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PubMed1981

Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion.

The hepatic metabolism of arylamine bladder carcinogens to N-hydroxy arylamine N-glucuronides, their excretion in the urine, and their subsequent acidic hydrolysis to highly carcinogenic and reactive N-hydroxy arylamines have been proposed as essential steps in arylamine-induced urinary bladder carcinogenesis. In this study, alteration of urinary pH, inhibition of metabolic sulfation, and blockage of biliary disposition were shown to profoundly affect the urinary excretion of the probable ultimate bladder carcinogen, N-hydroxy-2-naphthylamine (N-HO-2-NA) and its N-glucuronide conjugate. The normal pH of rat urine (6.7) was altered to 5.7 or 7.7 by administration of NH4Cl or NaHCO3 in the drinking water. Subsequent treatment with either 2-naphthylamine (2-NA) or 2-nitronaphthalene (2-NN) resulted in increased urinary levels of free N-HO-2-NA (relative to its N-glucuronide) in acidic urines and decreased relative amounts of free N-HO-2-NA in alkaline urines. In addition, 2-NN yielded 5--10-fold greater levels of urinary N-HO-2-NA and its N-glucuronide than rats given 2-NA; and 2-NA was not detected as a urinary metabolite of 2-NN. Some 12 additional metabolites of 2-NA and 2-NN were also found. Of these, 2-amino-1-naphthol and its sulfate and glucuronide conjugates were quantitated. From these data, 2-NA and 2-NN appear to share common metabolic pathways which yield free N-HO-2-NA as a putative ultimate urinary bladder carcinogen. Pentachlorophenol, a known inhibitor of hepatic sulfotransferases, was shown to cause a 2--3-fold increase in the urinary levels of N-HO-2-NA N-glucuronide and N-HO-2-NA from 2-NA-treated rats. Similarly, inhibition of the biliary excretion of 2-NA by bile duct ligation resulted in a 6-fold increase in total urinary N-HO-2-NfA. Furthermore, analyses of bile revealed that substantial amounts of N-HO-2-NA N-glucuronide, but not free N-HO-2-NA, were present. The role of urinary versus biliary excretion of N-hydroxy arylamines in relation to bladder and colon carcinogenesis is discussed.

2-Naphthylamine↗
PubMed1982

Identification of glutathione conjugates formed from N-hydroxy-2-acetylaminofluorene in the rat.

Rats which had received N-hydroxy-2-acetylaminofluorene (N-OH-AAF) excreted two glutathione conjugates in the bile. Pretreatment with the sulphotransferase inhibitor pentachlorophenol reduced the amounts excreted by 50% suggesting that these conjugates were formed in vivo from the highly reactive N-O-sulphate ester of N-OH-AAF (AAF-N-sulphate). In order to identify these biliary conjugates synthetic GSH conjugates were prepared by the reaction of N-acetoxy-AAF, (a model compound for AAF-N-sulphate), with GSH. Four conjugates were isolated and characterized by ultraviolet, proton magnetic resonance, mass spectroscopy and by the determination of their amino acid composition. These conjugates were identified as 1-, 3-, 4- and 7-(glutathion-S-yl)-N-acetyl-2-aminofluorene, respectively. The two biliary conjugates were identified as 1- and 3-(glutathion-S-yl)-N-acetyl-2-aminofluorene.

2-Acetylaminofluorene↗
PubMed1990

The role of hydroxyl radicals in tetrachlorohydroquinone induced DNA strand break formation in PM2 DNA and human fibroblasts.

Tetrachlorohydroquinone (TCHQ), which has previously been identified as a metabolite of pentachlorophenol, induces DNA strand breaks in isolated DNA and in human fibroblasts. Strand break formation in PM2 DNA is prevented by the addition of catalase and the hydroxyl radical scavengers DMSO, ethanol and mannitol, whereas addition of SOD reduced SSB only slightly. Oxygen radicals are formed by the autoxidation of TCHQ to the tetrachlorosemiquinone radical. Desferrioxamine (0.2 mM) completely abolished strand break formation, whereas the metal chelator DETAPAC (1 mM) reduced SSB by only 8.5%. The formation of the semiquinone radical at physiological conditions is shown by ESR spectroscopy. Exposure of human fibroblasts to TCHQ also leads to DNA single strand breaks measured by the alkaline elution assay. These were reduced by addition of 5% DMSO. This indicates that at least part of the strand break formation in human cells is also due to the action of hydroxyl radicals.

