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PubMed1997

Study of a lanthanide fluorescence system with a coupled reaction based on hemin catalysis.

The oxidation reactions of three substrates, p-hydroxybenzoic acid (HBA), p-hydroxyphenylacetic acid, and p-hydroxyphenylpropionic acid, with H2O2 catalysed by hemin were studied. It was significant that only the oxidation product of HBA, di-p,p'-hydroxybenzoic acid, forms a long-lived fluorescent complex with Tb3+. The three substrates themselves do not form fluorescent complexes with Tb3+ although they have chemical structural similarities. Based on this, a novel lanthanide fluorescence system with a coupled reaction was developed. The possible reactive mechanism is discussed. HBA was concluded to be well suited to several types of application from hemin determination to bovine serum albumin labeling.

Catalysis↗
PubMed1965

The metabolism of 2,6-di-tert.-butyl-4-hydroxymethylphenol (Ionox 100) in the dog and rat.

1. A single oral dose of [(14)C]Ionox 100 to rats is almost entirely eliminated in 11 days: 89.1-107.2% of the (14)C is excreted and 0.29+/-0.02% of the dose is present in the carcass plus viscera after removal of the gut. Rats exhibit an individual variation in the elimination pattern, 15.6-70.8% of (14)C being excreted in the urine and 75.2-27.0% in the faeces during 11 days. 2. After the oral administration of [(14)C]Ionox 100 to dogs, 87.1-90.3% of the (14)C is excreted in the faeces and urine during 4 days. 3. Dogs and rats do not show a species difference in this pattern of elimination. 4. The rate of elimination from dogs and rats given a single dose of Ionox 100 is not affected by the size of the dose and the presence of triglyceride fat in the diet. 5. Ionox 100 is completely metabolized in dogs and rats: unchanged Ionox 100 is absent from the urine and faeces, and from the carcass when elimination is complete. In rats, 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 50-85% of a dose of Ionox 100 and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid for 47-10%; in dogs, the unconjugated acid accounts for 85% and the ester glucuronide for 10-12%. 3,5-Di-tert.-butyl-4-hydroxyhippuric acid is not formed. Other metabolites, which have been detected in small quantity in the faeces and urine of animals dosed with Ionox 100, have not been identified. 6. 3,5-Di-tert.-butyl-4-hydroxybenzoic acid and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid are also the major metabolites of Ionol (2,6-di-tert.-butyl-p-cresol) in rats. 7. The elimination of Ionox 100 metabolites from rats is faster than that of Ionol and its metabolites. Unlike Ionol, unchanged Ionox 100 could not be detected in the bodies of these animals.

Journal Article↗
PubMed1966

The fate of di-(3,5-di-tert.-butyl-4-hydroxyphenyl)methane (Ionox 22) in the rat.

1. A large proportion of a single oral dose of [(14)C]Ionox 220 to rats is eliminated in 24 days: 89.3-97.4% of the label is excreted in the faeces (much of this is eliminated in the first 4 days after dosage), 1% in the urine and less than 0.1% in the expired gases; 4.06% of (14)C is present in the carcass and viscera after removal of the gut, and most of this is in the fatty tissues. 2. About 87% of (14)C in the faeces is due to unchanged antioxidant, 5% to the quinone methide, 5% to the free acid and 3% to an unidentified polar constituent. Three-fifths of (14)C in the urine is due to 3,5-di-tert.-butyl-4-hydroxybenzoic acid and the remainder to the ester glucuronide. In three individual animals, one-half of (14)C in the bile is due to the free acid, one-quarter to the ester glucuronide and the remainder to unchanged antioxidant, whereas in another all of (14)C in the bile is due to Ionox 220. About 97% of (14)C in the body fat is due to unchanged antioxidant and the remainder to the free acid. 3. Up to 20% of a single oral dose of Ionox 220 is absorbed in rats: 13-14% is metabolized. 3,5-Di-tert.-butyl-4-hydroxybenzoic acid accounts for just over 5% of a dose of Ionox 220, 3,5-di-tert.-butyl-4-hydroxybenzoyl-beta-d-glucopyranosiduronic acid for less than 0.4%, the quinone methide for just over 5% and an unidentified compound for less than 3%. 4. The physiological and biochemical implications of ingesting Ionox 220 are discussed.

