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PubMed2003

Toxicokinetics of organic contaminants in Hyalella azteca.

Uptake, biotransformation, and elimination rates were determined for pentachlorophenol (PCP), methyl parathion (MP), fluoranthene (FU), and 2,2',4,4',5,5'-hexachlorobiphenyl (HCBP) using juvenile Hyalella azteca under water-only exposures. A two-compartment model that included biotransformation described the kinetics for each chemical. The uptake clearance coefficients (k(u)) were 25.7 +/- 2.9, 11.5 +/- 1.1, 184.4 +/- 9.3, and 251.7 +/- 9.0 (ml g(-1) h(-1)) for PCP, MP, FU, and HCBP, respectively. The elimination rate constant of the parent compound (k(ep)) for MP was almost an order of magnitude faster (0.403 +/- 0.070 h(-1)) than for PCP and FU (0.061 +/- 0.034 and 0.040 +/- 0.008 h(-1)). The elimination rate constants for FU and PCP metabolites (k(em)) were similar to the parent compound elimination 0.040 +/- 0.005 h(-1) and 0.076 +/- 0.012 h(-1), respectively. For MP, the metabolites were excreted much more slowly than the parent compound (0.021 +/- 0.001 h(-1)). For PCP, FU, and MP whose metabolites were measured, the biological half-life (t(1/2p)) of the parent compound was shorter than the half-life for metabolites (t(1/2m)) because the rate is driven both by elimination and biotransformation processes. Thus, H. azteca is capable of metabolizing compounds with varying chemical structures and modes of toxic action, which may complicate interpretation of toxicity and bioaccumulation results. This finding improves our understanding of H. azteca as a test organism, because most biomonitoring activities do not account for biotransformation and some metabolites can contribute significantly to the noted toxicity.

Animals↗
PubMed2005

Sorption of chlorophenolates in soils and aquifer and marine sediments.

This article describes the sorption behavior of 3 hydrophobic ionizable chlorophenols-2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol, and pentachlorophenol-in different types of natural sorbents. A series of experiments was carried out with 11 topsoil samples, 9 aquifer sediments, and 12 marine sediments differing in pH, organic-matter content, and mineral composition and presumably also in type of organic matter due to their differing origins. Ionized forms of chlorophenols dominated in almost all sorption experiments. Freundlich isotherm coefficients K(f) and 1/n, as well as organic-matter sorption coefficient (log K(om)) and free-energy change (DeltaG(o)), were calculated for all 3 compounds in all sorbents. The sorption intensity of predominantly ionized chlorophenols increased linearly with the increase of sorbent organic-matter content and decreased with the increasing sorbent pH. Different sorption behavior of all 3 compounds in marine sediments with respect to topsoils and aquifer sediments was indicated by significant differences in K(f) and 1/n coefficients as well as in log K(om) and DeltaG(o) values. The highest K(f) and log K(om) values were obtained for sorption of chlorophenolic compounds in topsoils and the lowest in marine sediments, although both groups of sorbents had similar organic-matter content. The 1/n coefficient, reflecting the isotherm nonlinearity, was considerably lower than unity for all compounds in almost all sorbents. The most significant deviation of sorption isotherms from linearity was observed in marine sediments. Only marine sediments showed a linear increase in sorption intensity of all 3 compounds with the increase in sorbent-specific surface area. These results pointed to a different mechanism of sorption in marine and terrestrial sorbents and confirmed that the capacity of sorption was related to amount as well as type and origin of organic matter.

Adsorption↗
PubMed1999

Divergent kinetics of hsp70 induction in Oniscus asellus (Isopoda) in response to four environmentally relevant organic chemicals (B[a]P, PCB52, gamma-HCH, PCP): suitability and limits of a biomarker.