Cells, Cultured↗
PubMed1994

Comparison of the urinary metabolite profiles of hexachlorobenzene and pentachlorobenzene in the rat.

The urinary metabolite profile of hexachlorobenzene (HCB) and pentachlorobenzene (PCBz) in the rat is compared after dietary exposure for 13 weeks. Both HCB and PCBz are oxidized to pentachlorophenol (PCP) and tetrachlorohydroquinone (TCHQ), which were the only two mutual metabolites formed. Additional urinary metabolites of HCB are N-acetyl-S(pentachlorophenyl)cysteine (PCTP-NAC), which appeared to be quantitatively the most important product, and mercaptotetrachlorothioanisole (MTCTA), which was excreted as a glucuronide. PCBz is more extensively metabolized to the major metabolites 2,3,4,5-tetrachlorophenol (TCP), mercaptotetrachlorophenol (MTCP) and the glucuronide of pentachlorothiophenol (PCTP), and the minor metabolites methylthiotetrachlorophenol (MeTTCP), hydroxytetrachlorophenyl sulphoxide (HTCPS), and bis(methylthio)-trichlorophenol (bis-MeTTriCP). The biotransformation of HCB and PCBz was modulated by selective inhibition of cytochrome P450IIIA in rats which received combined treatment of HCB or PCBz with triacetyloleandomycin (TAO). Rats receiving this diet had a strongly diminished excretion of both PCP and TCHQ, as compared to rats fed HCB or PCBz alone, indicating the involvement of P450IIIA in the oxidation of both compounds. However, the excretion of 2,3,4,5-TCP was not diminished by co-treatment of rats with PCBz and TAO, indicating that: (i) the oxidation of PCBz to PCP and 2,3,4,5-TCP does not proceed via a common intermediate; and (ii) oxidation of PCBz to 2,3,4,5-TCP is not mediated by P450IIIA. Co-treatment of rats with PCBz and TAO had a differential effect on the excretion of sulphur-containing metabolites, resulting in a decrease in the excretion of PCTP glucuronide, whereas no change was observed in the excretion of MTCP, as compared to rats receiving PCBz alone. The observed differences in HCB and PCBz metabolites clearly deserve further in vitro studies to elucidate their origin.

Animals↗
PubMed1975

Analysis of polychlorinated dibenzo-p-dioxins and dibenzofurans in chlorinated phenols by mass fragmentography.

A rapid, highly specific method for the analysis of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in pentachlorophenol and other chlorinated phenols is described. The rapid sample preparation procedure includes an alkaline extraction of phenolic compounds and chromatography of the neutral substances on an alumina micro-column. After gas chromatographic separation, individual polychlorinated dibenzo-p-dioxins and dibenzofurans are detected and quantified by mass fragmentography. The sample purification procedure removes polychlorinated diphenyl ethers, polychlorinated biphenyls and benzenes, phthalates and polychlorinated phenoxyphenols (predioxins), which might otherwise severely interfere in the analysis. Significant levels of hexa-, hepta- and octachlorodibenzo-p-dioxin and of hexa-, hepta- and octachlorodibenzofuran were found in two commercial products.

Aluminum↗
PubMed1977

Gas chromatographic determination of microamounts of carbaryl and 1-naphthol in natural water as sources of water supplies.

A method for the clean-up and quantitative determination of Carbaryl and its hydrolysis product, 1-naphthol, in natural waters is described. After extraction of a water sample with methylene chloride, the two compounds were separated from possible organochlorine pollutants such as Endrin, gamma-BHC, p,p'-DDT, pentachlorophenol and polychlorinated biphenyl, and their heptafluorobutyryl derivatives obtained. Determination by electron-capture gas chromatography at the 2.5-10 ppb level, using 11 of water samples, was carried out.

