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PubMed1999

BadR, a new MarR family member, regulates anaerobic benzoate degradation by Rhodopseudomonas palustris in concert with AadR, an Fnr family member.

A cluster of genes for the anaerobic degradation of benzoate has been described for the phototrophic bacterium Rhodopseudomonas palustris. Here we provide an initial analysis of the regulation of anaerobic benzoate degradation by examining the contributions of two regulators: a new regulator, BadR, encoded by the benzoate degradation gene cluster, and a previously described regulator, AadR, whose gene lies outside the cluster. Strains with single mutations in either badR or aadR grew slowly on benzoate but were relatively unimpaired in growth on succinate and several intermediates of benzoate degradation. A badR aadR double mutant was completely defective in anaerobic growth on benzoate. Effects of the regulators on transcriptional activation were monitored with an R. palustris strain carrying a chromosomal fusion of 'lacZ to the badE gene of the badDEFG operon. This operon encodes benzoyl-coenzyme A (benzoyl-CoA) reductase, an unusual oxygen-sensitive enzyme that catalyzes the benzene ring reduction reaction that is the rate-limiting step in anaerobic benzoate degradation. Expression of badE::'lacZ was induced 100-fold when cells grown aerobically on succinate were shifted to anaerobic growth on succinate plus benzoate. The aadR gene was required for a 20-fold increase in expression that occurred in response to anaerobiosis, and badR was responsible for a further 5-fold increase in expression that occurred in response to benzoate. Further studies with the badE::'lacZ fusion strain grown with various kinds of aromatic acids indicated that BadR probably responds to benzoyl-CoA acting as an effector molecule. Sequence information indicates that BadR is a member of the MarR family of transcriptional regulators. These studies expand the range of functions regulated by MarR family members to include anaerobic aromatic acid degradation and provide an example of a MarR-type protein that acts as a positive regulator rather than as a negative regulator, as do most MarR family members. AadR resembles the Escherichia coli Fnr regulator in sequence and contains cysteine residues that are spaced appropriately to serve in the capacity of a redox-sensing protein.

Anaerobiosis↗
PubMed2002

Genes coding for a new pathway of aerobic benzoate metabolism in Azoarcus evansii.

A new pathway for aerobic benzoate oxidation has been postulated for Azoarcus evansii and for a Bacillus stearothermophilus-like strain. Benzoate is first transformed into benzoyl coenzyme A (benzoyl-CoA), which subsequently is oxidized to 3-hydroxyadipyl-CoA and then to 3-ketoadipyl-CoA; all intermediates are CoA thioesters. The genes coding for this benzoate-induced pathway were investigated in the beta-proteobacterium A. evansii. They were identified on the basis of N-terminal amino acid sequences of purified benzoate metabolic enzymes and of benzoate-induced proteins identified on two-dimensional gels. Fifteen genes probably coding for the benzoate pathway were found to be clustered on the chromosome. These genes code for the following functions: a putative ATP-dependent benzoate transport system, benzoate-CoA ligase, a putative benzoyl-CoA oxygenase, a putative isomerizing enzyme, a putative ring-opening enzyme, enzymes for beta-oxidation of CoA-activated intermediates, thioesterase, and lactone hydrolase, as well as completely unknown enzymes belonging to new protein families. An unusual putative regulator protein consists of a regulator protein and a shikimate kinase I-type domain. A deletion mutant with a deletion in one gene (boxA) was unable to grow with benzoate as the sole organic substrate, but it was able to grow with 3-hydroxybenzoate and adipate. The data support the proposed pathway, which postulates operation of a new type of ring-hydroxylating dioxygenase acting on benzoyl-CoA and nonoxygenolytic ring cleavage. A beta-oxidation-like metabolism of the ring cleavage product is thought to lead to 3-ketoadipyl-CoA, which finally is cleaved into succinyl-CoA and acetyl-CoA.

Aerobiosis↗
PubMed2001

The ZbYME2 gene from the food spoilage yeast Zygosaccharomyces bailii confers not only YME2 functions in Saccharomyces cerevisiae, but also the capacity for catabolism of sorbate and benzoate, two major weak organic acid preservatives.