Mature specimens of the isopod Oniscus asellus were maintained on soil and leaf litter to which was added different concentrations of either benzo[a]pyren (B[a]P), 2,2',5,5'-tetrachlorobiphenyl (PCB52), gamma-hexachlorocyclohexane (gamma-HCH), or pentachlorophenol (PCP) for a maximum of 14 days. Time-dependent investigation of the body level of the 70 kD stress protein group (hsp70) in the isopods revealed a significant but transient induction of the hsp70 response after about 24 h of exposure to PCB52 or B[a]P. Despite continuous exposure, the hsp70 level decreased subsequently and ended up close to or below the control level independent of the concentration of PCB52 or B[a]P in the substrate. All applied PCP or gamma-HCH concentrations also resulted in an initial peak of hsp70 response after 24 h of exposure and a second peak after several days of exposure, as well as an elevated hsp70 level throughout the period of exposure. Although acute stress conditions posed by all four organic chemicals were monitored by stress protein induction, hsp70 can act as a biomarker of chronic exposure and effect for PCP and gamma-HCH only.

Animals↗
PubMed2002

Expression of a gene for Mn-peroxidase from Coriolus versicolor in transgenic tobacco generates potential tools for phytoremediation.

In efforts aimed at the detoxification of contaminated areas, plants have many advantages over bacteria and fungi. We are attempting to enhance the environmental decontamination functions of plants by transferring relevant genes from microorganisms. When the gene for Mn-peroxidase (MnP) from Coriolus versicolor was expressed in transgenic tobacco plants, one line (designated fMnP21) expressed MnP activity at levels 54-fold higher than in control lines. When undamaged roots of transgenic plants were applied to liquid medium supplemented with 250 microM pentachlorophenol (PCP), the decrease in the level of PCP in fMnP21 (86% reduction) was about 2-fold higher than that in control lines (38% reduction). Expression of the gene for MnP in the transgenic plants had no obvious negative effects on their vegetative and sexual growth. Our system should contribute to the development of novel methods for the removal of hazardous chemicals from contaminated environments using transgenic plants.

Basidiomycota↗
PubMed2004

Transgenic tobacco expressing fungal laccase promotes the detoxification of environmental pollutants.

The phytoremediation of soils contaminated with organic pollutants offers a low-cost method for removal of such pollutants. We have attempted to enhance the environmental decontamination functions of plants by introducing appropriate enzymatic activities from microorganisms. In the present study, we introduced an extracellular fungal enzyme, the laccase of Coriolus versicolor, into tobacco plants. One transgenic plant, designated FL4, produced laccase that was secreted into the rhizosphere. FL4 was able to remove 20 micromol bisphenol A or pentachlorophenol per gram dry weight. The efficiency of this removal was apparently greater than that of control lines. Our results should stimulate efforts to develop plant-based technologies for the removal of environmental pollutants from contaminated environments.

Benzhydryl Compounds↗
PubMed1998

Simulation of in situ subsurface biodegradation of polychlorophenols in air-lift percolators.

Air-lift percolator experiments simulated in situ subsurface degradation of 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol and pentachlorophenol, in mixtures and individually, by indigenous microorganisms from a chlorophenol-contaminated aquifer. Inoculation with a chlorophenol(CP)-degrading gram-positive isolate from the CP-contaminated groundwater did not significantly increase CP degradation rates. Feed concentrations of up to 55 mg CP l-1 were degraded. Stable CP degradation was maintained for over 6 months. CP degradation rates up to 54.3 mg l-1 day-1 and effluent concentrations below 40 micrograms CP l-1 were achieved. CP were mineralized as shown by CP reduction, dissolved organic carbon removal and release of inorganic chloride.

Bacteria↗
PubMed2001

Carcinogenicity assays of wood dust and wood additives in rats exposed by long-term inhalation.

