摘要:

Acetaminophen (APAP) toxicity has been closely associated with covalent binding to a cytosolic protein of approximately 58 kDa (58‐ABP). To determine if metabolites of other toxicants might also selectively target this protein, studies were conducted with bromobenzene (BrB). Mice were given phenobarbital (80 mg/kg/d × 4 d) and were killed 4 h after challenge with 800 mg BrB/kg. Liver cytosols from BrB‐treated or naive mice were incubated with an APAP activating system. Cytosolic fractions were analyzed for APAP binding by Western blotting with anti‐APAP antibody. Binding to 58‐ABP was selectively decreased in liver cytosol from BrB‐treated mice while binding to other targets was minimally affected. Western blotting of the same samples with anti‐58‐ABP antisera showed that this decrease in binding did not result from diminished 58‐ABP content. HPLC analysis of APAP‐N‐acetyl cysteine conjugate formation in vitro indicates that APAP activation was not altered in the incubates with cytosol from BrB‐treated mice. These results suggest that the 58‐ABP may be a common target for electrophiles in reactive intermediate toxicity.

ISSN:0098-4108    

DOI:10.1080/15287399509532034

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Cytochrome P‐450 (CYP) induction (consisting of increases in cellular RNA and protein content and associated catalytic activities) occurs predominantly in the liver, but also in small intestine, lung, kidney, and placenta, of Norway rats (Rattus norvegicus.) exposed to certain types of potential environmental contaminants. The specific isoform(s) induced in the rat and the magnitudes of the increases observed depend upon the chemical nature of the xenobiotic. For instance, the predominant isoforms induced by nonhalogenated polycyclic aromatic hydrocarbons, such as petroleum derivatives and coal‐tar constituents such as the benzopyrenes and the anthracenes, are those of the CYP1A subfamily. Poly‐halogenated aromatic hydrocarbons, such as the halogenated dibenzodioxins, dibenzofurans, and biphenyls, may cause the induction of predominantly the CYP1A subfamily, predominantly the CYP2B subfamily, or mixed CYP1A‐ and CYP2B‐type induction, depending upon the halogen substitution pattern. In contrast, the chlorinated hydrocarbon pesticides, such as DDT, dieldrin, chlordane, and mirex, cause almost exclusively the induction of isoforms of the CYP2B (and to a lesser extent the CYP3A) subfamilies. The commonly employed plasticizing agent di‐(2‐ethylhexyl)phthalate elicits predominantly induction of the CYP4A subfamily. Those xenobiotics that would be expected to be the most pervasive environmental contaminants are typically those that have also been found to cause the most profound CYP induction responses. Such chemicals are extremely lipophilic and tend to accumulate in animal tissues, especially fatty tissues such as the liver. The hepatic CYP induction response to such potential environmental contaminants is typical of the animals’ response to lipophilic xenobiotics in general, and serves as a mechanism by which the excretion of such compounds from the body is facilitated.

ISSN:0098-4108    

DOI:10.1080/15287399509532035

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Organochlorine compounds have been analyzed in human samples from residents of Genoa, a city in Northern Italy. Twenty‐eight specimens of adipose tissue from 17 males and 11 females deceased from accidental causes in March and April 1989 were examined. In 12 of the 17 males, liver tissue specimens were also analyzed. DDE was the major organochlorine pesticide (OCP) found in all human adipose tissues (395 ± 264 ng/g); additional OCPs found in our series of human subjects with an occurrence greater than 80% included p,p‐DDT (64 ± 31 ng/g), lindane (104 ± 93 ng/g), and beta‐BHC (213 ± 260 ng/g). Statistical analysis showed positive correlation of DDE and p,p‐DDT with age with an annual increase of 7 ng/yr and 0.9 ng/yr, respectively. No statistically significant differences were found (or OCPs concentration between sexes. The DDE to SDDT (o,p‐DDT + p,p‐DD7 + o,p‐TDE + p,p‐TDE) ratio changed in the last two decades from 0.95 (1966) to 5.2. Significant correlation was found between paired liver‐adipose tissues concentrations of DDE and p,p‐DDT (1: 2 ratio). No correlation was found between age of subjects and the DDE to SDDT ratio. This study indicates that the ban on DDT use as a pesticide has been largely effective in Liguria, as supported by the lower concentrations of the compound in youngsters and the increase in the DDE to SDDT ratio with time. However, other data, such as the lack of correlation between age of subject and the DDE to SDDT ratio, indicate that intake of minimal amounts of DDT may have taken place even recently. This intake could depend on contamination of food imported from abroad or on illegal, or incorrect, use of these compounds in Italy.