A factor influencing resistances of food spoilage microbes to sorbate and benzoate is whether these organisms are able to catalyse the degradation of these preservative compounds. Several fungi metabolize benzoic acid by the beta-ketoadipate pathway, involving the hydroxylation of benzoate to 4-hydroxybenzoate. Saccharomyces cerevisiae is unable to use benzoate as a sole carbon source, apparently through the lack of benzoate-4-hydroxylase activity. However a single gene from the food spoilage yeast Zygosaccharomyces bailii, heterologously expressed in S. cerevisiae cells, can enable growth of the latter on benzoate, sorbate and phenylalanine. Although this ZbYME2 gene is essential for benzoate utilization by Z. bailii, its ZbYme2p product has little homology to other fungal benzoate-4-hydroxylases studied to date, all of which appear to be microsomal cytochrome P450s. Instead, ZbYme2p has strong similarity to the matrix domain of the S. cerevisiae mitochondrial protein Yme2p/Rna12p/Prp12p and, when expressed as a functional fusion to green fluorescent protein in S. cerevisiae growing on benzoate, is largely localized to mitochondria. The phenotypes associated with loss of the native Yme2p from S. cerevisiae, mostly apparent in yme1,yme2 cells, may relate to increased detrimental effects of endogenous oxidative stress. Heterologous expression of ZbYME2 complements these phenotypes, yet it also confers a potential for weak acid preservative catabolism that the native S. cerevisiae Yme2p is unable to provide. Benzoate utilization by S. cerevisiae expressing ZbYME2 requires a functional mitochondrial respiratory chain, but not the native Yme1p and Yme2p of the mitochondrion.

ATP-Dependent Proteases↗
PubMed2005

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia.

High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.

Adolescent↗
PubMed1991

Effect of substituted benzoates on p-aminohippurate transport in dog renal membrane vesicles.

The effect of substituted benzoates on the transport of p-aminohippurate (PAH) was studied in basolateral (BLMV) and brush border membrane vesicles (BBMV) isolated from dog kidney cortex. For both membranes, kinetic analysis of [3H]PAH transport in the presence of a fixed concentration of two different benzoates, respectively, revealed an increase in the apparent Km for PAH, while the transport capacity (Vmax) was unaffected. This is compatible with competitive inhibition of a common transport pathway. A range of 19 monosubstituted benzoates were then tested as potential inhibitors by measuring the probenecid-sensitive fraction of 100 mumol/l PAH uptake into BLMV and BBMV in the presence of 5 mmol/l benzoate, and apparent inhibition constants (Ki) were calculated. For all benzoates the inhibitory potency in BBMV was lower than in BLMV, but the pattern of inhibition was similar; the most pronounced inhibition was found for 3-Cl- and 4-Cl-benzoate, while the least pronounced inhibition was found for the 3-NH2 and 4-NH2 substitutes. The inhibitory potency, expressed as logKi, correlated significantly with the relative hydrophobicity of the benzoates determined by reversed phase HPLC, whereas a poor correlation was found between pKa and logKi. This indicates that hydrophobic and electronic parameters are the main determinants of affinity for the PAH transport system. It is suggested that the PAH transport system present in the proximal tubules is responsible for the active secretion of benzoates by the mammalian kidney.

Animals↗
PubMed1976

Anaerobic degradation of benzoate to methane by a microbial consortium.

A stabilized consortium of microbes which anaerobically degraded benzoate and produced CH4 was established by inoculation of a benzoate-mineral salts medium with sewage sludge; the consortium was routinely subcultured anaerobically in this medium for 3 years. Acetate, formate, H2 and CO2 were identified as intermediates in the overall conversion of benzoate to CH4 by the culture. Radioactivity was equally divided between the CH4 and CO2 from the degradation of uniformly ring-labeled [14C]benzoate. The methyl group of acetate was stoichiometrically converted to CH4. Acetate, cyclohexanecarboxylate, 2-hydroxycyclohexanecarboxylate, o-hydroxybenzoic acid and pimelic acid were converted to CH4 without a lag suggesting that benzoate was degraded by a reductive pathway. Addition of o-chlorobenzoate inhibited benzoate degradation but not acetate degradation or methane formation. Two methanogenic organisms were isolated from the mixed culture; neither organism was able to degrade benzoate, showing that the methanogenic bacteria served as terminal organisms of a metabolic food chain composed of several organisms. Removal of intermediates by the methanogenic bacteria provided thermodynamically favorable conditions for benzoate degradation.

