bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of hypergastrinemia in the antiatrophy effect of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin on oxyntic gland mucosa of the rat stomach
Authors: Michael Theobald H. , Mably Thomas A. , Ingall Glynnis B. , Peterson Richard E. 
Published: October 2006

AbstractAtrophy of the gastrointestinal mucosa that occurs in pair‐fed control rats is not observed in 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD)‐treated rats (1). Our objective was to determine if the gastrointestinal trophic hormone, gastrin, is involved in the antiatrophy effect of TCDD on the gut mucosa. Adult male Sprague‐Dawley rats treated with 100 μg/kg of TCDD were slightly hypergastrinemic 7 days after dosing and markedly hypergastrinemic 14 days after treatment whereas pair‐fed control rats were normogastrinemic. After 14 days of feed restriction, atrophy of the oxyntic gland and ileum mucosa occurred in pair‐fed control rats but only atrophy of the ileum mucosa developed in TCDD‐treated animals. The oxyntic gland mucosa of TCDD‐treated rats was protected from mucosa atrophy as well as from mucosa erosions. The protection against feed restriction‐induced atrophy was demonstrated by measurements of oxyntic gland mucosal height and DNA and protein content. Since hypergastrinemia stimulates growth of oxyntic gland mucosa, but not ileum mucosa, the antiatrophy effect of TCDD on mucosa of the oxyntic gland might in part be due to hypergastrinemia. In support of this interpretation, TCDD treatment exerted an antiatrophy effect on the oxyntic gland mucosa only when TCDD‐treated animals were hypergastrinemic. For example, hypergas‐trinemia does not develop within the first 48 hr after TCDD administration, and TCDD treatment affords no protection against fasting‐induced atrophy of the oxyntic gland mucosa during this time. On the other hand, the ability of TCDD treatment to protect against feed restriction‐induced erosions of the oxyntic gland mucosa might be mediated by hypergastrinemia since these events occur at a later time. It is unlikely, however, that increased gastric mucosa production of cytoprotective prostaglandins is involved in the antierosion action of TCDD, because TCDD treatment does not protect the oxyntic gland mucosa against ethanol‐ or indomethacin‐induced erosions. The significance of these findings is that this is one of the first reports of a gastrointestinal trophic hormone, gastrin, being involved in the mechanism of action of TCDD.
Periportal hepatotoxicity due to allyl alcohol: A myriad of proposed mechanisms
Authors: Badr Mostafa Z. 
Published: October 2006

AbstractIt has long been recognized that periportal and centrilobular regions of the liver lobule differ in their sensitivity to many hepatotoxins. For example, carbon tetrachloride damages centrilobular regions while allyl alcohol damages periportal areas of the liver lobule (1). One determinant of the selective susceptibility of different areas of the liver lobule to chemically induced injury is believed to be the sublobular distribution of enzymes involved in detoxification, or activation to more toxic metabolites (2–4). In addition to sublobular enzyme activity, substrate delivery and the availability of necessary cofactors can influence the zone‐specific toxicity of some chemicals. Furthermore, it has been proposed that oxygen gradient across the liver lobule is an important determinant of zonal hepatotoxicity. Thus, studies regarding the zone‐specific nature of hepatotoxicants require that a variety of complex interrelated metabolic processes be considered, and so far exact mechanisms responsible for zone‐selective hepatotoxicity are not completely understood.
Interaction of benzanthrone with cytochrome p450: Altered patterns of hepatic xenobiotic metabolism in rats
Authors: Das Mukul , Garg Kalpana , Joshi Anjulika , Singh Giriraj B. , Khanna Subhash K. 
Published: October 2006

