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1.
The major polychlorinated biphenyl (PCB) components identified in human breast milk have been synthesized and a reconstituted breast milk PCB mixture representing the average levels determined in the Osaka Prefecture in Japan has been prepared. The dose effecting the half-maximal (ED50) induction of rat hepatic microsomal aryl hydrocarbon hydroxylase (AHH) for the reconstituted breast milk PCBs (ED50 ~12 μmol·kg?1) was approximately seven times less than the ED50 for the commercial PCB mixture, Kanechlor 500. The increased biological potency of the former mixture reflects the preferential bioconcentration of the toxic PCB congeners, 2,3,3′,4,4′-penta-, 2,3′,4,4′,5-penta- and 2,3,3′,4,4′,5-hexachlorobiphenyl.  相似文献   

2.
A number of isomerically pure polychlorinated biphenyls (PCBs) were tested as inducers of hepatic drug-metabolizing enzymes in the rat. The chlorinated biphenyl isomers can be categorized into two distinct groups of inducers, while commercial PCB mixtures have characteristics of both groups. Biphenyls chlorinated symmetrically in both the meta and para positions (3,4,3′,4′- and 3,4,5,3′,4′,5′-) increase the formation of cytochrome P-448, the ratio of the 455 to 430 peaks of the ethyl isocyanide difference spectrum, and aryl hydrocarbon hydroxylase and glucuronyl transferase activities, but decrease aminopyrine N-demethylase activity. These isomers are also the most toxic, as measured by weight loss. Biphenyl isomers chlorinated in both the para and ortho positions induce the formation of cytochrome P-450 rather than P-448, regardless of the chlorination of the meta position. These isomers, which include 2,4,2′,4′-tetra- and 2,4,5,2′,4′,5′-, 2,3,4,2′,3′,4′- and 2,4,6,2′,4′,6′-hexachlorobiphenyls, increase cytochrome P-450 and N-demethylase activity, but produce only a slight increase in aryl hydrocarbon hydroxylase activity, and do not alter the peak of the CO-difference spectrum or the ratio of the 455/430 peaks of the ethyl isocyanide difference spectrum. Isomers which are chlorinated in only one ring, or are chlorinated in both rings but not in the para positions, have very little activity as inducers of liver enzymes. Of the dichlorobiphenyls tested, 3,3′- and 4,4′-dichlorobiphenyls have very slight activity at extremely high doses.  相似文献   

3.
Methadone . HCl given in the drinking water for 4 weeks increased microsomal epoxide hydratase activity in the liver of adult male Wistar rats, with no change in aryl hydrocarbon hydroxylase activity. In contrast, in female rats it raised aryl hydrocarbon hydroxylase with no change in epoxide hydratase activity. Gonadectomy altered the effect of methadone on epoxide hydratase, but not on aryl hydrocarbon hydroxylase activity, in both sexes. In ovariectomized rats, but not in controls, methadone nearly doubled the epoxide hydratase activity, whereas in male rats castration decreased the inductive effect of methadone. Gonadectomy had a significant effect on the results of methadone treatment with respect to glutathione S-transferase activity in female rats. A sex difference was noted in the control levels of aryl hydrocarbon hydroxylase and glutathione S-transferase, but not of epoxide hydratase activity. The glutathione S-transferase and aryl hydrocarbon hydroxylase activities were decreased in castrated male rats, whereas epoxide hydratase activity was unaltered. It is concluded that sex hormones play an important role in the induction of epoxide hydratase and glutathione S-transferase by methadone, but not of aryl hydrocarbon hydroxylase, at this particular dosage regime.  相似文献   