Acetates↗
PubMed1975

Purification, properties and induction of a specific benzoate-4-hydroxylase from Aspergillus niger (UBC 814).

An inducible benzoate-4-hydroxylase has been partially purified from crude extracts of the mycelial felts of Aspergillus niger. This enzyme catalyzes the transformation of benzoate to p-hydroxybenzoate with equimolar consumption of NADPH and O2. It requires tetrahydropteridine as a prosthetic group. The optimum activity was found at pH 6.2 with a Km value at 30 degrees C of 1.6-10-minus 4 for NADPH and 1.3-10-minus 4 M for benzoate. Fe-2+ (iron) is required for the enzyme activity. The enzyme is stabilized by the inclusion of benzoate, EDTA and glutathione in the extracting buffer. The enzyme is specific for benzoate as substrate. Sulfhydryl groups(s) are essential for enzyme activity as indicated by p-chloromercuri-benzoate and N-ethylmaleimide inactivation. Benzoate-4-hydroxylase activity is decreased in the mycelial felts of Aspergillus niger grown in the presence of higher concentrations of benzoate. Maximum activity of the enzyme was observed at 36 h after inoculation.

Aspergillus↗
PubMed1993

Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia.

The sparse-fur (spf) mutant mouse has an X-linked deficiency of ornithine transcarbamylase and develops congenital hyperammonemia similar to that seen in human patients. We studied the effect of sodium benzoate (2.5, 5 and 10 mmol/kg body wt) on ammonia, glutamine and glutamate, as well as various intermediates of energy metabolism in brain and liver of normal CD-1/Y and hyperammonemic spf/Y mice. The ammonia concentration of brain was decreased with 2.5 mmol sodium benzoate in spf/Y mice, whereas higher doses resulted in a significant increase in both liver and brain. Cerebral glutamine content decreased generally in a dose-dependent manner, both in normal and affected mice, following treatment with various doses of sodium benzoate. Cerebral glutamate concentrations were increased only in spf mice treated with sodium benzoate, whereas ATP and acetyl CoA were decreased (P < 0.001), in both normal and affected mice, indicating that glutamine synthesis may be affected by ATP availability. Free CoA levels were decreased (P < 0.05) only in liver in both groups of treated mice, whereas pyruvate concentrations were elevated (P < 0.05) in affected mice following sodium benzoate administration. The results demonstrate that a dose of 2.5 mmol sodium benzoate/kg body wt has a beneficial effect in reducing cerebral ammonia with a concomitant decrease in glutamine. However, the results suggest that many of the metabolite changes observed following higher doses of benzoate could be due to depletion of ATP, free CoA and acetyl CoA levels, possibly secondary to benzoyl CoA accumulation. The response of the spf/Y mouse to sodium benzoate was different from that of the control CD-1/Y mouse, which could be due to its urea cycle dysfunction and a chronic hyperammonemic state. Hence, the spf/Y mouse may be the ideal animal model for studying the pharmacology of sodium benzoate in hyperammonemic disorders at both the cerebral and hepatic levels.

Acetyl Coenzyme A↗
PubMed1988

Loss of the toluene-xylene catabolic genes of TOL plasmid pWW0 during growth of Pseudomonas putida on benzoate is due to a selective growth advantage of 'cured' segregants.