AbstractBenzanthrone, an anthraquinone dye intermediate, is commonly used for the synthesis of a number of polycyclic vat and disperse dyes. Our prior studies have shown that benzanthrone can be metabolized by rat hepatic microsomal cytochrome P450 (P450) (Biochem. Int., 18, 1989, 1237). In this study, the interaction of benzanthrone with rat hepatic microsomal P‐450 and its effect on xenobiotic metabolism have been investigated. Parenteral administration of benzanthrone (40 mg/kg body weight) for 3, 7, or 21 days caused no change in the relative body weight or organ weight of rats. The levels of P450 were found to be reduced (33%‐50%) in all the benzanthrone‐exposed animals at all the time periods. In vitro addition of benzanthrone caused a spectral change with oxidized P450 and concentration‐dependent reduction in the carbon monoxide spectrum of dithionite‐reduced P450. The addition of benzanthrone to hepatic microsomes prepared from phenobarbital‐treated rats resulted in spectral changes characterized by an absorbance maximum at 397 nm indicative of type I binding. In vitro addition of benzanthrone showed a concentration‐dependent inhibition of hepatic aminopyrine N‐demethylase (APD) and ethoxyresorufin‐O‐deethylase (ERD) activities with respective I50 values of 9.5 × 10−4 and 8.0 × 10−5 M. However, the inhibition of aryl hydrocarbon hydroxylase (AHH) even at the highest concentration of benzanthrone (10−2 M), was of the order of only 29%. In vivo administration of benzanthrone also led to the inhibition of APD, AHH, and ERD activities at all treatment times although the magnitude of inhibition was of a lower order. Benzanthrone treatments caused significant depletion of glutathione content with a concomitant enhancement of lipid peroxidation. Also, benzanthrone resulted in a significant inhibition of the cytosolic enzyme, GSH‐transferase (23%–34%), although the other enzyme, quinone reductase, which helps in the removal of toxic quinones, was found to be elevated (184%–199%). These results suggest several mechanisms by which benzanthrone may inhibit P450. This impairment of xenobiotic metabolism as well as the enhancement of lipid peroxidation may be relevant to the observed symptoms of benzanthrone‐induced hepatotoxicity.
Effects of diethyldithiocarbamate (ddtc) on the plasma biotransformations of tetrachloro(d,i‐trans)‐1,2‐diaminocyclohexaneplatinum(iv) (tetraplatin) in fischer 344 rats
Authors: Carfagna Patrick F. , Wyrick Steven D. , Holbrook David J. , Chaney Stephen G. 
Published: October 2006

AbstractWe have studied the effects of diethyldithiocarbamate (DDTC) on the biotransformations of toxic doses of tetrachloro (d,l‐trans)1,2‐diaminocyclohexaneplatinum(IV) (tetraplatin) in Fischer 344 rats. In animals not treated with DDTC, tetraplatin was rapidly converted to dichloro(d,I‐trans)1,2‐diaminocyclohexaneplatinum(II) [PtCl2(dach]. Subsequent biotransformations included the transient formation of the (d,I‐trans)1,2‐diaminocyclohexane‐aquachloroplatinum(II) [Pt(H2O)(Cl)(dach)]+ complex, followed by formation of the platinum (Pt)‐methionine and either Pt‐cysteine or Pt‐ornithine complexes. Significant amounts of free (d,I‐trans) 1,2‐diaminocyclohexane (dach) were observed in plasma as a result of intracellular trans‐labilization reactions. DDTC caused a marked decrease in both total and protein‐bound platinum in the circulation. A significant increase in the plasma concentration of free dach was also observed as a result of formation of the Pt(DDTC)2 complex. Some of the free dach could have arisen from intracellular reactions with DDTC, but the displacement of platinum from plasma proteins was more than sufficient to account for the increase in free dach in the circulation. DDTC treatment also decreased plasma concentrations of tetraplatin, PtCl2(dach), [Pt(H2O)(Cl)(dach)]+, the Pt‐methionine complex, and one unidentified biotransformation product, but had no effect on the Pt‐cysteine (or Pt‐ornithine) complex. These effects of DDTC on protein‐bound platinum and low‐molecular‐weight biotransformation products in plasma may contribute to the decrease in tetraplatin toxicity seen in DDTC‐treated rats.
Evidence for stimulated glutathione synthesis by phenobarbital pretreatment during an oxidative challenge in isolated hepatocytes
Authors: Utley William S. , Mehendale Harihara M. 
Published: October 2006