Animals↗
PubMed1968

The metabolism of aromatic acids by micro-organisms. Metabolic pathways in the fungi.

1. The metabolic pathways of aromatic-ring fission were examined in a range of fungal genera that utilize several compounds related to lignin. 2. Most of the genera, after growth on p-hydroxybenzoate, protocatechuate or compounds that are degraded to the latter (e.g. caffeate, ferulate or vanillate), rapidly oxidized these compounds, but not catechol. 3. Such genera possessed a protocatechuate 3,4-oxygenase and accumulated beta-carboxymuconate as the product of protocatechuate oxidation. This enzyme had a high pH optimum in most organisms; the Rhodotorula enzyme was competitively inhibited by catechol. 4. beta-Carboxymuconate was converted by all competent fungi into beta-carboxymuconolactone, which was isolated and characterized. None of the fungi produced or utilized at significant rates the corresponding bacterial intermediate gamma-carboxymuconolactone. 5. The lactonizing enzymes of Rhodotorula and Neurospora crassa had a pH optimum near 5.5 and approximate molecular weights of 19000 and 190000 respectively. 6. The fungi did not degrade the isomeric (+)-muconolactone, gamma-carboxymethylenebutanolide or beta-oxoadipate enol lactone at significant rates, and thus differ radically from bacteria, where beta-oxoadipate enol lactone is the precursor of beta-oxoadipate in all strains examined. 7. The end product of beta-carboxymuconolactone metabolism by extracts was beta-oxoadipate. 8. Evidence for a coenzyme A derivative of beta-oxoadipate was found during further metabolism of this keto acid. 9. A few anomalous fungi, after growth on p-hydroxybenzoate, had no protocatechuate 3,4-oxygenase, but possessed all the enzymes of the catechol pathway. Catechol was detected in the growth medium in one instance. 10. A strain of Penicillium sp. formed pyruvate but no beta-oxoadipate from protocatechuate, suggesting the existence also of a ;meta' type of ring cleavage among fungi.

Ascomycota↗
PubMed1969

The metabolism of aromatic compounds by Rhodopseudomonas palustris. A new, reductive, method of aromatic ring metabolism.

1. Rhodopseudomonas palustris grows both aerobically and photosynthetically on aromatic acids. p-Hydroxybenzoate and protocatechuate are able to support aerobic growth; these compounds are metabolized by the protocatechuate 4,5-oxygenase pathway. 2. The photoassimilation of benzoate and hydroxybenzoates and the effects of air and darkness on the photoassimilation of benzoate are described. 3. Evidence in conflict with the pathway previously proposed for the photometabolism of benzoate is discussed. 4. The photometabolism of benzoate is accomplished by a novel reductive pathway involving its reduction to cyclohex-1-ene-1-carboxylate, followed by hydration to 2-hydroxycyclohexanecarboxylate and after dehydrogenation to 2-oxocyclohexanecarboxylate further hydration results in ring-fission and the production of pimelate. 5. Attempts were made to prepare cell-free extracts capable of dissimilating benzoate.

Benzoates↗
PubMed1977

Generation of hydrogen peroxide, superoxide and hydroxyl radicals during the oxidation of dihydroxyfumaric acid by peroxidase.

1. Dihydroxyfumarate slowly autoxidizes at pH6. This reaction is inhibited by superoxide dismutase but not by EDTA. Mn2+ catalyses dihydroxyfumarate oxidation by reacting with O2 leads to to form Mn3+, which seems to oxidize dihydrofumarate rapidly. Cu2+ also catalyses dihydroxyfumarate oxidation, but by a mechanism that does not involve O2 leads to. 2. Peroxidase catalyses oxidation of dihydroxyfumarate at pH6; addition of H2O2 does not increase the rate. Experiments with superoxide dismutase and catalase suggest that there are two types of oxidation taking place: an enzymic, H2O2-dependent oxidation of dihydroxyfumarate by peroxidase, and a non-enzymic reaction involving oxidation of dihydroxyfumarate by O2 leads to. The latter accounts for most of the observed oxidation of dihydroxyfumarate. 3. During dihydroxyfumarate oxidation, most peroxidase is present as compound III, and the enzymic oxidation may be limited by the low rate of breakdown of this compound. 4. Addition of p-coumaric acid to the peroxidase/dihydroxyfumarate system increases the rate of dihydroxyfumarate oxidation, which is now stimulated by addition of H2O2, and is more sensitive to inhibition by catalase but less sensitive to superoxide dismutase. Compound III is decomposed in the presence of p-coumaric acid. p-Hydroxybenzoate has similar, but much smaller, effects on dihydroxyfumarate oxidation. However, salicylate affects neither the rate nor the mechanism of dihydroxyfumarate oxidation. 5. p-Hydroxybenzoate, salicylate and p-coumarate are hydroxylated by the peroxidase/dihydroxyfumarate system. Experiments using scavengers of hydroxyl radicals shown that OH is required. Ability to increase dihydroxyfumarate oxidation is not necessary for hydroxylation to occur.