OBJECTIVE: This study evaluates whether wood dust and/or wood preservatives develop a carcinogenic potential against the tissues of the airways of rats. METHODS: The formation of tumors of the respiratory tract after exposure to wood dust was studied in six groups of approximately 60 female Fischer 344 rats exposed by long-term inhalation to mean concentrations of (1) 18 mg/m3 of untreated oak wood dust, (2) wood preservatives containing ca. 1 microgram/m3 lindane and 0.2 microgram/m3 of pentachlorophenol (PCP) in the exposure air, or lindane and 18 micrograms/m3 of PCP (group lindane/PCP vapors, and group oak wood treated with lindane/PCP), (3) 21 or 39 micrograms/m3 of sodium dichromate (calculated as CrO3, group chromate aerosol and group oak wood with chromate), and 72 micrograms/m3 of N-nitrosodimethylamine vapors as positive control. The negative control group consisted of 115 animals (sham-exposed). RESULTS: Tumors of the nasal cavity developed in two rats exposed to chromate aerosol or in combination with wood dust (2/102, 2%). Malignant tumors of the lower respiratory tract were induced only in exposed groups of rats (three adenocarcinomas of the lung and four bronchiolar lung carcinomas, 7/254, 2.8%). More respiratory tract tumors were observed in rats exposed to chromate or wood with chromate (5/102, 5%), also in groups exposed to oak wood dust (oak untreated, oak + chromate, oak + lindane/PCP; together 5/155, 3.2%). Analysis of 'unpreserved' oak wood dust revealed up to 5 micrograms/m3 of chromate. When this exposure was taken into account, eight of nine animals with respiratory tract tumors (including nasal cavity) had exposure to chromate, while only one tumor occurred in the group lindane/PCP. Otherwise the incidence of systemic tumors was increased in animals exposed to lindane/PCP, due in particular to a significantly increased incidence of liver tumors (OR = 3.7; 1.24-11.3; P = 0.019). Fatal (mucoepidermoid) tumors were induced by N-nitrosodimethylamine (NDMA) in the positive control (14/46, 30%). No such tumors of the respiratory tract were observed in the negative control. CONCLUSIONS: Tumors in the respiratory tract were found only in exposed animals, predominantly in the groups which inhaled oak wood dust and chromate stain. Chromate may play a decisive role for the etiology of tumors of the nasal cavity in wood workers. This assumption should be supported by further dose-response studies.

Air Pollutants↗
PubMed1986

Thermotropic properties of human erythrocyte membrane proteins as affected by hydroxychloroaromatic compounds.

The thermal stability of the anion transport protein (band 3) and other proteins of the human erythrocyte membrane, as influenced by hydroxychloroaromatic (HO-Cl2-Ar) compounds, was studied by differential scanning calorimetry. Various hydroxychlorodiphenyl ethers (HO-Clx-DPEs) and hexachlorophene, but not pentachlorophenol, caused a marked decrease in the thermal stability of band 3. Most of the other calorimetric transitions of the erythrocyte membrane were only slightly affected. The activity of HO-Clx-DPEs toward lowering the transition temperature of band 3 generally increased with the degree of chlorination, and was somewhat dependent on the position of hydroxyl substitution. At higher concentrations of HO-Clx-DPEs, there was a decrease in the enthalpy change and a broadening of the endothermic transition of band 3. The order of effectiveness of these compounds, as determined from band 3 denaturation temperatures, was similar to the order of potency previously observed for hemolysis of human erythrocytes.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

Plant biochemistry of xenobiotics: isolation and properties of soybean O- and N-glucosyl and O- and N-malonyltransferases for chlorinated phenols and anilines.

O-Glucosyltransferase (O-GT), O-malonyltransferase (O-MAT), N-glucosyltransferase (N-GT), and N-malonyltransferase (N-MAT) activities have been detected in cultured soybean cells, using pentachlorophenol and 3,4-dichloroaniline as xenobiotic standard substrates. The O-GT was purified approximately 1000-fold, and the N-MAT approximately 70-fold. There was an extensive copurification of O-GT and O-MAT. The following functional molecular weight values were obtained, 47 kDA (O-GT), 48 kDA (O-MAT) 43 kDa (N-GT), and 48 kDa (N-MAT). O-GT and N-MAT appeared to be monomeric polypeptides with isoelectric points of approximately 4.8 and approximately 6.1, respectively. The O-GT, N-GT, and N-MAT activities had marked substrate specificities for chlorinated aromatic xenobiotics and thus illustrate the existence of plant isoenzymes with specificity for xenobiotics.

Acyltransferases↗
PubMed1986

Studies on the succinate dehydrogenating system. Interaction of the mitochondrial succinate-ubiquinone reductase with pyridoxal phosphate.