Carbaryl↗
PubMed1996

Toxicological evaluation of harmful substances by in situ enzymatic and biological detection in high-performance thin-layer chromatography.

The efficiency of a chromatographic analysis method is determined by the selectivity of the chromatographic separation and the specificity of the detection method. In the case of high-performance thin-layer chromatography (HPTLC) the separated components can be detected and quantified directly on the chromatogram by physical and chemical methods. By coupling high-performance thin-layer chromatography with biological or biochemical inhibition tests it was possible to detect toxcologically active substances in situ. A linear relationship was shown between the signal of the inhibition of cholinesterase and the concentration of the inhibitor using a constant enzyme concentration and a constant incubation time. The graph of the inhibition of the luminescence of Photobacterium vibrio fisheri in relation to the concentration of pentachlorophenol (range 20-80 ng) is nearly linear. Measurements were done by using a densitometer or a videodensitometric scanner.

Animals↗
PubMed1987

Chemical and biological characterization of hazardous industrial waste. I. Prokaryotic bioassays and chemical analysis of a wood-preserving bottom-sediment waste.

Prokaryotic bioassays, capable of detecting point mutations and lethal damage to DNA, and a GC/MS/Data System analysis were employed to evaluate the genotoxic characteristics of wood-preserving bottom sediment. Organic compounds in the waste were initially extracted with dichloromethane and then fractionated by liquid-liquid extraction into acid, base and neutral fractions. The crude extract and each of 3 subfractions were tested in 4 strains of S. typhimurium to detect point mutations and 6 strains of B subtilis to detect lethal damage to DNA. The assay using S. typhimurium responded to indirect-acting mutagens in the crude extract and all 3 primary fractions, with the maximum mutagenic response of 181 net revertants induced by the base fraction at a dose of 500 micrograms/plate. In the DNA-repair assay, the survival ratio for the repair-deficient strain recE4 when compared to the repair-proficient strain 168 wt was 0.17 and 0.09 in the acid and base fractions, respectively, at a dose of 100 micrograms/plate. Potentially genotoxic compounds identified in the waste fractions by GG/MS/DS analysis include acenaphthylene, pentachlorophenol, methyl phenanthrene, fluoranthene and pyrene. However, it appears that these identified chemicals did not contribute significantly to the observed mutagenic activity of the sample extracts.

Bacillus subtilis↗
PubMed1988

Mutagenic activation of xenobiotics by plant enzymes.

Genetic evidence has indicated that plants can activate certain xenobiotics to mutagens, but biochemical evidence is as yet scarce. Nevertheless, plant microsomal enzymes and peroxidases have been shown to form reactive intermediates, the best studied examples being 2-aminofluorene, benzo[a]pyrene and pentachlorophenol. The latter two xenobiotics are converted to quinoid derivatives which are, in principle, able to redox cycle and generate active oxygen species. In analogy to results obtained in mammalian systems, covalent binding of reactive intermediates to DNA as well as fragmentation of DNA, are proposed as major mechanisms of action of mutagenic plant metabolites.

Animals↗
PubMed1988

Modulation of the mutagenic effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) in bacteria with rat-liver 9000 x g supernatant or monolayers of rat hepatocytes as an activation system.

