SCK6-mediated G(1)-phase arrest. Furthermore, the decrease in Bcl-2 and the activation of caspase-9/caspase-3 may be the effector mechanism through which SCK6 induces apoptosis.

Acetamides↗

PubMed1995

Butyrate and phenylacetate as differentiating agents: practical problems and opportunities.

Differentiating agents, including butyrate, phenylacetate and several other agents, have long been known to alter abnormal or transformed cell lines in vitro to a more normal state including phenotype and function. The effect depends on prolonged exposure to a minimum concentration of the agent. In vivo studies of butyrate and analogues have been limited, largely due to rapid in vivo metabolism. A butyrate prodrug, the triglyceride tributyrin, shows great promise in achieving effective and prolonged serum levels when given orally to mice and rats, and has been recommended for human trial. In vitro, butyrate and its mono- and triglyceride have shown potent synergy with retinoic acid, suggesting a ten-fold reduction in serum level requirements. Other butyrate prodrugs have been prepared and studied; several sugar esters of butyrate show promise. Phenylacetate, a normal mammalian metabolite, is also a potent differentiating agent, but its clinical use is limited by its objectionable odor per se and in treated subjects. Phenylbutyrate, a prodrug of phenylacetate, is more acceptable and may have greater promise. The availability of effective prodrugs of effective differentiating agents, such as tributyrin and phenylbutyrate, creates many opportunities for possible therapeutic and chemopreventive applications, especially if synergy in vivo can be demonstrated with retinoids (e.g., retinoic acid) or deltanoids (e.g., active vitamin D analogues), confirming in vitro studies. Particular disease targets would include certain leukemias, thalassemia, and sickle cell anemia.

Animals↗

PubMed1997

Expression of transcription factors during sodium phenylacetate induced erythroid differentiation in K562 cells.

During 15 days of treatment of K562 cells with sodium phenylacetate, we observed an increase in the cellular hemoglobin concentration with a similar increase in the expression of gamma-globin mRNA. Morphological studies demonstrated characteristic features of erythroid differentiation and maturation. At the same time there was no change in the level of expression of the cell surface antigenes CD33, CD34, CD45, CD71 and glycophorin A. Likewise, the level of expression of the erythroid transcription factors GATA-1, GATA-2, NF-E2, SCL and RBTN2, all expressed in untreated K562 cells, did not increase during sodium phenylacetate induced erythroid differentiation. The expression of the nuclear factors Evi-1 and c-myb, known to inhibit erythroid differentiation, did not decrease. We conclude that sodium phenylacetate treatment of K562 cells increases gamma-globin mRNA and induces cell maturation as judged by morphology without affecting the expression of the erythroid transcription factors, some of which are known to be involved in the regulation of beta-like globin genes.

Antigens, Surface↗

PubMed1983

Experimental phenylketonuria: effect of phenylacetate intoxication on number of synapses in the cerebellar cortex of the rat.

In experimental phenylketonuria, induced in the rat by exposure to phenylacetate during the first 21 days of life, there was a significant reduction of boutons, a decrease of an average of 25% in the whole cerebellar molecular layer. Both the density of synaptic profiles per square unit and the number of synapses per unit volume were decreased in the phenylacetate-treated rat as compared to the age-matched control. Neuronal density was unaffected. Results are interpreted to show a deficit of synapses per neuron, probably due to a decrease in synaptic formation in phenylacetate-induced phenylketonuria. Undernutrition was eliminated as a contributing factor.

Animals↗

PubMed2002

Aerobic metabolism of phenylacetic acids in Azoarcus evansii.