The inhibitory effect of pyridoxal phosphate on the Triton X-100 solubilized purified bovine heart succinate-ubiquinone reductase (Choudhry, Z.M., Gavrikova, E.V., Kotlyar, A.B., Tushurashvilli, P.R. and Vinogradov, A.D. (1985) FEBS Lett. 182, 171-175) was studied. The kinetics of the enzyme inactivation by pyridoxal phosphate was found to be strongly dependent both qualitatively and quantitatively on the concentration of the protein-detergent complexes. In the diluted system the inactivation of the ubiquinone-depleted enzyme was completely prevented by the saturating concentrations of Q2, carboxin, thenoiltrifluoroacetone and pentachlorophenol, i.e., by the substrate and specific inhibitors of the enzyme. The protective effects of Q2 and the inhibitors was employed to quantitate the affinities of the ligands to their specific binding sites. Strong difference in the affinity of Q2 to the reduced and oxidized enzyme was found. When the soluble reconstitutively active succinate dehydrogenase was treated with pyridoxal phosphate, the reactivity of the enzyme towards low ferricyanide concentrations and its reconstitutive activity was significantly protected against aerobic inactivation.

Animals↗
PubMed1993

The role of protonic and sodium potentials in the motility of E. coli and Bacillus FTU.

The motility of Escherichia coli and of alkalo- and halotolerant Bacillus FTU has been studied. It is found that Bac. FTU motility (i) requires Na+, (ii) is resistant to the protonophorous uncoupler pentachlorophenol (PCP) if cells grow at high pH, and is sensitive to the uncouplers at neutral pH, (iii) is sensitized to the uncouplers with the addition of monensin, (iv) sensitive to amiloride and (v) can be supported by an artificially imposed Na+ gradient in the presence of uncoupler, cyanide and arsenate. On the other hand, E. coli motility (a) does not require Na+, (b) is always uncoupler-sensitive, (c) is amiloride-resistant, and (d) can be supported by an artificially-imposed gradient of H+, not Na+. It is concluded that the motilities of Bac. FTU and E. coli are due to the operation of the Na+ and the H+ motors, respectively. In Bac. FTU growing at alkaline pH, the Na+ motors are assumed to be energized by delta mu Na+ produced by the Na(+)-motive respiratory chain, and therefore delta mu H+ is not involved in the motility process. As to Bac. FTU growing in a neutral medium, delta mu Na+ is produced secondarily, via the Na+/H(+)-antiporter, i.e., at the expense of delta mu H+ formed by the H(+)-motive respiratory chain.

Amiloride↗
PubMed1991

Age- and sex-related differences in activation of the carcinogen 7-hydroxymethyl-12-methylbenz[a]anthracene to an electrophilic sulfuric acid ester metabolite in rats. Possible involvement of hydroxysteroid sulfotransferase activity.

Metabolic activation of 7-hydroxymethyl-12-methylbenz[a]anthracene (HMBA) and related hydroxymethyl polycyclic aromatic hydrocarbons to electrophilic and mutagenic sulfuric acid esters has been demonstrated previously (Watabe et al., In: Xenobiotic Metabolism and Disposition (Eds. Kato R, Estabrook RW and Cayen MN), pp. 393-400. Taylor & Francis, London, 1989). In the present study, the rat hepatic sulfotransferase activity catalyzing the formation of such reactive sulfuric acid esters was inhibited strongly by dehydroepiandrosterone, a typical substrate hydroxysteroid sulfotransferases (HSSTs). Pentachlorophenol, a potent phenol sulfotransferase inhibitor, had little effect in this regard. A marked sex difference was observed for the hepatic cytosolic sulfotransferase activity for HMBA in rats. This sex difference was age-related; no significant difference was observed in preweanling rats, whereas in adult rats female rat liver showed a much higher enzyme activity. These age- and sex-related differences in the sulfonation of HMBA reflect the regulation of HMBA sulfotransferase activity by gonadal hormones as previously demonstrated with HSSTs. Thus, pretreatment with estradiol benzoate significantly enhanced the sulfotransferase activity for HMBA in both male and female rats, (P less than 0.01 and P less than 0.05 respectively), whereas testosterone propionate pretreatment decreased this activity. Castration of male rats increased the HMBA sulfotransferase activity 2- to 3-fold compared with that in control animals. By contrast, ovariectomy reduced the enzyme activity 38% in females. These results imply that rat liver HSST activity is responsible for the sulfonation of HMBA. Intraperitoneal injection of HMBA (0.25 mumol/g body wt) into infant rats produced benzylic DNA adducts in the liver which were chromatographically identical with those obtained from incubations of HMBA with deoxyguanosine and deoxyadenosine in the presence of hepatic cytosolic sulfotransferase activity. Intraperitoneal administration of sodium 7-sulfooxymethyl-12-methylbenz[a]anthracene resulted in much higher levels of these adducts and the deoxycytidine adduct in the liver DNA than did an equimolar amount of the parent hydroxymethyl hydrocarbon. The levels of hepatic benzylic DNA adducts formed from HMBA were reduced markedly by pretreatment of rats with dehydroepiandrosterone, a strong inhibitor of hepatic sulfotransferase activity for this hydrocarbon.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Activation of 6-aminochrysene to genotoxic products by different forms of rat liver cytochrome P450 in an O-acetyltransferase-overexpressing Salmonella typhimurium strain (NM2009).