AbstractHepatocytes isolated from phenobarbital‐pretreated and naive male Sprague‐Dawley rats were preincubated with 80 μM N, N‐bis (2‐chloroethyl)‐N‐nitrosourea and subsequently exposed to varying concentrations of menadione. We observed that the reduced glutathione levels of the hepatocytes isolated from the sodium phenobarbital(PB)‐pretreated, but not the naive rats, recovered to near‐control levels after exposure to 200 μM menadione. Since this recovery occurred in the presence of N, N‐bis (2‐chloroethyl)‐N‐nitrosourea (an inhibitor of glutathione reductase), we hypothesized that this represented a PB‐mediated increase in de novo synthesis of glutathione. To test this hypothesis and to further assess the possible contribution of glutathione reductase in the recovery of the glutathione levels, we preincubated hepatocytes isolated from PB‐pretreated and naive rats with 2 mM buthionine sulfoximine, with or without N, N‐bis (2‐chloroethyl)‐N‐nitrosourea. Following exposure to menadione, samples were periodically removed for glutathione assessment. Consistent with our hypothesis, the addition of buthionine sulfoximine abrogated the ability of the PB‐pretreated hepatocytes to restore glutathione levels following a menadione challenge. Buthionine sulfoximine in combination with N, N‐bis (2‐chloroethyl)‐N‐nitrosourea completely abolished hepatocellular glutathione homeostasis for all of the concentrations of menadione employed. The findings from this investigation underscore the importance of phenobarbital‐mediated increases in glutathione synthesis, as well as the enhanced levels of glutathione reductase, in maintaining the pool of reduced glutathione and ultimately mitigating the consequences of oxidative stress. In addition, these findings suggest that PB pretreatment increases the reserve capacity of the hepatocyte for glutathione synthesis via a hitherto undescribed hormetic mechanism, a reserve expressed fully only on an oxidative stress of sufficient magnitude.
Glutathione S‐transferase‐catalyzed conjugation of 9,10‐epoxystearic acid with glutathione
Authors: Sharma Rajendra , Gupta Sanjiv , Singhal Sharad S. , Ansari G. A. S. , Awasthi Yogesh C. 
Published: October 2006

AbstractThe possible role of glutathione S‐transferases (GST) in detoxification of fatty acid epoxides generated during lipid peroxidation has been evaluated. Present studies showed that cytosolic human glutathione S‐transferases belonging to α, H, and μ classes isolated from human liver and lung catalyzed the conjugation of glutathione and 9,10‐epoxystearic acid. The product of enzymatic reaction, i.e., conjugate of GSH and epoxystearic acid, was isolated and characterized. The Michaelis constant (Km) values of the α, μ, and π classes of GSTs for 9,10‐epoxystearic acid were found to be 0.47, 0.32 and 0.80 mM, respectively, whereas the maximal velocity (V max) values for the α, μ, and π classes of GSTs were found to be 142, 256, and 52 mol/min/mol, respectively. These results indicate that even though 9,10‐epoxystearic acid is a substrate for all the three classes of GSTs, the μ class isozymes have maximum activity toward this substrate and may preferentially metabolize fatty acid epoxides more effectively as compared to the other classes of GSTs.
Purified NAD(P)H‐quinone oxidoreductase enhances the mutagenicity of dinitropyrenes in vitro
Authors: Hajos Antal K. D. , Winston Gary W. 
Published: October 2006