The aerobic metabolism of phenylacetic acid (PA) and 4-hydroxyphenylacetic acid (4-OHPA) was investigated in the beta-proteobacterium Azoarcus evansii. Evidence for the existence of two independent catabolic pathways for PA and 4-OHPA is presented. 4-OHPA metabolism involves the formation of 2,5-dihydroxyphenylacetate (homogentisate) and maleylacetoacetate catalyzed by specifically induced 4-OHPA 1-monooxygenase and homogentisate 1,2-dioxygenase. The metabolism of PA starts by its activation to phenylacetyl-CoA (PA-CoA) via an aerobically induced phenylacetate-coenzyme A ligase. Phenylalanine (Phe) aerobic metabolism in this bacterium proceeds also via PA and PA-CoA. Whole cells of A. evansii transformed [1-(14)C]PA to (14)C-phenylacetyl-CoA and subsequently to a number of unknown labeled products, which were also observed in PA-degrading bacteria from different phylogenetic groups, i.e. Escherichia coli, Rhodopseudomonas palustrisand Bacillus stearothermophilus. A chromosomal region from A. evansiiof 11.5 kb containing a cluster of 11 phenylacetic acid catabolic ( paa) genes ( paaYZGHIKABCDE) was sequenced and characterized. The derived gene products were similar to the characterized putative gene products involved in PA catabolism in E. coli and Pseudomonas putida and to other putative PA catabolic gene products of diverse bacteria. RT-PCR analysis of the paa genes of A. evansiigrowing aerobically with PA showed a probable organization of the paa genes in three operons. The similarity of the PA metabolic products pattern and of gene sequences suggests a common aerobic bacterial PA pathway.

Aerobiosis↗

PubMed2004

Identification and antimicrobial activity of phenylacetic acid produced by Bacillus licheniformis isolated from fermented soybean, Chungkook-Jang.

A bacterial strain, B65-1, which showed strong antimicrobial activity, was isolated from Chungkook-Jang, a traditional Korean fermented-soybean food with antimicrobial properties. Based on carbon utilization pattern and partial 16S rRNA sequence analysis, the B65-1 strain was identified as Bacillus licheniformis. An antibiotic compound, active against bacteria and yeast such as Staphylococcus aureus, Escherichia coli, and Candida albicans, was isolated by various chromatographic procedures from culture filtrates of B. licheniformis B65-1. The purified antibiotic was identified to be phenylacetic acid, with the molecular formula C(8)H(8)O(2) by analyses of EI-MS and NMR. The phenylacetic acid was detected in fermented soybean made with the strain B65-1 as a starter, but was not present in extracts of nonfermented soybean. Our results indicated that the phenylacetic acid produced by B. licheniformis during fermentation of soybean is one of the main compounds of antimicrobial activity of Chungkook-Jang.

Anti-Bacterial Agents↗

PubMed1996

Activation of a human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs.

The aromatic fatty acid phenylacetate and its analogs induce tumor cytostasis and differentiation in experimental models. Although the underlying mechanisms of action are not clear, effects on lipid metabolism are evident. We have now examined whether these compounds, structurally similar to the peroxisome proliferator clofibrate, affect the human peroxisome proliferator-activated receptor (hPPAR), a homolog of the rodent PPAR alpha, a transcriptional factor regulating lipid metabolism and cell growth. Gene transfer experiments showed activation of hPPAR, evident by the increased expression of the reporter gene chloramphenicol acetyltransferase linked to PPAR-response element from either the rat acyl-CoA oxidase or rabbit CYP4A6 genes. The relative potency of tested drugs in the co-transfection assay was: 4-iodophenylbutyrate > 4-chlorophenylbutyrate > clofibrate > phenylbutyrate > naphthylacetate > 2,4-D > 4-chlorophenylacetate > phenylacetate >> indoleacetate. Phenylacetylglutamine, in which the carboxylic acid is blocked, was inactive. The ability of the aromatic fatty acids to activate PPAR was confirmed in vivo, as CYP4A mRNA levels increased in hepatocytes of treated rats. Further studies using human prostate carcinoma, melanoma, and glioblastoma cell lines showed a tight correlation between drug-induced cytostasis, increased expression of the endogenous hPPAR, and receptor activation documented in the gene-transfer model. These results identify phenylacetate and its analogs as a new class of aromatic fatty acids capable of activating hPPAR, and suggest that this nuclear receptor may mediate tumor cytostasis induced by these drugs.