During growth on benzoate-minimal medium Pseudomonas putida mt-2 (PaW1) segregates derivative ('cured') strains which have lost the ability to use the pathway encoded by its resident catabolic plasmid pWW0. Experiments with two plasmids identical to pWW0 but each with an insert of Tn401, which confers resistance to carbenicillin, suggested that the 'benzoate curing' occurs far more frequently by the specific deletion of the 39 kbp region carrying the catabolic genes than by total plasmid loss. This effect was not pH-dependent, and was not produced during growth on other weak organic acids, such as succinate or propionate, or when benzoate was present in the medium with an alternative, preferentially used carbon source such as succinate. Growth on benzoate did not cause loss from strain PaW174 of the plasmid pWW0174, a derivative of pWW0 which has deleted the 39 kbp region but carries Tn401. Similarly the naphthalene-catabolic plasmid pWW60-1, of the same incompatibility group as pWW0, was not lost from PaW701 during growth on benzoate. Competition between wild-type PaW1 and PaW174, which has the 'cured' phenotype, showed that the latter has a distinct growth advantage on benzoate over the wild-type even when initially present as only 1% of the population: when PaW174 was seeded at lower cell ratios, spontaneously 'cured' derivatives of PaW1 took over the culture after 60-80 generations, indicating that they are present in PaW1 cultures at frequencies between 10(-2) and 10(-3). We conclude that the progressive takeover of populations of PaW1 only occurs when benzoate is present as the sole growth source and that neither benzoate, nor other weak acids, affect plasmid segregation or deletion events: a sufficient explanation is that the 'cured' segregants grow faster than the wild-type using the chromosomally determined beta-ketoadipate pathway.

Benzoates↗
PubMed2004

Sodium benzoate-induced repeated episodes of acute urticaria/angio-oedema: randomized controlled trial.

BACKGROUND: Sodium benzoate (E 211) is widely used to delay yeast spoilage of acidic foods and beverages. Numerous cases of adverse reactions to benzoate have been recorded, but most of the studies that have been conducted lacked proper placebo controls or blinding. OBJECTIVE: The aim of this study is to determine the incidence of intolerance to sodium benzoate among subjects who experienced repeated episodes of acute urticaria/angio-oedema following the ingestion of a meal or a product containing this substance. METHODS: This was a retrospective study based on the analysis of data from patients reported to have experienced episodes of urticaria, with or without angio-oedema, after ingesting meals or products containing sodium benzoate. At the first visit to the outpatients clinic, a careful history was taken. Patients were then given the following diagnostic tests: tests for IgE for common inhalant allergens and food allergens, and a double-blind, placebo-controlled challenge with sodium benzoate. RESULTS: A total of 47 subjects were enrolled in the study; five (11%) showed at least one relevant positive reaction to an IgE test for food allergy. Only one subject (2%) had a reaction after the ingestion of 75 mg of sodium benzoate without an adverse reaction to placebo. CONCLUSION: This study shows that the percentage of repeated episodes of acute urticaria/angio-oedema reactions induced by sodium benzoate is very low (2%). In view of our results, we suggest that when faced with patients who have suffered adverse reactions that could be attributed to sodium benzoate, physicians should also carefully evaluate other possible causes.

Acute Disease↗
PubMed1989

A methyl-accepting protein is involved in benzoate taxis in Pseudomonas putida.

Pseudomonas putida is attracted to at least two groups of aromatic acids: a benzoate group and a benzoylformate group. Members of the benzoate group of chemoattractants stimulated the methylation of a P. putida polypeptide with an apparent molecular weight of 60,000 in sodium dodecyl sulfate-polyacrylamide gels. This polypeptide is presumed to be a methyl-accepting chemotaxis protein for several reasons: its molecular weight is similar to the molecular weights of Escherichia coli methyl-accepting chemotaxis proteins, the amount of time required to attain maximal methylation correlated with the time needed for behavioral adaptation of P. putida cells to benzoate, and methylation was stimulated by benzoate only in cells induced for chemotaxis to benzoate. Also, a mutant specifically defective in benzoate taxis failed to show any stimulation of methylation upon addition of benzoate. Benzoylformate did not stimulate protein methylation in cells induced for benzoylformate chemotaxis, suggesting that sensory input from this second group of aromatic-acid attractants is processed through a different kind of chemosensory pathway. The chemotactic responses of P. putida cells to benzoate and benzoylformate were not sensitive to external pH over a range (6.2 to 7.7) which would vary the protonated forms of these weak acids by a factor of about 30. This indicates that detection of cytoplasmic pH is not the basis for aromatic-acid taxis in P. putida.

Bacterial Proteins↗
PubMed2003

Characterization of hybrid toluate and benzoate dioxygenases.