Coumaric Acids↗
PubMed2004

Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ.

The COQ2 gene in Saccharomyces cerevisiae encodes a Coq2 (p-hydroxybenzoate:polyprenyl transferase), which is required in the biosynthetic pathway of CoQ (ubiquinone). This enzyme catalyses the prenylation of p-hydroxybenzoate with an all-trans polyprenyl group. We have isolated cDNA which we believe encodes the human homologue of COQ2 from a human muscle and liver cDNA library. The clone contained an open reading frame of length 1263 bp, which encodes a polypeptide that has sequence homology with the Coq2 homologues in yeast, bacteria and mammals. The human COQ2 gene, when expressed in yeast Coq2 null mutant cells, rescued the growth of this yeast strain in the absence of a non-fermentable carbon source and restored CoQ biosynthesis. However, the rate of CoQ biosynthesis in the rescued cells was lower when compared with that in cells rescued with the yeast COQ2 gene. CoQ formed when cells were incubated with labelled decaprenyl pyrophosphate and nonaprenyl pyrophosphate, showing that the human enzyme is active and that it participates in the biosynthesis of CoQ.

Alkyl and Aryl Transferases↗
PubMed2004

Monosodium benzoate hypersensitivity in subjects with persistent rhinitis.

BACKGROUND: Very few data are available from the literature on whether nonatopic subjects affected by persistent rhinitis may show the appearance of objective symptoms of rhinitis after the ingestion of food additives such as tartrazine (E102), erythrosine (E127), monosodium benzoate (E211), p-hydroxybenzoate (E218), sodium metabisulphite (E223), and monosodium glutamate (E620). It is still unclear whether the ingestion of food additive may cause, as well, a consensual reduction of nasal peak inspiratory flow (NPIFR). Therefore, we used a double-blind placebo-controlled (DBPC) study to evaluate this hypothesis. PATIENTS AND METHODS: Two hundred and twenty-six consecutive patients (76 males and 150 females) aged 12-60 years (mean age 40.2 +/- 16.3 years). After 1 month of an additive-free diet regimen, an open challenge was carried out (food additive-rich diet for 2 weeks). After this period, challenges were administered in a DBPC manner using the above-mentioned substances under investigation. RESULTS: Twenty of 226 subjects (8.8%) reported an improvement of the symptoms of rhinitis after additive-free diet. More precisely, six of 226 (2.6%) were symptom-free and 14 of 226 (6.2%) showed an improvement in their symptoms after an additive-free diet. As far as the results for DBPC are concerned, 20 challenges with monosodium benzoate induced both objective (i.e. sneezing and rhinorrhoea) and subjective symptoms (nasal blockage and nasal itching) of rhinitis with reduction of NPIFR >/=20%, 45 challenges induced subjective symptoms of rhinitis (i.e. nasal blockage and nasal itching), without reduction of NPIFR >/=20% of the basal value, two with tartrazine, seven with erythrosine, 19 with monosodium benzoate, three with p-hydroxybenzoate, six with sodium metabisulphite, and eight with monosodium glutamate, respectively. CONCLUSIONS: The observation that nonatopic persistent rhinitis may be caused by the frequent, probably daily, ingestion of small doses of a nontolerated substance is intriguing and suggests that at least some patients with 'chronic vasomotor rhinitis' may be intolerant to a particular food additive. Therefore, food additives can be considered triggers or aggravating factors, rather than aetiological factors.