Animals↗

PubMed1991

Longitudinal effect of amitriptyline and fluoxetine treatment on plasma phenylacetic acid concentrations in depression.

Unconjugated (U-PAA), conjugated (C-PAA), and total phenylacetic acid (T-PAA) concentrations in blood plasma and monoamine oxidase (MAO) activity in platelets towards phenylethylamine (PE) were determined in 40 drug-free, depressed patients (23 melancholic, 17 nonmelancholic) from five psychiatric treatment centers, and in 34 normal healthy volunteers. No significant differences were found between controls and all depressed patients or between melancholic and nonmelancholic depressed patients. Treatment of the depressed patients with amitriptyline or fluoxetine over a 6-week period resulted in clinical improvement and in a significant increase in plasma PAA concentrations. A decline in the Beck and Hamilton rating scores during treatment correlated significantly with increases in the concentrations of unconjugated, conjugated, and total phenylacetic acid but not with MAO activity, which did not change during treatment. At each of the three assessment times, however, plasma PAA concentrations and psychiatric rating scores were not significantly correlated. Except for higher end-of-study T-PAA concentrations in the amitriptyline-treated subjects, no significant differences were found between the effects of the two drugs with regard to plasma phenylacetic acid levels, MAO activity, or rating scores.

Adult↗

PubMed1989

CSF phenylacetic acid and hostility in paranoid schizophrenia.

Lumbar cerebrospinal fluid concentrations of phenylacetic acid were significantly elevated in paranoid vs. nonparanoid schizophrenics. Further, phenylacetic acid concentrations were correlated with hostility. These results are consistent with the hypothesis that phenylethylamine, the proposed precursor of phenylacetic acid, plays a role in schizophrenia.

Adult↗

PubMed1980

Clinical value of 14C-phenylacetic oil as a fat absorption test.

The value of [1-14C] phenylacetic oil as a clinical test for malassimilation was evaluated in 20 normal volunteers, 20 patients with various non-gastrointestinal illnesses, 10 patients with malabsorption, and 7 patients with maldigestion. All subjects were given a test meal composed of 0.5 ml of 14C-phenylacetic oil (0.5 muCi) in 30 g of cheese and 40 g of bread. The test was simultaneously run with D-xylose. Urine was collected over a 5 h period and assayed for 14C and D-xylose. Mean urinary recovery of 14C label in volunteers was 65 +/- 15% of th: administered dose. All 10 patients with malabsorption had abnormal D-xylose excretion and excreted less than 35% of the 14C-phenylacetate. 6 of 7 patients with maldigestion excreted less than 15%, while in the 7th patient excretion of 14C label was borderline (35%). 4 of the 7 patients with maldigestion had abnormal D-xylose excretion, probably as a result of bacterial overgrowth. The procedure described is a cost-effective, simple, rapid, and safe test for fat absorption which may be conveniently run with a D-xylose excretion test.

Bread↗

PubMed2000

Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia.

Intravenous sodium benzoate and sodium phenylacetate have been used successfully in the treatment of acute hyperammonaemia in patients with urea cycle disorders. They provide alternative pathways for waste nitrogen disposal and help maintain nitrogen homeostasis. However, we report three patients with hyperammonaemia who received inappropriate doses of intravenous sodium benzoate and sodium phenylacetate that resulted in severe complications. Ambiguous medical prescriptions and inadequate cross-checking of drug dosage by physicians, nurses and pharmacists were the main causes of these incidents. All the patients presented with alteration in mental status, Kussmaul respiration and a partially compensated metabolic acidosis with an increased anion gap. Two patients developed cerebral oedema and hypotension and died. The third survived after haemodialysis. Plasma levels of benzoate and phenylacetate were excessively high. The possible mechanisms of toxicity, management and safety measures are discussed.