4.
There are significant differences between mice and hamsters in polycyclic hydrocarbon and nitrosamine metabolism. Homogenates of liver, lung and intestinal mucosa from 6 strains of Syrian golden hamster were compared for their ability to metabolize benzo[α]pyrene (BP) and dimethylnitrosamine (DMN) to mutagens. Females of strains MHA/SsLak, LSH/SsLak, CB/SsLak, PD4/Lak LHC/Lak and Lak:LVG (SYR) were either untreated or received phenobarbital (PB), 3-methylcholanthrene (MC) or polychlorinated biphenyls (AR) to induce drug-metabolizing enzymes. Salmonella typhimurium TA92 and TA98 were used as indicators of the formation of mutagens. Dimethyl-nitrosamine demethylase (DMND) was assayed using 1 mM DMN as substrate. Aryl hydrocarbon hydroxylase (AHH) was measured using benzo[α]pyrene as substrate. MC does not induce AHH activity in hamster liver, but is an excellent inducer of enzymes converting BP to mutagens. This lack of correlation between increased AHH activity and increased metabolism of BP to mutagen in liver is in marked contrast to correlations seen in mice. MC induces AHH in hamster lung and intestinal mucosa. AR induces AHH in liver, lung and intestinal mucosa. Activity of DMND in liver is not affected by treatment of hamsters with BP or AR, but is repressed approx. 30% by treatment with MC.  相似文献   

5.
The polychlorinated biphenyls mixture, Aroclor 1254, generally considered a powerful inducer of rat hepatic and pulmonary microsomal monooxygenases, caused a 70% decrease in ethylmorphine N-demethylase activity, a 31% decrease in benzo(a)pyrene hydroxylase activity, and a 42% decrease in cytochrome P-450 content in rabbit lung microsomes. When pulmonary cytochrome P-450 was solubilized and subjected to column chromatography, the elution profiles of the two forms of the hemeprotein showed a marked decrease in cytochrome P-450I in treated rabbits, with no significant alteration in cytochrome P-450II content. These data were confirmed by subjecting the two cytochromes to gel electrophoresis and staining the electrophoretic bands for protein and heme-associated peroxidase activity. Cytochromes P-450I and P-450II isolated from Aroclor 1254-treated rabbits showed differences in spectral properties as well as in their stabilities. The CO difference spectral determinations showed absorbance maxima at 452 and 450 nm for cytochromes P-450I and P-450II, respectively. At room temperature, cytochrome P-450II was much more stable than P-450I. The present studies provide evidence not only for species differences in the biological actions of the polychlorinated biphenyls but also demonstrate differential effects of the environmental pollutant on the two major forms of cytochrome P-450 and associated enzymic activities in rabbit lungs.  相似文献   

6.
There are significant differences between mice and hamsters in polycyclic hydrocarbon and nitrosamine metabolism. Homogenates of liver, lung and intestinal mucosa from 6 strains of Syrian golden hamster were compared for their ability to metabolize benzo[alpha]pyrene (BP) and dimethylnitrosamine (DMN) to mutagens. Females of strains MHA/SSLak, LSH/SlLak, CB/SsLak, PD4/Lak LHC/Lak and Lak:LVG (SYR) were either untreated or received phenobarbital (PB), 3-methylcholanthrene (MC) or polychlorinated biphenyls (AR) to induce drug-metabolizing enzymes. Salmonella typhimurium TA92 and TA98 were used as indicators of the formation of mutagans. Dimethylnitrosamine demethylase (DMND) was assayed using 1 mM DMN as substrate. Aryl hydrocarbon hydroxylase (AHH) was measured using benzo[alpha]pyrene as substrate. MC does not induced AHH activity in hamster liver, but is an excellent inducer of enzymes converting BP to mutagens. This lack of correlation between increased AHH activity and increased metabolism of BP to mutagen in liver is in marked contrast to correlations seen in mice. MC induces AHH in hamster lung and intestinal mucosa. AR induces AHH in liver, lung and intestinal mucosa. Activity of DMND in liver is not affected by treatment of hamsters with BP or AR, but is repressed approx. 30% by treatment with MC. Activity of DMND and conversion of DMN to mutagen are correlated (r = 0.59) in hamster liver. Microsomes of hamster liver are more effective than those from mouse in converting DMN to mutagen, despite similar DMND activities in livers from the two species.  相似文献   