An in vitro protocol was designed to separate the process of metabolic activation from the mutational events. Cultured rat hepatocytes were first incubated with the food mutagens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) or 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ). After the incubation period the medium was removed and further incubated with Salmonella typhimurium TA98. A high direct mutagenic activity of the culture medium was then measured. The half-lives of the mutagenic metabolites formed from IQ and MeIQ were in the order of 45 min. The presence of the cytochrome P450 inhibitors alpha-naphthoflavone and metyrapone during the pre-incubation period reduced the accumulation of mutagenic metabolites. No effects of ascorbate on the mutagenic effects of IQ and MeIQ were seen. (+)-Catechin, another antioxidant and free-radical scavenger, markedly enhanced the number of IQ/MeIQ-induced revertants when added to the hepatocytes. In contrast, (+)-catechin clearly decreased the number of revertants when 9000 X g supernatant from rat liver (S9) was used as an activation system. No marked effect of pentachlorophenol, an inhibitor of hepatocyte sulfation and bacterial O-acetylation, was seen using hepatocytes as an activation system, while the mutagenic activity of both IQ and MeIQ was reduced by 90% in the S9/Salmonella system. The addition of an inhibitor of glucuronidation, galactosamine, or the nucleophile glutathione caused no or only minor decreases in the genotoxic effects of the IQ compounds. With both S9 and hepatocytes as activation systems the relative mutagenic effects observed in the S. typhimurium strains TA98 and TA98 NR were in the same order of magnitude, while a large decrease was seen with TA98/1,8-DNP6. The results show that this in vitro test protocol may be useful as a tool to study mechanisms involved in the formation of mutagenic metabolites.

Animals↗
PubMed1989

Nucleic acid binding and mutagenicity of active metabolites of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a potent mutagen and carcinogen present in heated foodstuffs. The covalent binding of MeIQx to calf thymus DNA and calf liver RNA with microsomal activation was demonstrated. A major metabolite which exerts a direct mutagenic effect on S. typhimurium TA98 was found by HPLC analysis after incubation of MeIQx with rat liver microsomal fraction. The metabolite was identified as 2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-OH-MeIQx). Synthetic N-OH-MeIQx was found to bind non-enzymatically to DNA and RNA at neutral pH even at 0 degrees C. Addition of acetic anhydride increased the binding of N-OH-MeIQx to DNA 10 times. These results suggest that MeIQx is metabolized to N-OH-MeIQx by microsomal cytochrome P-450 and further activated to an acetylated form that binds efficiently to nucleic acids in rat liver. Preferential modification of polyguanylic acid suggests that guanine residues of DNA are mainly modified with MeIQx. Synthetic N-OH-MeIQx exerted direct mutagenic activity on S. typhimurium TA98 inducing 150,000 rev/micrograms. Pentachlorophenol (PCP) caused a dose-dependent inhibition of this mutagenic effect, but 2,6-dichloro-4-nitrophenol (DCNP) did not. Thus the acetyltransferase of S. typhimurium seems to be important for the high mutagenicity of MeIQx after its microsomal activation.

Biotransformation↗
PubMed1987

Mechanisms of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD)-induced humoral immune suppression: evidence of primary defect in T-cell regulation.

The antibody response of C57B1/6 mice to sheep erythrocytes (SRBCs), a macrophage and T-cell-dependent antigen, is highly sensitive to suppression by 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), a major immunotoxic contaminant of pentachlorophenol. The present studies have used several in vivo approaches to characterize the humoral immune suppression produced by an acute oral exposure to HpCDD and to assess the potential cellular defects responsible for the suppression. Administration of HpCDD at various times prior to or following antigen challenge indicated that HpCDD induced rapid yet prolonged suppression of the antibody response. Timing studies also suggested that initial processing of antigen by the macrophage and antibody production by the mature plasma cell were resistant to HpCDD. The demonstration that antibody responses could not be improved by either increasing or decreasing the antigen dose indicated that the effects of HpCDD were not related to the level of antigenic stimulation per se. In addition, there was no evidence for a shift in the kinetics of the antibody response of HpCDD-treated mice at any antigen dose that might have reflected a delay in the development of the response. The dose-response effects of HpCDD on antibody responses to T-helper-cell-dependent (SRBC) and T-helper-cell-independent type 1 (TNP-LPS) and type 2 (DNP-Ficoll) antigens indicated that sensitivity to HpCDD-induced suppression directly correlated with the sensitivity of the response to T-cell regulation. Nonspecific activation of T-amplifier cells with concanavalin A was capable of reconstituting the depressed antibody response of mice treated with 100 micrograms/kg HpCDD but not of mice treated with 500 micrograms/kg HpCDD, further suggesting that regulatory T cells are most sensitive to HpCDD. Definitive evidence for the role of regulatory T cells in mediating HpCDD-induced suppression of the antibody response was obtained in studies using congenitally T-cell-deficient nude (nu/nu) mice. The antibody response to DNP-Ficoll was was assayed since the anti-DNP response proceeds in the absence of T-helper cells in nu/nu mice yet the response can be modulated by changes in the activity of T-amplifier and T-suppressor cells present in nu/+ mice. Results of these studies showed that nu/nu mice were significantly more resistant to the immunosuppressive effects of HpCDD as compared with their nu/+ littermates.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Evaluation of the developmental toxicity of chlorinated phenols utilizing Hydra attenuata and postimplantation rat embryos in culture.