Adolescent↗
PubMed2002

Streptomycin-resistant (rpsL) or rifampicin-resistant (rpoB) mutation in Pseudomonas putida KH146-2 confers enhanced tolerance to organic chemicals.

We found that certain Str-, Gen- or Rif- mutants derived from Pseudomonas putida KH146-2, which are resistant to streptomycin, gentamicin or rifampicin, respectively, are tolerant to the aromatic compound 4-hydroxybenzoate (4HBA). The minimum inhibitory concentration (MIC) of 4HBA as the sole carbon source for the wild-type strain was 1%, whereas the MIC for the mutants was 1.7%. Frequency of 4HBA-tolerant mutants among spontaneous Str-, Gen- and Rif- mutants was 5-15%, 3-5%, and 3% respectively. These 4HBA-tolerant mutants also tolerated to a variety of organic chemicals such as 3-hydroxybenzoate, aliphatic and heterocyclic compounds, chlorobenzoates, as well as organic solvents toluene and m-xylene. The Str mutants had a point mutation in the rpsL gene, which produces the ribosomal protein S12. The Rif mutants were found to have a point mutation in the rpoB gene, which encodes the RNA polymerase beta-subunit. Mutation points in Gen mutants still remain unknown. Str-, Gen- and Rif-phenotypes occurred in spontaneous 4HBA-tolerant mutants which had been selected by successively increasing concentrations (from 0.8% to 5%) of 4HBA. Complementation experiments with one of the Str mutants demonstrated a causal relationship between a rpsL mutation (str-1) and 4HBA tolerance. Uptake experiments using [14C]-4HBA revealed that apparent ability of 4HBA to be taken up by the membrane transport system was reduced two to threefold in the mutants compared to the wild-type strain, accounting at least partly for the enhanced tolerance to 4HBA. Our approaches thus could be effective in improvement of tolerance to aromatic compounds of bacteria applicable for bioremediation.

Adaptation, Physiological↗
PubMed2003

CloQ, a prenyltransferase involved in clorobiocin biosynthesis.

Ring A (3-dimethylallyl-4-hydroxybenzoic acid) is a structural moiety of the aminocoumarin antibiotics novobiocin and clorobiocin. In the present study, the prenyltransferase involved in the biosynthesis of this moiety was identified from the clorobiocin producer (Streptomyces roseochromogenes), overexpressed, and purified. It is a soluble, monomeric 35-kDa protein, encoded by the structural gene cloQ. 4-Hydroxyphenylpyruvate and dimethylallyl diphosphate were identified as the substrates of this enzyme, with K(m) values determined as 25 and 35 microM, respectively. A gene inactivation experiment confirmed that cloQ is essential for ring A biosynthesis. Database searches did not reveal any similarity of CloQ to known prenyltransferases, and the enzyme did not contain the typical prenyl diphosphate binding site (N/D)DXXD. In contrast to most of the known prenyltransferases, the enzymatic activity was not dependent on the presence of magnesium, and in contrast to the membrane-bound polyprenyltransferases involved in ubiquinone biosynthesis, CloQ did not accept 4-hydroxybenzoic acid as substrate. CloQ and the similar NovQ from the novobiocin producer seem to belong to a new class of prenyltransferases.

Anti-Bacterial Agents↗
PubMed1975

Mutagenic and cytotoxic activity of benzol[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols.

The benzo[a]pyrene 4,5-, 7,8-, and 9,10-oxides and the six corresponding phenols (4-, 5-, 7-, 8-, 9-, and 10-hydroxybenzo[a]pyrene) have been tested for mutagenic and cytotoxic activity in bacteria and in a mammalian cell culture system. Benzo[a]pyrene 4,5-oxide (K-region) was highly mutagenic in two histidine-dependent strains (TA1537 and TA1538) of Salmonella typhimurium which detect frameshift mutagens. In contrast, benzo[a]pyrene 7,8- and 9,10-oxides were less than 1% as mutagenic as the 4,5-oxide. Benzo[a]pyrene 7,8- and 9,10-oxides were unstable in aqueous media, whereas the 4,5-oxide was stable for several hours. This difference in stability could not account for the different mutagenic activities of the three arene oxides. The benzo[a]pyrene oxides were inactive in a strain (TA1535) that is reverted by base pair mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine or in a strain (TA1536) that detects framshift mutagens similar to the acridine half-mustard ICR-191. Benzo-[a]-pyrene and the six phenols were all stable in aqueous media, but they had little or no mutagenic activity in any of the four Salmonella strains. Conversion of 8-azaguanine-sensitive Chinese hamster V79 cells to 8-azaguanine-resistant variants was increased by benzo[a]pyrene 4,5-oxide, whereas the 9,10-oxide was considerably less active. Benzo[a]pyrene and the other derivatives had little or no effect. Benzo[a]yrene 4,5-oxide was more cytotoxic to the Chinese hamster V79 cells than the 7,8- and 9,10-oxides, while 8-hydroxybenzo[a]pyrene was the most cytotoxic of the six phenols.