7.
Epithelial rat liver cell line RL-19 was checked for aryl hydrocarbon hydroxylase and dimethylnitrosamine demethylase activity. Aryl hydrocarbon hydroxylase activity was found at the rate of about 14.5 pmoles 3-hydroxy-benzopyrene per min per mg protein. This activity was not inducible by 3-methylcholanthrene or by phenobarbital and was independent of the subculture level. From the 45th up to the 59th subculture the mean demethylase activity was about 1.08 nmoles HCHO per min per mg protein, but was decreased to 0.64 nmoles HCHO per min per mg protein at the 131st subculture. RL-19 cells were treated with 3-methylcholanthrene (0.5-1.0 microgram/ml), dimethylnitrosamine (100-400 micrograms/ml), or Natulan (50 micrograms/ml), respectively, for 7 to 10 days. During a 6 months subsequent cultivation no neoplastic changes were observed as revealed by morphological investigation, soft agar assay, and transplantation. It is suggested that metabolic competence for carcinogen activation is only one prerequisite for neoplastic alteration in vitro, and that RL-19 cells are refractory to the action of carcinogens in spite of their metabolic capacity.  相似文献   

8.
The optimum conditions (pH, microsomal protein amount and substrate concentration) of guinea-pig liver, lung and kidney microsomal aniline 4-hydroxylase, ethylmorphine N-demethylase and benzo[a]pyrene hydroxylase activities were determined. Male guinea-pigs weighing 500-700 g were administered 3-methylcholanthrene (25 mg/kg, i.p. 3 days), phenobarbital (75 mg/kg, i.p. 3 days), pyrethrum (120 mg/kg, i.p. 2 days) and 2,4,5-T isooctylester (200 mg/kg, i.p. 3 days). 3-Methylcholanthrene treatment caused significant increases in liver microsomal benzo[a]pyrene hydroxylase and kidney microsomal aniline 4-hydroxylase activities. However, with phenobarbital treatment the only significant increase was observed in liver microsomal ethylmorphine N-demethylase activity. Pyrethrum treatment decreased kidney microsomal ethylmorphine N-demethylase activity significantly. 2,4,5-T isooctylester treatment increased liver microsomal aniline 4-hydroxylase and lung microsomal ethylmorphine N-demethylase activities significantly. Liver microsomal NADPH-cytochrome c reductase activity was increased significantly by phenobarbital and pyrethrum treatment. The other treatments did not cause any significant changes in microsomal NADPH-cytochrome c reductase activities of liver, lung and kidney. Cytochrome P-450 content of guinea-pig liver microsomes were increased significantly about 2.5-fold and 2-fold by treatment with 3-methylcholanthrene and phenobarbital, respectively. 3-Methylcholanthrene also caused 1 nm spectral shift in the absorption maxima of CO difference spectrum of the dithionite-reduced liver microsomal cytochrome P-450, forming P-449.  相似文献   

9.
1. Syrian golden hamsters were treated with a single subcutaneous dose of 200mg of diethylnitrosamine/kg. In the liver the treatment produced a significant and early inhibition of the incorporation of orotic acid into RNA and of leucine into protein. Diethylnitrosamine also lowered basal and 20-methylcholanthrene-stimulated activities of hepatic aryl hydrocarbon hydroxylase. 2. RNA synthesis, protein synthesis and aryl hydrocarbon hydroxylase activity were also evaluated in the lungs of the same animals. In this organ only protein synthesis was affected by diethylnitrosamine, but not RNA synthesis or aryl hydrocarbon hydroxylase activity. 3. The incorporation of thymidine into DNA was inhibited in both organs early after diethylnitrosamine treatment and increased 2–3 days later. 4. Although diethylnitrosamine, injected subcutaneously, accumulates in liver and lung in toxicologically active amounts, the acute biochemical responses of the two organs are not identical.  相似文献   