Chlorinated phenols (CPs) represent a major component of hazardous oily and wood-preserving wastes that are widely distributed in chemical dumpsites throughout the United States. Pentachlorophenol (C5P) has been reported to be highly embryolethal and embryotoxic in rats. However, data pertaining to the developmental toxicities of other important CPs are limited. In this study, the toxicities of phenol, CP homologues and their isomers, selected phenyl acetates, anisoles, sodium phenates, and tetrachlorobenzoquinones (a total of 38 chemicals) were evaluated using cultures of Hydra attenuata (HA). Developmental hazard index (A/D ratio) was determined for selected test chemicals (i.e., those chemicals which resulted in an early toxic endpoint at the lowest whole-log concentration in the adult hydra assay). These same chemicals were evaluated at equimolar concentration in postimplantation rat whole embryo culture (WEC). HA and WEC studies demonstrated a linear relationship between toxicity and the degree of chlorine substitution with C5P greater than 2,3,4,5-C4P greater than 2,3,5-C3P greater than 3,5-C2P greater than 4-CP greater than phenol. The A/D ratios from the HA assay were approximately 1 for all of the chemicals tested. Findings from the WEC assay indicated similar results based on growth, gross morphology, and DNA and protein content of embryos. The results obtained in the HA and WEC assays suggest that the chlorinated phenols are not potent teratogens. The combination of HA and WEC may facilitate the rapid detection and ranking of hazardous chemicals associated with complex mixtures of chemical wastes.

Animals↗
PubMed1995

PCDD/Fs and non-o-PCBs in digested U.K. sewage sludges.

Twelve digested sewage sludges from rural and urban waste water treatment works in the north-west of England were analysed for PCDD/Fs and non-o-PCBs. The PCDD/F analysis of eight samples was repeated using high-resolution mass spectrometry, which enabled detection of the lower chlorinated congeners and calculation of TE values. sigma TEQ values for these eight samples ranged from 19-206 ng/kg with the higher values detected in the samples from urban/industrial areas. Examination of the congener/homologue profiles for the more contaminated samples suggests a major input from the use of pentachlorophenol. Archived sewage sludge samples collected and stored from one sewage treatment works in the south of England between 1942 and 1960 were analyzed to gain some insight into temporal trends and possible variations in source inputs. These provide some evidence of changing sources of PCDD/Fs over time and a decline in sigma TEQs since the 1950s.

England↗
PubMed1995

PCDD/DFs and coplanar PCBs in sediment and fish samples from the Er-Jen river in Taiwan.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/DFs) and coplanar polychlorinated biphenyls (Co-PCBs) have been determined in sediment and fish samples from the Er-Jen river in Taiwan. Sediment samples collected near the incineration site show TEQ of PCDD/DFs ranging from 14 pg/g to 14200 pg/g and 2,3,7,8-tetrachlorodibenzo-p-dioxins equivalents (TCDD-EQ) of Co-PCBs ranging from 9 pg/g to 1030 pg/g. The fish samples show TEQ of PCDD/DFs ranging from 37 pg/g to 2084 pg/g and TCDD-EQ of Co-PCBs ranging from 12 pg/g to 120 pg/g. Possible PCDD/DFs sources are discharged PCBs, open-air incineration activities, and pentachlorophenol. PCB#126 was found to degrade more readily than PCB#77. TCDD-EQ of Co-PCBs could be estimated from the total concentration of PCBs. A daily intake value of 28 pg/kg/day to 450 pg/kg/day was estimated when consuming fish caught from the Er-Jen river.