Metabolic activation of a potent mutagen, 6-aminochrysene, to genotoxic products in a newly developed tester strain, Salmonella typhimurium NM2009, was studied in a rat liver microsomal monooxygenase system containing cytochrome P450 (P450). Since the tester strain was constructed by introducing an O-acetyltransferase gene into the original strain S. typhimurium TA1535/pSK1002, it is highly sensitive toward the reactive metabolites of carcinogenic arylamines. DNA-damaging activities of 6-aminochrysene were detected at very low concentrations of substrate (between 0.01 and 0.2 microM) and liver microsomes (from 0.2 to 2 micrograms protein/mL) in the S. typhimurium NM2009 strain. Thus, the potency of genotoxic activities induced by 6-aminochrysene was about 10- to 20-times greater than those induced by the well-known mutagens 2-aminoanthracene and 2-amino-3,5-dimethylimidazo[4,5-f]quinoline. Liver microsomes isolated from rats treated with phenobarbital (PB) and a polychlorinated biphenyl mixture, Kanechlor 500, catalyzed very efficiently the activation of 6-aminochrysene to genotoxic metabolites. Treatment of rats with beta-naphthoflavone (BNF) and with dexamethasone also caused moderate induction of the microsomal activation of 6-aminochrysene. Studies employing immunoinhibition of microsomal catalytic activities and reconstitution with purified P450 enzymes suggested that the most important enzymes involved in the activation of 6-aminochrysene were P450 2B1 and 2B2; other enzymes including P450 1A1 and 1A2 participated to some extent. We also found that the microsomal activation of 6-aminochrysene was catalyzed more effectively in an acetyltransferase-overexpressing strain (NM2009) than in the original TA1535/pSK1002 strain and that these activities could be inhibited by an acetyltransferase inhibitor, pentachlorophenol, in liver microsomes from PB-treated rats, but not in those from BNF-treated rats. These results suggest that the P450/acetyltransferase system is one of the most important catalysts for the activation of 6-aminochrysene in liver microsomes of PB-treated rats, and that activation by BNF-induced P450 enzymes occurs by different mechanisms, probably through the ring oxidation pathway.

Acetyltransferases↗
PubMed1993

Hexachlorobenzene-induced hypothyroidism. Involvement of different mechanisms by parent compound and metabolite.

Rats received repeated oral treatment with different doses of hexachlorobenzene (HCB) (0-3.5 mmol/kg) for 2 or 4 weeks. Measurements of thyroid hormone status after 2 weeks showed a dose-dependent decrease of total thyroxine (TT4) levels, decreased free thyroxine (FT4) levels and little change of total triiodothyronine (TT3) levels. The effects on thyroid hormone status were more pronounced after 4 weeks and also included increased thyroid stimulating hormone (TSH) levels. These conditions suggest that HCB had induced hypothyroidism in these animals. Indications for occupation of thyroid hormone binding proteins were found in serum of exposed animals. The major metabolite pentachlorophenol (PCP) also caused, by competitive interactions with thyroid hormone binding proteins in serum, a rapid and dose-dependent decrease of TT4 and FT4 levels, but not of TT3 levels in serum. The decrease of serum TT4 levels by repeated dosing with 3.5 mmol HCB/kg for 4 weeks could be attributed to competitive interactions of PCP with hormone serum binding proteins and to increased metabolism induced by HCB to an equal degree. At lower dose levels or with shorter dosing periods, increased metabolism of T4 is the main cause of decreased TT4 serum levels. This is the first indication that a similar effect is caused simultaneously by the parent compound and its metabolite through different and independent mechanisms.