10.
Biphenyl-utilizing polychlorinated biphenyls (PCB)-degrading bacteria were isolated from sites highly contamined by PCBs, and their degradation abilities were determined using GC for typical commercial PCB mixtures (Delor 103 and Delor 106). Out of twelve strains which utilized biphenyl as a sole source of carbon and energy, strainsPseudomonas alcaligenes KP2 andP. fluorescens KP12, characterized by the BIOLOG identification system and the NEFERM test, were shown to significantly co-metabolize the PCB mixture Delor 103. DNA-DNA hybridization was used to compare both strains with well-known PCB-degradersBurkholderia cepacia strain LB400 andRalstonia eutropha strain H850. The strain KP12 employs the samemeta-fission route for degradation of chlorobenzoates as a chlorobiphenyl degraderPseudomonas cepacia P166. Both isolates KP2 and KP12 belong to different phylogenetic groups, which indicates that the same geographical location does not ensure the same ancestor of degradative enzymes. We confirmed that also highly chlorinated and the most toxic congeners, which are contained in commercial PCB mixtures, can be biotransformed by members of indigenous bacterial-soil community under aerobic conditions.  相似文献   

11.
The elevation of aryl hydrocarbon hydroxylase by various microsomal enzyme inducers in mouse tissues from five inbred strains was examined in vivo and in fetal liver expiants. The magnitude of 3-methylcholanthrene- or β-naphthoflavone-inducible AHH activities in the intact animal varied greatly with the tissue and strain—from no induction in the liver and less than a 2- to 3-fold increase in the lung of DBA/2+ and AKR mice to 4- to 5- and 6- to 7-fold elevation, respectively, in the liver and lung of C57BL mice. Treatment of At or C3H+ mice with these inducers increased AHH activity in liver and lung to levels which were intermediate between those observed with tissues from DBA/2+ and C57BL mice. These strain-specific differences in the expression of AHH induction in response to polycyclic hydrocarbons and flavones were also present in fetal liver expiants and were measurable as early as 6 days before parturition. In expiants derived from polycyclic hydrocarbon-“responsive” strains, the extent of enzyme induction was greatest with 4′-bromoflavone, less with β-naphthoflavone and least with 3-methylcholanthrene. Trans-1, 2-dihydroxy-3-methylcholanthrene was about twice as effective in this regard as the parent compound 3-methylcholanthrene. Among expiants from 3-methylcholanthrene-“resistant” strains (DBA/2+, AKR), a disparity in the effects of different classes of compounds was apparent: the flavone derivatives induced aryl hydrocarbon hydroxylase activity from DBA/2+ and AKR expiants by 2- to 3-fold despite the absence of polycyclic hydrocarbon induction in these cultures. Furthermore, although phenobarbital was a comparatively weak inducer under the conditions used in these experiments, this substance stimulated aryl hydrocarbon hydroxylase activity from 3-methylcholanthrene-“responsive” and -“resistant” explants by similar degrees (i.e., about 30%). The results are discussed in the light of previous suggestions on the genetically determined regulation of aryl hydrocarbon hydroxylase induction in mouse tissues.  相似文献   

12.
Aryl hydrocarbons such as dioxins, polychlorinated biphenyls and polyaromatic hydrocarbons bind to the cellular aryl hydrocarbon receptor (AhR) in the initial step of their metabolism. The activation of intracellular signaling subsequent to the AhR binding is highly correlated with the toxicity and carcinogenicity of these chemicals. We produced Saccharomyces cerevisiae coexpressing mouse AhR and aryl hydrocarbon receptor nuclear translocator (Arnt) protein in accordance with Miller III's method for constructing yeasts with human Ahr and Arnt [Toxicol. Appl. Pharmacol. 160 (1998) 297]. Ligand treatment induced a dose-dependent increase in beta-galactosidase activity from a reporter plasmid in the yeast. Then, we compared activities of several ligands in yeast having the mouse Ahr/Arnt genes with those in yeast having the human genes, both of which have the same genetic background. There was no significant difference in the EC50 values of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), benzo[a]pyrene, 3-methylcholanthrene and beta-naphthoflavone between the mouse and human genes. However, indirubin, which was recently found in human urine as a potent AhR ligand [J. Biol. Chem. 276 (2001) 31475], had a 35-140 times higher EC50 value in the yeast with human genes than mouse genes. This difference might reflect species-specificity between mouse and human AhR/Arnt.  相似文献   