Toluate dioxygenase of Pseudomonas putida mt-2 (TADO(mt2)) and benzoate dioxygenase of Acinetobacter calcoaceticus ADP1 (BADO(ADP1)) catalyze the 1,2-dihydroxylation of different ranges of benzoates. The catalytic component of these enzymes is an oxygenase consisting of two subunits. To investigate the structural determinants of substrate specificity in these ring-hydroxylating dioxygenases, hybrid oxygenases consisting of the alpha subunit of one enzyme and the beta subunit of the other were prepared, and their respective specificities were compared to those of the parent enzymes. Reconstituted BADO(ADP1) utilized four of the seven tested benzoates in the following order of apparent specificity: benzoate > 3-methylbenzoate > 3-chlorobenzoate > 2-methylbenzoate. This is a significantly narrower apparent specificity than for TADO(mt2) (3-methylbenzoate > benzoate approximately 3-chlorobenzoate > 4-methylbenzoate approximately 4-chlorobenzoate >> 2-methylbenzoate approximately 2-chlorobenzoate [Y. Ge, F. H. Vaillancourt, N. Y. Agar, and L. D. Eltis, J. Bacteriol. 184:4096-4103, 2002]). The apparent substrate specificity of the alphaBbetaT hybrid oxygenase for these benzoates corresponded to that of BADO(ADP1), the parent from which the alpha subunit originated. In contrast, the apparent substrate specificity of the alphaTbetaB hybrid oxygenase differed slightly from that of TADO(mt2) (3-chlorobenzoate > 3-methylbenzoate > benzoate approximately 4-methylbenzoate > 4-chlorobenzoate > 2-methylbenzoate > 2-chlorobenzoate). Moreover, the alphaTbetaB hybrid catalyzed the 1,6-dihydroxylation of 2-methylbenzoate, not the 1,2-dihydroxylation catalyzed by the TADO(mt2) parent. Finally, the turnover of this ortho-substituted benzoate was much better coupled to O2 utilization in the hybrid than in the parent. Overall, these results support the notion that the alpha subunit harbors the principal determinants of specificity in ring-hydroxylating dioxygenases. However, they also demonstrate that the beta subunit contributes significantly to the enzyme's function.

Acinetobacter calcoaceticus↗
PubMed2004

The bzd gene cluster, coding for anaerobic benzoate catabolism, in Azoarcus sp. strain CIB.

We report here that the bzd genes for anaerobic benzoate degradation in Azoarcus sp. strain CIB are organized as two transcriptional units, i.e., a benzoate-inducible catabolic operon, bzdNOPQMSTUVWXYZA, and a gene, bzdR, encoding a putative transcriptional regulator. The last gene of the catabolic operon, bzdA, has been expressed in Escherichia coli and encodes the benzoate-coenzyme A (CoA) ligase that catalyzes the first step in the benzoate degradation pathway. The BzdA enzyme is able to activate a wider range of aromatic compounds than that reported for other previously characterized benzoate-CoA ligases. The reduction of benzoyl-CoA to a nonaromatic cyclic intermediate is carried out by a benzoyl-CoA reductase (bzdNOPQ gene products) detected in Azoarcus sp. strain CIB extracts. The bzdW, bzdX, and bzdY gene products show significant similarity to the hydratase, dehydrogenase, and ring-cleavage hydrolase that act sequentially on the product of the benzoyl-CoA reductase in the benzoate catabolic pathway of Thauera aromatica. Benzoate-CoA ligase assays and transcriptional analyses based on lacZ-reporter fusions revealed that benzoate degradation in Azoarcus sp. strain CIB is subject to carbon catabolite repression by some organic acids, indicating the existence of a physiological control that connects the expression of the bzd genes to the metabolic status of the cell.

Anaerobiosis↗
PubMed2005

Growth substrate- and phase-specific expression of biphenyl, benzoate, and C1 metabolic pathways in Burkholderia xenovorans LB400.