Animals↗
PubMed1983

The major role of glutathione in the metabolism and excretion of N,N-dimethyl-4-aminoazobenzene in the rat.

In the normal rat given a single dose of one mg N,N-dimethyl-4-aminoazobenzene (DAB) via the hepatic portal vein the following biliary metabolites reached their maximal rates of excretion in the sequence: 4'-sulphonyloxy-DAB, N-(glutathione-S-methylene)-4-aminoazobenzene (GSCH2AB), 4'-sulphonyloxy-N-methyl-4-aminoazobenzene (4'-sulphonyloxy-MAB) 4'-sulphonyloxy-GSCH2AB and MAB-4'-beta-glucuronide. The unusual and relatively unstable N-methylene glutathione conjugates were major metabolites accounting for up to 70% of the whole. It was shown that all the 4-aminoazobenzene (AB) and perhaps all of the 4'-sulphonyloxy-AB, which may be observed in bile, are artefacts due to decomposition of GSCH2AB and 4'-sulphonyloxy-GSCH2AB respectively and that biliary excretion of N-methyl oxidised products of MAB and 4'-hydroxy-MAB is dependent on their conversion to the GSH conjugates, GSCH2AB and 4'-hydroxy-GSCH2AB respectively. Sulphotransferase inhibition by pentachlorophenol caused a reduction in the excretion of all sulphate conjugates, but biliary excretion as a whole was not reduced significantly due to a compensatory increase in the excretion of MAB-4'-beta-glucuronide and the appearance of 4'-OH-GSCH2AB. Glutathione (GSH) depletion by diethylmaleate caused a reduction in biliary metabolites of DAB by lowering the levels of GSH conjugates. This was because the amount of N-methyl oxidation of MAB and 4'-hydroxy-MAB were proportional to the amount of GSH present. The fall in N-methyl oxidation was not compensated for by an increase in 4'-hydroxylation and was accompanied by a delay in the appearance of 4'-hydroxylated metabolites. The administration of potential precursors of 4'-sulphonyloxy-GSCH2AB establishes the sequence of reactions resulting in its formation to be 4'-hydroxylation, N-methyl oxidation, GSH conjugation and O-sulphation.

Animals↗
PubMed1984

Hepatic macromolecular covalent binding of mononitrotoluenes in Fischer-344 rats.

The mononitrotoluenes are important industrial chemicals which display isomeric specificity in their ability to induce hepatic DNA excision repair in Fischer-344 rats. Covalent binding of the structurally related hepatocarcinogen, 2,6-dinitrotoluene, to hepatic DNA is markedly decreased by prior administration of the sulfotransferase inhibitors pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP). The objectives of this study were to determine whether hepatic macromolecular covalent binding of the mononitrotoluene isomers differed and to determine whether covalent binding of the mononitrotoluenes to hepatic DNA in vivo was decreased by inhibitors of sulfotransferase. Male Fischer-344 rats were given a single oral dose of [ring-U-14C]-2-, 3- or 4-nitrotoluene (2-, 3- or 4-NT) and killed at various times thereafter. Livers were removed and analyzed for total and covalently bound radiolabel. Maximal concentrations of total radiolabel were observed between 3 and 12 h after the dose, and there were no large differences among the 3 isomers in peak concentrations achieved. Covalent binding to hepatic macromolecules was maximal 12 h after administration for all three isomers. Thereafter, concentrations of covalently bound 2-NT-derived material were always 2-6 times higher than those of 3- or 4-NT-derived material. When DNA was isolated from livers of rats given the mononitrotoluenes 12 h previously, only 2-NT was observed to covalently bind at concentrations above the limits of detection of the assay. The covalent binding of 2-NT, but not that of 3- or 4-NT, to both total hepatic macromolecules and DNA was markedly decreased by prior administration of either PCP or DCNP. Covalent binding to hepatic DNA was decreased by greater than 96%. The results of this study correlate well with studies which have demonstrated that 2-NT, but not 3- or 4-NT, induces DNA excision repair. Furthermore, they suggest that 2-NT, like the hepatocarcinogen 2,6-dinitrotoluene, requires the action of sulfotransferase for its conversion to a species capable of covalently binding to hepatic DNA.