13.
Solubilized NADPH-cytochrome P-450 reductase has been purified from liver microsomes of phenobarbital-treated rats. When added to microsomes, the reductase enhances the monoxygenase, such as aryl hydrocarbon hydroxylase, ethoxycoumarin O-dealkylase, and benzphetamine N-demethylase, activities. The enhancement can be observed with microsomes prepared from phenobarbital- or 3-methylcholanthrene-treated, or non-treated rats. The added reductase is believed to be incorporated into the microsomal membrane, and the rate of the incorporation can be assayed by measuring the enhancement in ethoxycoumarin dealkylase activity. It requires a 30 min incubation at 37 degrees C for maximal incorporation and the process is much slower at lower temperatures. The temperature affects the rate but not the extent of the incorporation. After the incorporation, the enriched microsomes can be separated from the unbound reductase by gel filtration with a Sepharose 4B column. The relationship among the reductase added, reductase bound and the enhancement in hydroxylase activity has been examined. The relationship between the reductase level and the aryl hydrocarbon hydroxylase activity has also been studied with trypsin-treated microsomes. The trypsin treatment removes the reductase from the microsomes, and the decrease in reductase activity is accompanied by a parallel decrease in aryl hydrocarbon hydroxylase activity. When purified reductase is added, the treated microsomes are able to gain aryl hydrocarbon hydroxylase activity to a level comparable to that which can be obtained with normal microsomes. The present study demonstrates that purified NADPH-cytochrome P-450 reductase can be incorporated into the microsomal membrane and the incorporated reductase can interact with the cytochrome P-450 molecules in the membrane, possibly in the same mode as the endogenous reductase molecules. The result is consistent with a non-rigid model for the organization of cytochrome P-450 and NADPH-cytochrome P-450 reductase in the microsomal membrane.  相似文献   

14.
Several aerobic co-cultures capable of co-metabolizing polychlorinated biphenyls (PCBs) were acquired by cultivation on biphenyls (BP). The source of micro-organisms was PCB-contaminated soil taken from various sites in the Czech Republic. Several bacterial strains (Gram-negative rods) were isolated, and their capacity to degrade Delor 103 (a PCB mixture containing di- to hexachlorobiphenyls) was analysed. This study was focused on co-culture 319 and isolate 2. The growth parameters of both those cultures were studied on BP ; for isolate number 2 the specific growth rate μ = 0·122 (h−1) was calculated. The degradation of the individual congeners was estimated and resulted in more than 50% of the degradation of nearly all congeners during a 2-week experiment. Toxicity of Delor 103 on the vitality of the cells was followed by using viable plate count. The viability of the tested strain was preserved in the 100 times higher Delor 103 concentration compared with conditions in degradation experiments.  相似文献   

15.
The enzyme aryl hydrocarbon hydroxylase is present in murine and human cultures of keratinocytes. While the activity of aryl hydrocarbon hydroxylase in murine cultures was found to be inducible after exposure to benz(a)anthracene, human keratinocytes originating from the hair follicle did not respond to this treatment. Hence, cultured human keratinocytes are not suitable for studying the molecular events that mediate the proces of aryl hydrocarbon hydroxylase induction.  相似文献   

16.
Microscope immersion oil when administered intraperitoneally or applied to skin in experimental animals substantially increased liver weight, microsomal protein, NADPH-cytochrome c reductase activity, cytochrome P-450 content and the metabolism of the model substrates, ethylmorphine and benzo(a)pyrene. Immersion oil caused the induction of the polycyclic hydrocarbon type of hemoprotein, cytochrome P-448. When applied to skin, the oil also caused an 11-fold increase in benzo(a)pyrene hydroxylase activity at the skin sites.  相似文献   

17.
The effects of tetrahydrofuran (THF) on rat liver microsomes in vitro and in vivo were opposite. In vitro THF inhibited the p-nitrophenol (PNP) hydroxylase activity of microsomes from control rats and from rats treated with PB, acetone, and isoniazide--by 50, 20, 60, and 80%, respectively. THF inhibited dimethylnitrosamine (NDMA) demethylation in control and induced microsomes in a lesser degree. THF increased the total cytochrome P-450 content as well as the contents of cytochromes P-450IIE1 and P-450IIB1/B2. The activities of PNP-hydroxylation and NDMA-demethylation increased also, whereas the PR-dealkylation activity was unchanged. An increase in the THF dose caused inhibition of the rat liver microsomal monooxygenase system.  相似文献   