AbstractThe effect of highly purified rat liver cytosolic NAD(P)H‐quinone oxidoreductase [EC 1.6.99.2] on the mutagenicity of 1,3‐ 1,6‐ and 1,8‐dinitropyrene (DNP) was studied in the Ames Salmonella typhimurium mutagenicity assay. NAD(P)H‐quinone oxidoreductase over the range of 0.02–0.8 μ g/plate (38–1500) units increased up to threefold the mutagenicity of all three DNPs in S. typhimurium TA 98. In TA98NR, a strain deficient in “classical” nitroreductase, the mutagenicity of 1,6‐ and 1,8‐DNP was essentially unchanged, whereas that of 1,3‐DNP was markedly reduced. NAD(P)H‐quinone oxidoreductase enhanced the mutagenicity of 1,6‐ and 1,8‐DNP to approximately equivalent extents in TA98NR and TA98. The mutagenicity of 1,3‐DNP in TA98NR was potently enhanced by the addition of NAD(P)H‐quinone oxidoreductase in a dose‐responsive manner. In the presence of 0.8 μg NAD(P)H‐quinone oxidoreductase, 1,3‐DNP displayed a mutagenic response in TA98NR that was comparable to that obtained in TA98. NAD(P)H‐quinone oxidoreductase was found to increase the mutagenicity of 1,6‐ but not 1,3‐ or 1,8‐DNP to mutagenic intermediates in TA98/1,8‐DNP6, a strain deficient in O‐acetyltransferase activity. The results suggest that NAD(P)H‐quinone oxidoreductase not only catalyzes reduction of the parent DNP but also that of partially reduced metabolites generated from that DNP. Such reductive metabolism may lead to increased formation of the penultimate mutagenic species.
Ovarian toxicity of hexachlorobenzene (HCB) in the superovulated female rat
Authors: Foster Warren G. , Pentick Julie A. , McMahon Avril , Lecavalier Pierre R. 
Published: October 2006

AbstractHexachlorobenzene (HCB) is a persistent environmental contaminant which has been measured in human serum, fat, semen, and follicular fluid. In animal testing HCB has been shown to be a reproductive toxin. Discrepant results were obtained from prior studies concerning the effect of HCB treatment on ovarian steroidogenesis. The current study was designed to assess the impact of HCB on the ovary and gonadal steroid levels in the superovulated rat. Female Sprague‐Dawley rats (n = 24) were dosed with HCB (0.0, 1.0, 10.0, or 100.0 mg/kg BW/day) for 21 days. All rats received 10 IU pregnant mare serum gonadotropin (PMSG) s.c. on day 18 of treatment and 15 IU of human chorionic gonadotropin (hCG) on day 20. A terminal blood sample was collected and circulating levels of estradiol (Emr2) and progesterone. (P4) were determined. Serum concentrations of P4 were significantly (p < 0.0034) elevated by HCB treatment at all dose levels. Ovarian weights were significantly increased (p < 0.05) in the lowest dose group only compared to the control group. Serum concentrations of Ev uterine weight, weight gain, and general animal health were not affected by HCB treatment. We conclude that during HCB treatment the rat ovary remains responsive to gonadotropin stimulation. Moreover, it is suggested that HCB effects on ovarian steroidogenesis are indirect.
Oxidant and angiotensin II‐induced subcellular translocation of protein kinase C in pulmonary artery endothelial cells
Authors: Patel Jawaharalal M. , Sekharam K. Madhavi , Block Edward R. 
Published: October 2006