Recent microarray experiments suggested that Burkholderia xenovorans LB400, a potent polychlorinated biphenyl (PCB)-degrading bacterium, utilizes up to three apparently redundant benzoate pathways and a C(1) metabolic pathway during biphenyl and benzoate metabolism. To better characterize the roles of these pathways, we performed quantitative proteome profiling of cells grown on succinate, benzoate, or biphenyl and harvested during either mid-logarithmic growth or the transition between the logarithmic and stationary growth phases. The Bph enzymes, catabolizing biphenyl, were approximately 16-fold more abundant in biphenyl- versus succinate-grown cells. Moreover, the upper and lower bph pathways were independently regulated. Expression of each benzoate pathway depended on growth substrate and phase. Proteins specifying catabolism via benzoate dihydroxylation and catechol ortho-cleavage (ben-cat pathway) were approximately an order of magnitude more abundant in benzoate- versus biphenyl-grown cells at the same growth phase. The chromosomal copy of the benzoyl-coenzyme A (CoA) (box(C)) pathway was also expressed during growth on biphenyl: Box(C) proteins were approximately twice as abundant as Ben and Cat proteins under these conditions. By contrast, proteins of the megaplasmid copy of the benzoyl-CoA (box(M)) pathway were only detected in transition-phase benzoate-grown cells. Other proteins detected at increased levels in benzoate- and biphenyl-grown cells included general stress response proteins potentially induced by reactive oxygen species formed during aerobic aromatic catabolism. Finally, C(1) metabolic enzymes were present in biphenyl-grown cells during transition phase. This study provides insights into the physiological roles and integration of apparently redundant catabolic pathways in large-genome bacteria and establishes a basis for investigating the PCB-degrading abilities of this strain.

Aerobiosis↗
PubMed1986

Waste nitrogen excretion via amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance.

Benzoate and phenylacetate improve prognosis in inherited urea cycle enzyme deficiencies by increasing waste nitrogen excretion as amino acid acylation products. We studied metabolic changes caused by these substances and their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric protein intolerance (LPI), under strictly standardized induction of hyperammonemia. Five patients with LPI received an intravenous infusion of 6.6 mmol/kg L-alanine alone and separately with 2.0 mmol/kg of benzoate or phenylacetate in 90 min. Blood for ammonia, serum urea and creatinine, plasma benzoate, hippurate, phenylacetate, phenylacetylglutamine, and amino acids was obtained at 0, 120, 180, and 270 min. Urine was collected in four consecutive 6-h periods. Alanine caused hyperammonemia: maximum increase 107, 28-411 microM (geometric mean, 95% confidence interval); ammonia increments were nearly identical after alanine + benzoate (60, 17-213 microM) and alanine + phenylacetate (79, 13-467 microM) (NS). Mean plasma benzoate was 6.0 mM when extrapolated to the end of alanine + benzoate infusions; phenylacetate was 4.9 mM at the end of alanine + phenylacetate. Transient toxicity (dizziness, nausea, vomiting) occurred in four patients at the end of combined infusions, and we suggest upper therapeutic plasma concentrations of 4.5 mM for benzoate and 3.5 mM for phenylacetate. Benzoate and phenylacetate then decreased following first-order kinetics with t1/2S of 273 and 254 min, respectively. Maximal plasma hippurate (0.24, 0.14-0.40 mM) was lower than maximal phenylacetylglutamine (0.48, 0.22-1.06 mM, p = 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed1996

Analysis of in vitro iontophoretic skin permeation of sodium benzoate by transport numbers of drug and additives.

Effect of species and concentrations of pharmaceutical additives on the iontophoretic transport of benzoate anion through excised hairless rat skin was investigated using a 2-chamber iontophoretic diffusion cell equipped with platinum electrodes at 0 mA for 4h (control) followed by a constant direct current of 0.5 mA for another 4h. One cell facing the stratum corneum was filled with sodium benzoate solution, and the other cell facing the dermis with lithium chloride (LiCl), potassium chloride (KCl) or tetraethylammonium bromide (TEA-Br) solution. Iontophoretic delivery rate of benzoate anion that permeated through skin increased with an increase in the sodium benzoate concentration while maintaining a constant KCl concentration. In contrast, a flux of benzoate anion decreased with an increase in KCl concentration and a constant concentration of sodium benzoate. When KCl was replaced by LiCl or TEA-Br, the flux of benzoate anion was almost the same. These phenomena were evaluated by a concept of transport numbers: theoretical values of benzoate anion flux were very close to the observed data. Potential difference between the skin during the permeation study was also measured between two salt bridges which were connected via calomel electrodes to a potentiometer. It gradually decreased to a certain level in each case, but increased again in some cases. This gradual decrease and increase in the potential difference, in spite of a constant current, were theoretically explained by a gradual increase of ion concentration in the skin membrane and depletion of the cation in the receiver cell, respectively. Analysis of ionic mobility and concentration of penetrants gave a great deal of information on iontophoretic drug permeation through skin.