18.
A 4-S protein which specifically binds [3H]benzo(a)pyrene and other polycyclic aromatic hydrocarbons has been investigated in the rat using a hydroxylapatite assay and sucrose gradient analysis. Although there was significant interanimal variation, the specific polycyclic aromatic hydrocarbon binding activity appeared to be highest in 4-week-old male rats and declined with age. The specific [3H]benzo(a)pyrene binding activity was induced after pretreatment with either phenobarbital or isosafrole as evidenced by a 72 and 61% increase, respectively, over untreated controls. No apparent increase in specific binding activity was observed after pretreatment of animals with 3-methylcholanthrene. Pretreatment with either phenobarbital or isosafrole also resulted in the appearance of a small, nonspecific, benzo(a)pyrene binding peak at the 8- to 9-S region in the sucrose density gradients. This 8-S peak was not seen in untreated control animals and represented low affinity, high capacity binding sites. In contrast to the 8-S protein, the 4-S binding protein had low affinity for polychlorinated aromatic compounds such as tetrachlorodibenzodioxin and tetrachlorodibenzofuran. The addition of a 200-fold excess of tetrachlorodibenzofuran to incubations did not displace [3H]benzo(a)pyrene from the 4-S protein. The addition of sodium molybdate to isolation buffers, known to stabilize certain hormone receptors, did not alter the sedimentation coefficient or the specific binding activity of the 4-S protein. These experiments indicate that the 4-S protein does not appear to be a subunit of the 8-S protein. We conclude that in the rat the 4-S protein is distinct from the 8-S protein and the 4-S species may regulate the polycyclic aromatic hydrocarbon-induced expression of aryl hydrocarbon hydroxylase activity.  相似文献   

19.
Ability to utilize a technical mixture of polychlorinated biphenyls (PCB), Delor 103, as the sole carbon source, has been tested in 14 bacterial strains. For the five best growing strains (Alcaligenes latus, Alcalgenes eutrophus, Comamonas testosteroni, Micrococcus varians and Pseudomonas putida), the dependence of the degradation of individual PCB congeners on the number of chlorine substituents is discussed.  相似文献   

20.
Solubilized NADPH-cytochrome P-450 reductase has been purified from liver microsomes of phenobarbital-treated rats. When added to microsomes, the reductase enhances the monoxygenase, such as aryl hydrocarbon hydroxylase, ethoxycoumarin O-dealkylase, and benzphetamine N-demethylase, activities. The enhancement can be observed with microsomes prepared from phenobarbital- or 3-methylcholanthrene-treated, or non-treated rats. The added reductase is believed to be incorporated into the microsomal membrane, and the rate of the incorporation can be assayed by measuring the enhancement in ethoxycoumarin dealkylase activity. It requires a 30 min incubation at 37°C for maximal incorporation and the process is much slower at lower temperatures. The temperature affects the rate but not the extent of the incorporation. After the incorporation, the enriched microsomes can be separated from the unbound reductase by gel filtration with a Sepharose 4B column. The relationship among the reductase added, reductase bound and the enhancement in hydroxylase activity has been examined. The relationship between the reductase level and the aryl hydrocarbon hydroxylase activity has also been studied with trypsin-treated microsomes. The trypsin treatment removes the reductase from the microsomes, and the decrease in reductase activity is accompanied by a parallel decrease in aryl hydrocarbon hydroxylase activity. When purified reductase is added, the treated microsomes are able to gain aryl hydrocarbon hydroxylase activity to a level comparable to that which can be obtained with normal microsomes. The present study demonstrates that purified NADPH-cytochrome P-450 reductase can be incorporated into the microsomal membrane and the incorporated reductase can interact with the cytochrome P-450 molecules in the membrane, possibly in the same mode as the endogenous reductase molecules. The result is consistent with a non-rigid model for the organization of cytochrome P-450 and NADPH-cytochrome P-450 reductase in the microsomal membrane.  相似文献   

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