AbstractWe recently reported that nitrogen dioxide (NO2), an environmental oxidant, alters the dynamics of the plasma membrane lipid bilayer structure, resulting in increased phosphatidylserine content and angiotensin II (Ang II) receptor binding. Angiotensin II is known to elicit receptor‐mediated stimulation of diacylglycerol (DAG) production in pulmonary artery endothelial cells. Because protein kinase C (PKC) is a phosphatidylserine‐dependent enzyme and is activated by DAG, we examined whether NO2 resulted in activation and/or translocation of PKC from predominantly cytosolic to membrane fractions of these cells. We also evaluated whether NO2 exposure resulted in increased production of DAG in pulmonary artery endothelial cells. Exposure to 5 ppm NO2 for 1–24 hr resulted in significant increases in PKC activity in the cytosolic and membrane fractions (p < 0.05 for both fractions) compared to activities in control fractions. Exposure to Ang II resulted in translocation of PKC activity from cytosol to membrane fractions of both control and NO2‐exposed cells. This translocation of PKC from cytosolic to membrane fraction was prevented by the specific receptor antagonist [Sar1 Ile8] Ang II. Exposure of 5 ppm NO2 for 1–24 hr provoked rapid increases in [3H]glycerol labeling of DAG in pulmonary artery endothelial cells. These results demonstrate that exposure to NO2 increases the production of second messenger DAG and activates PKC in both the cytosolic and membrane fractions, whereas Ang II stimulates the redistribution of PKC from cytosolic to membrane fractions of pulmonary artery endothelial cells.
Action of some retinol derivatives and their provitamins on microsome‐catalyzed formation of benzo[a]pyrene‐DNA adduct
Authors: Shah G. M. , Goswami U. C. , Bhattacharya R. K. 
Published: October 2006

AbstractSeveral vitamin A compounds have been tested for their ability to suppress formation of DNA adduct by the carcinogen benzo[a]pyrene (B[a]P) in an in vitro reaction catalyzed by rat liver microsomes. Retinol, retinal, 3‐dehydroretinol and 3‐hydroxyretinol were found to be effective inhibitors of adduct formation. Certain carotenoids that are precursors of these retinoids also displayed considerable inhibitory capacity. Carotenoids and the 3‐substituted retinoids appeared to modulate the DNA adduct formation exclusively through their action on microsomal enzymes, since an effective inhibition in each case was observed on the formation of B[a]P‐7,8‐diol, a proximate carcinogenic metabolite of B[a]P. Unsubstituted retinoids, on the other hand, had marginal effect on enzymes but were found effective in accelerating inactivation of B[a]P‐7,8‐diol‐9,10‐epoxide, the ultimate carcinogenic metabolite that binds to DNA.
Effects of niacin on bleomycin‐induced increases in myeloperoxidase, prolyl hydroxylase, and superoxide dismutase activities and collagen accumulation in the lungs of hamsters
Authors: O'Neill Charles A. , Giri Shri N. 
Published: October 2006

AbstractIt has been shown that lung nicotinamide adenine dinucleotide (NAD) depletion accompanies bleomycin (BL)‐induced lung fibrosis in the hamster and that treatment with niacin (NA), a precursor of NAD, was found to attenuate lung fibrosis caused by this agent. Niacin was used in the present study to investigate changes in some biochemical parameters and enzymes involved in the development of BL‐induced lung fibrosis in the hamster. Niacin (500 mg/kg, IP), or an equivalent volume of saline (SA, IP), was given daily 2 days prior to intratracheal instillation of BL (7.5 U/5 mL/ kg) or SA and everyday thereafter throughout the study. Hamsters were killed at 1, 4, 7, 10, and 14 days after the BL or SA instillation and their lungs processed for various biochemical assays. Hydroxyproline content and superoxide dismutase (SOD) activity in SABL treated animals were significantly (P ± 0.05) elevated at 7 and 10 days, peaking at 14 days to 161 ± 11% and 159 ± 11% of the SASA treated animals, respectively. Although the hydroxyproline level of NABL treated animals was significantly elevated at 7 and 10 days and peaked at 14 days to 123 ± 8% of the NASA control, these values were significantly lower than the SABL treated animals at the corresponding times. The lung SOD activity of NABL groups was significantly higher at 4 days but significantly lower at 10 and 14 days than the SABL groups at the corresponding times. Prolyl hydroxylase (PH) activity and total lung calcium in SABL treated groups were significantly elevated compared to SASA treated groups starting at 4 days, with PH peaking at 10 days to 163 ± 13% and calcium peaking at 7 days to 148 ± 8% of SASA treated groups. The NABL treated animals displayed a significant elevation in PH activity at 4 days only (132 ± 15%), while the calcium content in this group was significantly increased at 4 and 14 days compared to NASA treated animals. However, the activity of PH in the NABL treated animals was significantly lower than the SABL treated animals at 7, 10, and 14 days. The calcium content of the NABL group was significantly lower than the SABL group at 7 and 10 days. The thiobarbituric acid reactive substance equivalents (TBARS) content and myeloperoxidase (MPO) activity were significantly elevated at all time points in SABL groups as compared to SASA groups, with peak elevation of TBARS to 160 ± 9% at 4 days and MPO to 268 ± 40% at 1 day. The TBARS content of NABL groups was significantly elevated above NASA groups at 1, 4, 7, and 10 days. The MPO activity in NABL groups was significantly elevated above NASA groups at 1, 4, 7, and 14 days, but the activity was significantly lower than SABL groups at 4 and 14 days. The data suggest that NA inhibits the extent of oxidative damage or enhances processes involved in the repair of BL‐induced alveolar epithelial damage.
Bioactivation of 7‐hydroxymethyl‐12‐ methyibenz[a]anthracene by rat liver bile acid sulfotransferase I
Authors: Falany Charles N. , Wheeler James , Coward Lori , Keehan Dawn , Falany Josie L. , Barnes Stephen 
Published: October 2006