Benzopyrenes↗
PubMed2000

Cloning, overexpression, and purification of novobiocic acid synthetase from Streptomyces spheroides NCIMB 11891.

Novobiocic acid synthetase, a key enzyme in the biosynthesis of the antibiotic novobiocin, was cloned from the novobiocin producer Streptomyces spheroides NCIMB 11891. The enzyme is encoded by the gene novL, which codes for a protein of 527 amino acids with a calculated mass of 56,885 Da. The protein was overexpressed as a His(6) fusion protein in Escherichia coli and purified to apparent homogeneity by affinity chromatography and gel chromatography. The purified enzyme catalyzed the formation of an amide bond between 3-dimethylallyl-4-hydroxybenzoic acid (ring A of novobiocin) and 3-amino-4,7-dihydroxy-8-methyl coumarin (ring B of novobiocin) in an ATP-dependent reaction. NovL shows homology to the superfamily of adenylate-forming enzymes, and indeed the formation of an acyl adenylate from ring A and ATP was demonstrated by an ATP-PP(i) exchange assay. The purified enzyme exhibited both activation and transferase activity, i.e. it catalyzed both the activation of ring A as acyl adenylate and the subsequent transfer of the acyl group to the amino group of ring B. It is active as a monomer as determined by gel filtration chromatography. The reaction was specific for ATP as nucleotide triphosphate and dependent on the presence of Mg(2+) or Mn(2+). Apparent K(m) values for ring A and ring B were determined as 19 and 131 micrometer respectively. Of several analogues of ring A, only 3-geranyl-4-hydroxybenzoate and to a lesser extent 3-methyl-4-aminobenzoate were accepted as substrates.

Amide Synthases↗
PubMed2001

Characterization of the B12- and iron-sulfur-containing reductive dehalogenase from Desulfitobacterium chlororespirans.

The United Nations and the U.S. Environmental Protection Agency have identified a variety of chlorinated aromatics that constitute a significant health and environmental risk as "priority organic pollutants," the so-called "dirty dozen." Microbes have evolved the ability to utilize chlorinated aromatics as terminal electron acceptors in an energy-generating process called dehalorespiration. In this process, a reductive dehalogenase (CprA), couples the oxidation of an electron donor to the reductive elimination of chloride. We have characterized the B12 and iron-sulfur cluster-containing 3-chloro-4-hydroxybenzoate reductive dehalogenase from Desulfitobacterium chlororespirans. By defining the substrate and inhibitor specificity for the dehalogenase, the enzyme was found to require an hydroxyl group ortho to the halide. Inhibition studies indicate that the hydroxyl group is required for substrate binding. The carboxyl group can be replaced by other functionalities, e.g. acetyl or halide groups, ortho or meta to the chloride to be eliminated. The purified D. chlororespirans enzyme could dechlorinate an hydroxylated PCB (3,3',5,5'-tetrachloro-4,4'-biphenyldiol) at a rate about 1% of that with 3-chloro-4-hydroxybenzoate. Solvent deuterium isotope effect studies indicate that transfer of a single proton is partially rate-limiting in the dehalogenation reaction.

Amino Acid Sequence↗
PubMed2004

Characterization of three glycosyltransferases involved in the biosynthesis of the phenolic glycolipid antigens from the Mycobacterium tuberculosis complex.