ISSN:0098-4108    

DOI:10.1080/15287399509532036

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Rainbow trout, dosed orally with 0.060–84 μg/kg of [3H]–2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), [14C]‐1,2,3,4,7,8‐hexachlorodibenzo‐p‐dioxin (HxCDD), or [14C]‐1,2,3,4,6,7,8‐heptachlorodibenzo‐p‐dioxin (HpCDD) showed dose‐dependent increases in hepatic ethoxyresorufin O‐deethylase (EROD) activity, up to 250‐fold, after 2–16 d. Induction of EROD activity was a sensitive and rapid indicator of exposure to PCDDs. The effects of time after exposure were not dramatic, but generally EROD activity after 2 d was lower than EROD activity after 16 d. Slopes of dose‐response curves relating EROD activity to hepatic concentrations of PCDDs significantly decreased and intercepts significantly increased with increasing time of exposure. When fish were grouped by oral doses, only the low doses of TCDD and HpCDD exhibited time‐dependent EROD induction, with significantly greater activity 16 d after dosing compared to 2 d. In most cases, hepatic and muscle concentrations of PCDDs did not significantly change over time. Concentrations of PCDDs in liver and muscle accounted for up to 7% of the orally administered dose. Hepatic levels of PCDDs ranged from 20–100 pg/g at the lowest doses to about 1000 pg TCDD/g, 2000 pg HxCDD/g, or 40,000 pg HpCDD/g at the highest doses. Of the PCDD in the liver, approximately one‐third to one‐half was associated with the postmitochondrial supernatant (PMS). PCDD concentrations in muscle did not span as wide a range of concentrations as did PCDD in liver; fish given low doses had 10 pg/g in muscle whereas fish given high doses had several hundred picograms per gram in muscle for all three PCDDs.

ISSN:0098-4108    

DOI:10.1080/15287399509532037

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Previous results in Sprague‐Dawley rats indicate that acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK) pretreatment (3 d, po) at dosages of 6.8 and 13.6 mmol/kg potentiate CCl4hepatotoxicity and CHCl3nephrotoxicity, respectively. The potentiation potency profile observed was MiBK > A > MEK for liver and A > MEK ≥ MiBK for kidney toxicity (Raymond & Plaa, 1995). In the present study, hepatic and renal microsomes from A‐, MEK‐, and MiBK‐pretreated rats (6.8 or 13.6 mmol/kg) were examined for cytochrome P‐450 content, substrate‐specific monooxygenase activity (aminopyrine and benzphetamine N‐demethylase, aniline hydroxylase) and in vitro covalent binding of14CHCl3and14CCl4. Of the three ketones, only MiBK significantly increased P‐450 content of liver and renal cortical microsomes. Similarly,14CCl4covalent binding under aerobic and anaerobic conditions was significantly increased by MiBK pretreatment only.14CHCl3covalent binding by renal cortical microsomes was significantly increased only under aerobic conditions by MiBK pretreatment. MiBK (13.6 mmol/kg) increased (threefold) aminopyrine N‐demethylation in both liver and kidney, but only benzphetamine N‐demethylation (twofold, at 6.8 and 13.6 mmol/kg) in liver; A and MEK had no effect on either monooxygenase. All ketones at dosages of 6.8 and 13.6 mmol/kg increased aniline hydroxylation in liver (two‐fold) and kidney (fivefold). Comparable profiles for P‐450 induction, haloalkane covalent binding, and aminopyrine or benzphetamine N‐demethylase activity were observed in liver and kidney microsomes. This profile was consistent with the ketone potentiation potency ranking profile observed in vivo for liver but not kidney injury. These findings affirm the importance of ketone‐enhanced bioactivation for potentiation of CCl4hepatotoxicity but suggest an alternative mechanism for CHCl3nephrotoxicity.