Child↗

PubMed2001

Suppression of tumourigenicity, and induction of differentiation of the canine mammary tumour cell line MCM-B2 by sodium phenylacetate.

The authors evaluated the cell growth inhibition, reduction of tumourigenicity, and differentiation-inducing effects of sodium phenylacetate (NaPA) on a canine mammary tumour cell line. Treatment of the canine mammary tumour cell line (MCM-B2) with NaPA lead to the arrest of cell growth. Sodium phenylacetate induced changes in the cells to non-malignant characteristics, as indicated by a reduction of colony formation in semi-solid agar and a decrease in tumour formation in athymic mice. Moreover, NaPA induced morphological changes from a spindle-shaped to an epithelial-like appearance, and significant accumulation of lipid droplets in the cytoplasm. Immunohistochemically, these treated cells reacted clearly with the antibody for keratin/cytokeratin. Sodium phenylacetate treatment increased the expression of the milk-specific genes alpha-lactalbumin and beta-casein. The results of this study warrant an evaluation of NaPA in a clinical trial to establish its possible value as adjunctive treatment of malignant canine mammary tumours.

Animals↗

PubMed1984

On the possible mechanism of phenylacetate neurotoxicity: inhibition of choline acetyltransferase by phenylacetyl-CoA.

The influence of phenylacetate, phenylbutyrate, and phenylacetyl-CoA on the activity of choline acetyltransferase and S-acetyl-CoA synthetase was investigated in vitro. Phenylacetyl-CoA was found to be a very potent inhibitor of choline acetyltransferase, competitive for acetyl-CoA with Ki of 3.1 X 10(-7)M. In contrast, millimolar concentrations of phenylacetate and phenylbutyrate were required to inhibit the activity of the enzyme. Activity of S-acetyl-CoA synthetase was affected only slightly by the three agents in concentrations of 10(-3)-10(-2)M. At this time, results are interpreted to suggest that in phenylketonuria, phenylacetate exerts its neurotoxic action through its metabolic product, phenylacetyl-CoA, which could severely decrease the availability of acetyl-CoA.

Acetate-CoA Ligase↗

PubMed2001

Reduced function of a phenylacetate-oxidizing cytochrome p450 caused strong genetic improvement in early phylogeny of penicillin-producing strains.

The single-copy pahA gene from Penicillium chrysogenum encodes a phenylacetate 2-hydroxylase that catalyzes the first step of phenylacetate catabolism, an oxidative route that decreases the precursor availability for penicillin G biosynthesis. PahA protein is homologous to cytochrome P450 monooxygenases involved in the detoxification of xenobiotic compounds, with 84% identity to the Aspergillus nidulans homologue PhacA. Expression level of pahA displays an inverse correlation with the penicillin productivity of the strain and is subject to induction by phenylacetic acid. Gene expression studies have revealed a reduced oxidative activity of the protein encoded by pahA genes from penicillin-overproducing strains of P. chrysogenum compared to the activity conferred by phacA of A. nidulans. Sequencing and expression of wild-type pahA from P. chrysogenum NRRL 1951 revealed that an L181F mutation was responsible for the reduced function in present industrial strains. The mutation has been tracked down to Wisconsin 49-133, a mutant obtained at the Department of Botany of the University of Wisconsin in 1949, at the beginning of the development of the Wisconsin family of strains.

Aspergillus nidulans↗

PubMed1988

Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse.