Animals↗
PubMed1996

Hydrophobicity and sorption of chlorophenolates to lipid membranes.

We have studied sorption of ionized species of chlorophenols and pentahalophenols to lipid membranes using egg-phosphatidylcholine (egg-PC) vesicles and measuring their zeta-potential as a function of aqueous concentration of the phenolates. The zeta-potential isotherms can be understood in terms of a sorption model that is a combination of the Gouy-Chapman model of the electrical double layer at the membrane-water interface and the Langmuir model for sorption. Two intrinsic sorption parameters were determined: the linear partition coefficient beta m, which relates the membrane surface density of the phenolates to their aqueous concentration and the area of the adsorption site, Ps. The linear partition coefficient is the measure of the affinity of phenolates to the lipid membrane. It depends strongly on the molecular structure: 2,6-dichlorophenolate beta m = (0.45 +/- 0.08) x 10(-7); m; 3,5-dichlorophenolate beta m = (0.22 +/- 0.02) x 10(-6) m; 2,4,6-trichlorophenolate beta m = (0.63 +/-0.06) x 10(-6) m; 2,4,5-trichlorophenolate beta m = (0.11 +/- 0.01) x 10(-5) m; 2,3,5,6-tetrachlorophenolate beta m = (0.56 +/- 0.07) x 10(-5) m; 2,3,4,5-tetrachlorophenolate beta m = (0.55 +/- 0.06) x 10(-5) m; pentachlorophenolate beta m = (0.34 +/- 0.05) x 10(-4) m; pentafluorophenolate beta m = (1.00 +/- 0.13) x 10(-7) m and pentabromophenolate beta m = (0.19 +/- 0.04) x 10(-3) m. Ps was found to be independent of phenolate structure, Ps = 3.3 +/- 0.1 nm2. The membrane affinity of chlorophenolates was compared with the octanol-water partition coefficients of un-ionized chlorophenols. It was shown that the free energy of transfer of chlorophenolates from water into the lipid membrane can be divided into non-electrostatic and electrostatic contributions. The no-nelectrostatic contribution corresponds to the hydrophobicity parameter alpha = 3.94 +/- 0.0.08 kcal per nm2 of molecular surface area. The electrostatic contribution contains a term inversely proportional to the molecular radius of the phenolate ion which has the physical meaning of the work of transfer of the phenolate ion from water into the membrane. The polarity of the sorption region of egg-PC membranes is given in terms of the dielectric constant and was estimated to be 12.4 (range 10.5-13.4).

1-Octanol↗
PubMed1996

Metabolism of organochlorine pesticides: the role of human cytochrome P450 3A4.

Organochlorine compounds are widely used as pesticides and are substantial environmental pollutants and carcinogens due to their extensive environmental release. In the present study biotransformation of these pesticides was observed in the microsomal fractions and whole cells of Saccharomyces cerevisiae expressing human cytochrome P450 3A4. In both in vitro and in vivo studies, hexachlorobenzene and pentachlorobenzene were metabolised into pentachlorophenol which was further transformed into tetrachlorohydroquinone. Metabolites were identified by thin layer chromatography and 13C-NMR spectroscopy. The formation of products was observed only in the presence NADPH in microsomal fractions and no activity was observed in control microsomal fractions, or in whole cells.

Aryl Hydrocarbon Hydroxylases↗
PubMed1987

Effects of aquatic humus on accumulation and acute toxicity of some organic micropollutants.

Accumulation experiments in a natural humic water revealed significantly lower bioconcentration of dehydroabietic acid and benzo(a)pyrene into Daphnia magna when compared with a standardized soft freshwater. For pentachlorophenol no such effect could be observed. Depending on the chemical involved, the natural humic water might affect the acute lethal toxicity of aquatic contaminants to this organism.

Abietanes↗