Mycobacterium tuberculosis and Mycobacterium leprae, the two main mycobacterial pathogens in humans, produce highly specific long chain beta-diols, the dimycocerosates of phthiocerol, and structurally related phenolic glycolipid (PGL) antigens, which are important virulence factors. In addition, M. tuberculosis also secretes glycosylated p-hydroxybenzoic acid methyl esters (p-HBAD) that contain the same carbohydrate moiety as the species-specific PGL of M. tuberculosis (PGL-tb). The genes involved in the biosynthesis of these compounds in M. tuberculosis are grouped on a 70-kilobase chromosomal fragment containing three genes encoding putative glycosyltransferases: Rv2957, Rv2958c, and Rv2962c. To determine the functions of these genes, three recombinant M. tuberculosis strains, in which these genes were individually inactivated, were constructed and biochemically characterized. Our results demonstrated that (i) the biosynthesis of PGL-tb and p-HBAD involves common enzymatic steps, (ii) the Rv2957, Rv2958c, and Rv2962c genes are involved in the formation of the glycosyl moiety of the two classes of molecules, and (iii) the product of Rv2962c catalyzes the transfer of a rhamnosyl residue onto p-hydroxybenzoic acid ethyl ester or phenolphthiocerol dimycocerosates, whereas the products of Rv2958c and Rv2957 add a second rhamnosyl unit and a fucosyl residue to form the species-specific triglycosyl appendage of PGL-tb and p-HBAD. The recombinant strains produced provide the tools to study the role of the carbohydrate domain of PGL-tb and p-HBAD in M. tuberculosis pathogenesis.

Antigens↗
PubMed1979

Glucuronidation of lipophilic substrates: preparation of 3-benzo[a]pyrenyl-beta-D-glucopyranosiduronic acid in multimilligram quantities by microsomal UDP-glucuronyl transferase.

A convenient method for the enzymic conversion of multimilligram quantities of 3-hydroxybenzo[a]pyrene to 3-benzo[a]pyrenyl-beta-D-glucopyranosiduronic acid in 90% yield is described. Commercially available freeze-dried rabbit liver microsomes were incubated in the presence of UDPGA, 3-hydroxybenzo[a]pyrene, and Triton X-100 detergent (Figure 1). The course of the biosynthetic reaction was followed by fluorimetry. The glucuronide product was extracted from the acidified incubation supernate with ethyl acetate and the acid function of the glucuronide was utilized in an acid-base extraction procedure to purify the glucuronide from biological and unreacted starting material. The glucuronide precipitated from ethyl acetate and was collected by centrifugation. High pressure liquid chromatography and spectroscopic techniques were used to verify the structure and purity of 3-benzo[a]pyrenyl-beta-D-glucopyranosiduronic acid.

Animals↗
PubMed2004

Biotransformation of chlorpropham (CIPC) in isolated rat hepatocytes and xenoestrogenic activity of CIPC and its metabolites by in vitro assays.