Animals↗
PubMed2006

The effect of cyclic aerobic-anoxic conditions on biodegradation of benzoate.

The response of a mixed microbial culture to cyclic aerobic and anoxic (denitrifying) conditions was studied in a chemostat with a 48-hour hydraulic residence time receiving a feed containing benzoate and pyruvate. When the cyclic conditions were 3-hour aerobic and 9-hour anoxic, the bacteria-degraded benzoate aerobically via the catechol 2,3-dioxygenase (C23DO) pathway. The quantity of C23DO remained constant throughout the anoxic period but decreased during the initial portion of the aerobic period before returning to the level present in the anoxic period. Anoxic biodegradation of benzoate was via benzoyl-CoA reductase, which remained constant regardless of the redox condition. The aerobic benzoate uptake capability (AeBUC) of the culture increased during the aerobic period but decreased during the anoxic period. The anoxic benzoate uptake capability (AnBUC) exhibited the opposite response. When the cycle was 6-hour aerobic and 6-hour anoxic, aerobic biodegradation of benzoate proceeded via the protocatechuate 4,5-dioxygenase (P45DO) pathway. The P45DO activity decreased early in the aerobic period, but then increased to the level present during the anoxic period. The level of benzoyl-CoA reductase was constant throughout the cycle. Furthermore, AeBUC and AnBUC responded in much the same way as in the 3/9-hour chemostat. During a 9-hour aerobic and 3-hour anoxic cycle, the culture synthesized both P45DO and C23DO, with the former having significantly higher activity. Unlike the other two cycles, AeBUC changed little during the aerobic period, although AnBUC decreased. The culture was well-adapted to the cyclic conditions as evidenced by the lack of accumulation of either substrate during any cycle tested. This suggests that cyclic aerobic-anoxic processes can be used in industrial wastewater-treatment facilities receiving significant quantities of simple aromatic compounds like benzoate. However, the results showed that the kinetics of benzoate degradation were different under aerobic and anoxic conditions, a situation that must be considered when modeling cyclic bioreactors receiving aromatic compounds.

Aerobiosis↗
PubMed1992

Clinical significance of benzoate-metabolizing capacity in patients with chronic liver disease: pharmacokinetic analysis.

Benzoate-metabolizing capacity was studied in control subjects and in liver disease patients after intra-venous loading of 15 mg benzoate per kg of body weight. In the 7 control subjects, the mean level (+/- SEM) of Cmax for serum benzoate was 104.1 +/- 6.8 micrograms/ml, AUC was 2.57 +/- 0.32 mg.min/ml, MRT was 21.5 +/- 1.5 min and T1/2 was 15.5 +/- 1.3 min. For serum hippurate, on the other hand, Tmax was 27.9 +/- 6.0 min, Cmax was 33.4 +/- 2.1 micrograms/ml, AUC was 1.96 +/- 0.13 mg.min/ml, MRT was 39.6 +/- 2.9 min and T1/2 was 30.7 +/- 2.4 min. In 12 patients with chronic hepatitis, Cmax, AUC, MRT and T1/2 for benzoate and Tmax, MRT and T1/2 for hippurate remained at control levels, but Cmax and AUC for hippurate were slightly decreased compared to controls. However, in 18 patients with liver cirrhosis, Cmax and AUC for benzoate were in the control range but MRT and T1/2 were significantly delayed (p less than 0.01 for both). Moreover, the MRT value was increased in proportion to the severity of liver disease (p less than 0.01). AUC for hippurate was not changed to any extent, and Tmax, MRT and T1/2 were slightly delayed, while Cmax was significantly reduced. AUC, MRT and T1/2 for benzoate and Tmax, MRT and T1/2 for hippurate showed significant correlation with serum albumin levels, prothrombin time and indocyanine green clearance rate. These results suggest that benzoate-metabolizing capacity, especially as indicated by the MRT value for serum benzoate, appears to be a better index than the indocyanine green clearance rate for determining hepatic functional reserve in chronic liver disease.

Adult↗