Herein we examine the effects of sodium benzoate and sodium phenylacetate on feeding and central serotonin turnover in a child with citrullinemia and in an animal model of congenital hyperammonemia, the ornithine transcarbamylase-deficient sparse-fur (spf/y) mouse. In the child, when the benzoate/phenylacetate dosage was increased from 200 to 375 mg/kg/day each, feeding decreased. There was an accumulation of benzoate and phenylacetate in blood and cerebrospinal fluid as well as an increased concentration of 5-hydroxyindoleacetic acid, a neurochemical marker for serotonin turnover, in cerebrospinal fluid. In the mouse, sodium benzoate had a biphasic effect on both plasma ammonium levels and brain serotonin turnover. Two percent oral benzoate was associated with an increase in ammonium level, while a 3% dose led to a decrease in ammonium. There was a similar effect on serotonin turnover noted in both the hyperammonemic spf/y and control CD-1/y mice. Sodium phenylacetate did not have a consistent effect on serotonin turnover. The mechanism by which benzoate increases brain serotonin turnover appears to involve competition with tryptophan for albumin binding sites. This results in increased free tryptophan in serum and brain. We speculate that some of the clinical symptoms of benzoate intoxication may be a consequence of altered serotonin turnover in the brain. We suggest that drug levels be monitored during therapy.

Administration, Oral↗

PubMed2001

Phenylacetate pharmacokinetics based on iterative two-stage population analysis.

STUDY OBJECTIVE: To determine the population pharmacokinetics of phenylacetate using iterative two-stage analysis implemented with ADAPT 11 software. SETTING: United States government research hospital. DESIGN: Retrospective pharmacokinetic analysis. SUBJECTS: Sixty-seven patients with refractory solid tumors. INTERVENTION: Subjects received from 1-10 courses/individual (total 141 courses) of therapy with either twice-daily administration or continuous infusions of phenylacetate. MEASUREMENTS AND MAIN RESULTS: Extensive plasma concentration measurements were performed after the initial dose or start of infusion, with sparse sampling during subsequent courses of therapy. Phenylacetate plasma concentration-time profiles were described by a one-compartment, capacity-limited clearance model with incorporation of parameters to describe extent of induction of clearance and the rate of induction. Median estimates for volume of distribution, maximum rate of drug elimination, Michaelis-Menten constant, and induction factor, and rate of onset of induction of drug clearance were 0.33 (0.26, 0.48) L/kg, 21.8 (16.3, 28.0) mg/kg/hour, 94.6 (48.8, 153.0) mg/L, 1.28 (1.06, 1.66), and 0.0038 (0.0019, 0.0058) hour(-1), respectively. CONCLUSION: The results of this study are similar to previous pharmacokinetic evaluations using the Abbottbase PKS system but suggest that earlier analyses were suboptimal.

Antimetabolites, Antineoplastic↗

PubMed1978

Cerebral changes in the course of intoxication with mercury phenylacetate.

A histoenzymic study of cerebral phosphatases and esterases was performed on rats subjected to experimental intoxication with mercury phenylacetate. Following intragastric application of mercury phenylacetate to experimental animals, decreased activities of cerebral ATPase, acP and AChE were observed. The intoxicated animals displayed enhanced cerebral TPPase and partially also NsChE activities. Apart from changes in the histoenzymic pattern of the experimental brains, the ingestion of mercury phenylacetate brought about evident morphological changes in form of neuronal vacuolisation and spongious degeneration of the white matter. The extent of morphological as well as histoenzymic alterations was dependent on the duration of the experimental poisoning.

Acetylcholinesterase↗

PubMed1977

Interference by a phenylacetate pathway in isotopic assays for phenylalanine ammonia-lyase in leaf extracts.

Particulate and soluble fractions from leaves of Sorghum, Spinacia (spinach), and Coleus, capable of metabolizing l-phenylalanine to cinnamate or to caffeate, are also able to convert l-and d-phenylalanine to phenylacetate. Since cinnamate and phenylacetate are not effectively separated in commonly used chromatographic solvents, some of the isotropic assays used for phenylalanine ammonia-lyase are rendered ambiguous by the interference of this second pathway. Therefore, a "double decker," two-dimensional paper chromatographic method was designed to separate cinnamate and phenylacetate. This was combined with the use of phenylalanine labeled randomly or just in either the carbon 1 or 2 position of the side chain.

Journal Article↗