ISSN:0098-4108    

DOI:10.1080/15287399509532038

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

We have investigated the possibility that tumor necrosis factor α (TNF) plays a role in the increased airway permeability and an inflammatory response following an acute ozone (O3) exposure. Male Sprague‐Dawley rats were injected, intraperitoneally, with either rabbit anti‐mouse antibody to TNF (anti‐TNF) or preimmune rabbit serum, 2 h before a 3‐h exposure to O3or purified air. Permeability, as determined by [99mTc] diethylenetriamine pentaacetate (DTPA) transport, total protein and albumin concentrations in the bron‐choalveolar lavage (BAL), and the inflammatory cell response in the BAL were assessed 10 h after the exposure was completed. The O3‐exposed group that was injected with anti‐TNF showed a significant decrease in permeability to DTPA in comparison to the O3‐exposed group injected with preimmune rabbit serum. There was no difference between the anti‐TNF group and the purified air group. In contrast, the total protein and albumin levels in the BAL were significantly greater in both of the O3‐exposed groups than in the purified air group. The concentrations of protein and albumin in the anti‐TNF group did, however, show an attenuating trend when compared to the preimmune O3‐exposed group. The polymorphonuclear leukocytes (PMNs) in BAL of the anti‐TNF group also showed an attenuating trend when compared to the preimmune O3‐exposed group, but both of these O3‐exposed groups were significantly greater than the purified air group. Lung sections stained with naphthol AS‐D chloroacetate esterase showed an increase in the number of stained PMNs in the anti‐TNF group in comparison to the preimmune O3‐ and air‐exposed groups. These data suggest that TNF plays a role in the increase in tracheal permeability as determined by DTPA transport, while the contributing role that TNF plays in bronchoalveolar permeability and the inflammatory response seen following an acute exposure to 0.8 ppm O3is less evident.

ISSN:0098-4108    

DOI:10.1080/15287399509532039

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

The mechanism by which methylmercury is cleared from hepatic portal blood was examined in isolated rat livers perfused single‐pass with Krebs‐Henseleit buffer. [203Hg]Methylmercury (0.24–24 μM) was infused over a 30‐min interval, followed by a 30‐min washout, as a complex with the endogenous ligands L‐cysteine (CH3Hg‐L‐cys), glutathione (CH3Hg‐SG), and serum albumin (CH3Hg‐albumin), or as a complex with dithiothreitol (CH3Hg‐DTT), chloride (CH3HgCl), and the D‐enantiomer of cysteine (CH3Hg‐D‐cys). The sulfhydryl‐containing compounds were added at a 10‐fold molar excess. When administered as the albumin complex, only a small fraction of the [2O3Hg]methylmercury was cleared from perfusate (∼8%) and excreted into bile (0.7%). Hepatic uptake and biliary excretion of methylmercury was considerably higher for the other complexes: The percent of the dose recovered in liver tissue and bile was, respectively, CH3Hg‐albumin, 6.9 and 0.7; CH3Hg‐L‐cys, 15.7 and 2.3; CH3Hg‐D‐cys, 27.1 and 2.8; CH3Hg‐SC, 17.7 and 2.1; CH3HgCl, 66.5 and 3.2; and CH3Hg‐DTT, 70.1 and 19.8. For the dithiothreitol complex, hepatic extraction of methylmercury was nearly complete during single‐pass perfusion. A comparison of hepatic removal of increasing doses of CH3Hg‐L‐cys and CH3Hg‐D‐cys revealed little difference in uptake between these two enantiomers. Moreover, the fraction of methylmercury removed was similar when infused at concentrations of 0.24, 2.4, and 24 μM, indicating no saturability of uptake within this dose range. Methylmercury was not hepatotoxic at concentrations up to 24 μM if administered as a mercaptide; however, the chloride complex (CH3HgCl) produced cholestasis and an increase in perfusion pressure at a concentration of only 0.24 μM. These findings indicate that hepatic methylmercury uptake and toxicity are dependent on the chemical form in blood plasma. Uptake was faster when methylmercury was present as a cysteine or glutathione complex, as compared to the albumin complex; however, the lack of stereoselectivity indicates that the uptake process may be relatively unselective.