AbstractThe bioactivation of 7‐hydroxy‐methyl‐12‐methylbenz[a]anthracene (HMBA) to an electrophilic sulfuric acid ester metabolite has been shown to be catalyzed by rat liver bile acid sulfotransferase I (BAST I). The sulfation and activation of HMBA by BAST I was determined by the ability of sulfated HMBA to form DNA ad‐ducts. The BAST I was also shown to react with rabbit anti‐human dehydroepiandrosterone sulfotransferase antisera and to represent a major form of hydroxysteroid/bile acid sulfotransferase in female rat liver cytosol. Higher levels of BAST I activity and immunoreactivity as well as HMBA‐DNA adduct formation were detected in female rat liver cytosol than in male rat liver cytosol. The bioactivation of HMBA by pure BAST I was dependent on the presence of 3′‐phosphoadenosine 5′‐phos‐phosulfate (PAPS) in the reaction and was inhibited by dehydroepiandrosterone, a physiological substrate for BAST I. Glutathione, a cellular nucleophile with important protective properties, decreased DNA adduct formation in the HMBA sulfation reaction in the absence of glutathione S‐transferase activity. These results indicate the usefulness of BAST I to investigate the sulfation and activation of HMBA and probably other hydroxy‐methylated polyaromatic hydrocarbons to electrophilic and mutagenic metabolites under defined reaction conditions.
Heterogeneity of rat hepatic Ah Receptor: Identification of two receptor forms which differ in their biochemical properties
Authors: Denison Michael S. 
Published: October 2006

AbstractIn cytosol, the rat hepatic Ah receptor (AhR) appears to exist in two distinct forms (AhRα, AhRβ) in similar concentration. The binding of ligand (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD)) to AhRα requires the receptor be in its oligomeric 8–10 to S conformation (bound to other protein subunits), while ligand binding to AhRβ can occur with the dissociated 5–6 S form. Occupancy of AhRβ by ligand (TCDD) protects it from salt‐dependent inactivation; AhRβ is not inactivated by high salt conditions. The addition of molybdate to cytosol during tissue homogenization stabilized AhRα against salt‐dependent inactivation and subunit dissociation but did not prevent dissociation of AhRβ by high salt. Although the presence of molybdate appears to stabilize AhRα in its oligomeric 8–10 S, it had no significant effect on the overall amount of TCDD:AhR complex which bound to its specific DNA recognition site, the dioxin responsive element (DRE). These results suggest that AhRα, unlike AhRβ, is either unable to transform or bind to the DRE with high affinity.