1: The metabolism and action of chlorpropham (isopropyl N-(3-chlorophenyl)carbamate; CIPC, a post-harvest agent) were studied in freshly isolated rat hepatocytes, and the oestrogen-like activity of CIPC and its metabolites was assessed by in vitro assays. The exposure of hepatocyte suspensions to CIPC caused concentration- (0.25-1.0 mM) and time- (0-3 h) dependent cell death, which was assessed by Trypan blue exclusion, accompanied by losses of cellular adenosine triphosphate and adenine nucleotide pools, and formation of cell bleb. 2: CIPC at a weakly toxic level (0.25 or 0.5 mM) was metabolized to isopropyl N-(3-chloro-4-hydroxyphenyl)carbamate (4OH-CIPC) and subsequently to its glucuronide and sulfate conjugates (major metabolites) or alternatively to the minor metabolites 3-chloroaniline (3CA) and 3-chloroacetanilide. CIPC (0.25 mM) added to hepatocyte suspensions was distributed equally between hepatocytes and the extracellular medium during the incubation. The glucuronide rather than the sulfate conjugate of 4OH-CIPC predominantly increased in the medium with time, while the amount of unconjugated free 4OH-CIPC in the extracellular medium increased by approximately threefold compared with the amount in the cell fraction after 0.5 h and then decreased rapidly accompanied by increases in the conjugates. This indicates that unconjugated free 4OH-CIPC produced in hepatocytes was temporarily excreted in the extracellular medium and subsequently converted to the conjugates via re-influx into hepatocytes. 3: Diethylstilbestrol (DES), bisphenol A (BPA) and 4-hydroxybenzoic acid butyl ester (butylparaben), which are known xenoestrogenic compounds, competitively displaced 17beta-oestradiol bound to the oestrogen receptor-alpha (ERalpha) in a concentration-dependent manner; IC50 values of DES, BPA, butylparaben and its derivative 3-chloro-4-hydroxybenzoic acid butyl ester (3-chloro-butylparaben) were approximately 10(-8), 10(-5), 5 x 10(-5) and 5 x 10(-4) M, respectively. In contrast, neither CIPC nor 4OH-CIPC impaired the binding of 17beta-oestradiol to ERalpha at concentrations ranging from 10(-9) to 10(-4) M, whereas at concentrations of >5 x 10(-4) M, the binding affinity of 4OH-CIPC was greater than that of CIPC. In a proliferation assay of MCF-7 cells, CIPC, 4OH-CIPC and 3CA did not increase cell numbers at concentrations ranging from 10(-9) to 10(-5) M, but these compounds at a concentration of 10(-4) M induced a considerable decrease in cell numbers relative to the control. The results suggest that even if CIPC is metabolized to 4OH-CIPC by hepatocytes, the chlorine adjacent to the 4-hydroxy group added to the intermediate as well as 3-chloro-butylparaben obstructs the appearance of oestrogen-like effects via an interaction between the intermediate and the ER.

Animals↗
PubMed1993

Cleavage of 3-phenoxybenzoic acid by chicken microsomal preparations.

3-Phenoxybenzoic acid, labelled at either the 3-phenoxy[U-ring C-14] or carbonyl C-14, produced the corresponding labelled transitory metabolite 4'-hydroxy-3-phenoxybenzoic acid when incubated with chicken liver microsomal preparation. The other radioactive reaction product identified from the metabolism of the carbonyl-labelled 3-phenoxybenzoic acid was labelled 3-hydroxybenzoic acid, whereas metabolism of the [U-ring] labelled 3-phenoxybenzoic acid produced labelled hydroquinone in addition to 4'-hydroxy-3-phenoxybenzoic acid. Formation of both 4'-hydroxy-3-phenoxybenzoic acid, and its subsequent conversion to 3-hydroxybenzoic andhydroquinone were NADPH and oxygen dependent. The reaction was inhibited by carbon monoxide, but not by piperonyl butoxide or metyrapone. The inhibition by carbon monoxide suggests that the enzyme(s) involved in the cleavage is a form of P450. The enzyme(s) is a monooxygenase and has requirement for NADPH and oxygen.

2,2'-Dipyridyl↗
PubMed1980

Fluorescence spectral evidence that benzo[a]pyrene is activated by metabolism in mouse skin to a diol-epoxide and a phenol-epoxide.

Hydrolysates of DNA that had been isolated from mouse skin treated with 3H-labelled benzo[a]pyrene were subjected to chromatography on Sephadex LH20. Two major products were eluted in the region expected for deoxyribonucleoside-hydrocarbon adducts and these were purified further by h.p.l.c. The fluorescence emission and excitation spectra of one of the adducts were identical to that of the adduct obtained from DNA that was treated with BP-7,8-diol 9,10-oxide (r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a] pyrene). The fluorescence emission and excitation spectra of the other adducts were identical to the published spectra of 9-OHBP-4,5-diol (4,5-dihydro-4,5,9-trihydroxy-benzo[a]pyrene) and of the deoxyribonucleoside-hydrocarbon adduct obtained from DNA that had been incubated with 9-OHBP (9-hydroxybenzo[a] pyrene) in the presence of a rat-liver microsomal system. The metabolic activation of benzo[a]pyrene in mouse skin, a target tissue for carcinogenesis by this hydrocarbon, thus appears to involve the formation of adducts derived from both BP-7,8-diol 9,10-oxide and 9-OHBP 4,5-oxide (9-hydroxybenzo-[a]pyrene 4,5-oxide), although quantitatively, the adduct derived from 9-OHBP 4,5-oxide is a minor product.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