Animals↗
PubMed1995

The metabolism and DNA binding of the cooked-food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in precision-cut rat liver slices.

Precision-cut liver slices prepared from Aroclor 1254 pretreated male rats were used to investigate the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The acetyltransferase and sulfotransferase inhibitors, pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol (DCNP), and the cytochrome P450 inhibitor, alpha-naphthoflavone (ANF), were used to modulate PhIP metabolism and DNA and protein adduct formation. PCP and DCNP had similar effects on the formation of some PhIP metabolites. PCP and DCNP decreased the formation of 4'-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate (4'-PhIP-sulfate) and 2-(hydroxyamino)-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP)-glucuronide to 10% and 55% of controls, respectively. 2-Amino-1-methyl-4'-hydroxy-6-phenylimidazo[4,5-b]pyridine (4'-hydroxy-PhIP) was increased by 50% relative to control levels due to PCP and DCNP treatment. PCP and DCNP had different effects on the formation of other PhIP metabolites. Metabolite formation as percent of control for the uncharacterized metabolite, 'Peak A', was 50% and 100% in incubations with PCP and DCNP, respectively. Formation of 4'-hydroxy-PhIP-glucuronide was decreased to 10% of controls with PCP and increased to 147% of controls with DCNP. PCP and DCNP had no effect on the formation of an unidentified metabolite, 'Peak B'. ANF decreased metabolite formation by 60-95%. None of the enzyme inhibitors had a statistically significant effect on PhIP-DNA binding. Covalent binding of PhIP to protein was slightly decreased in incubations containing DCNP or PCP. The lack of significant changes in covalent binding to either DNA or protein suggests that additional pathways may be important in PhIP bioactivation in rat liver slices. With ANF, there was a significant decrease (35%) in protein binding. These observations on the effects of PCP, DCNP and ANF on PhIP metabolism as well as on covalent binding of PhIP to tissue macromolecules are in close agreement with what was reported earlier in hepatocytes. This indicates that tissue slices from various target tissues for tumorigenesis will be a useful in vitro tool for future studies on heterocyclic amine metabolism. This study provides another important example of the utility of precision-cut tissue slices to investigate xenobiotic metabolism and toxicity.

Animals↗
PubMed1983

Effect of phenolic compounds on in vivo activity of transaminases in certain tissues of the fish, Notopterus notopterus.

Chronic effects of phenol (P), 2,4-dinitrophenol (DNP), and pentachlorophenol (PCP) individually and in three combinations, viz. (PCP + DNP)/P (highly antagonistic), (DNP + P)/PCP (additive), and (P + DNP)/PCP (highly synergistic) on in vivo activity of glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) in brain, liver, kidney, and gills of Notopterus notopterus were studied at subacute levels (1/10, 1/15, and 1/20 of 96-hr LC50) following exposure for 15 and 30 days. Significant stimulation in activity of GOT and GPT was observed in all the tissues at different concentrations of phenolic compounds after both the time intervals. However, stimulation in activity of both GOT and GPT was maximum (140.67% in GOT, 142.68% in GPT) in liver at 1/10 concentration of the (P + DNP)/PCP combination after 30 days, but minimum in gills, in case of GOT (17.29%) at 1/20 of P after 15 days and in case of GPT (7.68%) at 1/20 of the (PCP + DNP)/P combination after 30 days. Stimulatory effect of phenolic compounds on the activity of these enzymes indicates possibly the increased conversion of amino acids into keto acids and vice versa, thus resulting in the disturbance of protein metabolism.

2,4-Dinitrophenol↗