ISSN:0098-4108    

DOI:10.1080/15287399509532040

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Pregnant Swiss mice were treated with 0, 5, 10, 20, and 30 mg/kg body weight of bis(tri‐n‐butyltin) oxide (TBTO) on d 6–15 of gestation. At birth litters were normalized to eight pups, and postnatal evaluation of pup growth rate and behavioral observations of dams were carried out. Litters were sacrificed on postnatal days (pnd) 7, 14, and 21, to perform hematological analysis, in connection with another study. Dam weight gain was impaired in all the treated groups (except at the lowest dose level) in the late phase of gestation. A high incidence of anticipated or delayed parturitions, without any correlation with fetal mass, was observed in the treated groups. All the treated dams showed a significant increase in resorptions, and a decrease in body weight gain between gestational day (gd) 6 and pnd 1. At birth, only the 20 and 30 mg/kg dose groups showed reduced litter size and reduced pup weight. Body weight gain reduction of pups persisted in wk 1 of life only in the 10 and 20 mg/kg dose groups. In addition, the maternal weight trend was affected during the lactation period in the higher dose groups. Postnatal death rate and growth rate of treated pups were affected by an altered maternal behavior; pups, apparently viable and with normal weight, were found often scattered throughout the cage with signs of wounds, and the percentage of dams that had not built a nest increased in the 10, 20, and 30 mg/kg dose groups. Total absence of parental care was noted in many litters, and many infanticidal events were reported. Our results seem to confirm low TBTO embryo‐fetotoxicity, and strongly support the assumption that TBTO's toxicity to the mother is much stronger than its embryo‐fetotoxic potential. Most of the reproductive parameters examined in this study were unaffected in the low‐dose group, while some indices, such as gestation length and maternal weight gain between gd 6 and pnd 1, were markedly altered also at the 5 mg/kg dose level and appear to be sensitive parameters in assessing maternal toxicity.

ISSN:0098-4108    

DOI:10.1080/15287399509532041

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

The effect of in utero TBTO exposure on blood composition in neonates, pups during weaning, and dams in the same period were investigated in mice. The dams were gavaged at dose levels 0, 5, 10, and 20 mg TBTO/kg body weight on gestational days 6–15. At birth, litters were culled to eight pups, and blood analysis was performed on excess pups. On d 7, 14, and 21 the entire litters were sacrificed and blood (WBC, RBC, HGB, HCT, MCV, MCH, MCHC, and differential leukocyte count) of dams and pups was analyzed. Blood analysis of neonates revealed enhanced WBC count and altered red‐cell parameters. Increase in WBC persisted until postnatal day (pnd) 21, while red‐cell parameters regained normal values on pnd 7. No significant differences were found in thymus and spleen weights in the treated groups. Dams presented no alteration in blood composition or of spleen or thymus weights. The results of this investigation revealed that in utero exposure to TBTO induces a nonspecific alteration of hematological parameters in mice, but further studies are necessary to understand whether our results are either dependent on maternal status or a direct effect of TBTO on embryonic tissue.

ISSN:0098-4108    

DOI:10.1080/15287399509532042

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Arsenic—thiol interactions were investigated by determining changes in rat blood sulfhydryls after exposure to arsenate, As(V), or arsenite, As(III). Incubation with As(V) resulted in time‐and dose‐dependent depletion of nonprotein sulfhydryls (NPSH), specifically glutathione (GSH). At the highest As(V) concentration (10 mM), significant loss of glutathione was only observed after 3 h of incubation, but by 5 h 0.5 mM As(V) and higher was sufficient to deplete CSH. As(V) was reduced to As(III) at all dose levels, indicating a redox interaction with GSH, but oxidized glutathione (GSSG) was not formed in sufficient quantities to account for losses in GSH. This may be due to formation of another oxidized species such as a protein‐mixed‐disulfide (ProSSG). Further evidence that glutathione reduces arsenate was obtained by pretreating cells with the sulfhydryl derivatizing agent N‐ethylmaleimide (NEM). Removal of thiols with NEM severely inhibited the formation of As(III) in these incubations, indicating that the main pathway for arsenate reduction in red cells is sulfhydryl dependent. As(III) demonstrated a completely different profile of sulfhydryl interaction. Sulfhydryls (NPSH and GSH) were depleted but the losses were primarily accounted for by oxidation to CSSC. As(III) was also a more potent sulfhydryl depleting agent, requiring only 0.1 mM As(III) to significantly reduce GSH after 5 h of incubation. Significant levels of GSSG formed at all doses of As(III). Evidence is presented to suggest that As(III) also formed mixed complexes with protein and glutathione. Samples that were acid precipitated displayed loss of cytosolic glutathione, which could be reversed if NEM was added prior to protein precipitation. Arsenic was detected in high quantities in the protein precipitates, and this was also found to be reversible by NEM treatment. The fact that both GSH depletion and protein binding were reversible by NEM treatment points to formation of a mixed complex of protein, GSH, and As(III), possibly ProS‐As‐(SG)x. Arsenic affinity chromatography and polyacrylamide gel electrophoresis were used to characterize arsenic binding proteins in red‐cell cytosol. The main arsenic binding protein appeared to be hemoglobin.

ISSN:0098-4108    

DOI:10.1080/15287399509532043

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor