bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embryotoxicity induced by diethylstilbestrol in vitro1
Authors: Greenaway J. C. , Fantel A. G. , Beyer B. K. , Juchau M. R. 
Published: October 2006

AbstractThe embryotoxic potential of diethylstilbestrol (DES) was examined in a whole embryo culture system containing a P‐450–dependent bioactivating system. Sprague‐Dawley rat embryos were explanted on day 10 and cultured for 24 hours. Concentration‐dependent effects of DES on embryonic growth parameters, viability, and embryotoxicity were observed. Concentrations of DES greater than 0.26 mM (final concentration) produced 100% embryolethality, while those below 0.15 mM were without significant effects. At a final concentration of 0.19 mM, DES produced only a slight increase in embryolethality. The same concentration elicited a marked increase in observed embryotoxicity, including prosencephalic hypoplasia, incomplete axial rotation, and open neural tubes. In addition, reductions in embryonic length, somite number, and protein and DNA content were observed. An exogenous P‐450–dependent hepatic biotransforming (catechol‐generating) system failed to alter either the incidence of observed toxic effects or measured growth parameters. Likewise, exposure of cultured embryos to 20% carbon monoxide (CO) failed to reduce DES‐induced embryotoxicity, indicating a lack of participation of an endogenous P‐450‐dependent embryonic bioactivating system. Arachidonic acid (0.20 mM) and/or indomethacin (0.50 mM) also had no observable effect on DES‐induced embryotoxicity, suggesting that prostaglandin synthase was not involved in the embryotoxic activity of DES, as has been proposed to explain its carcinogenic effect. The antioxidants N‐acetylcysteine (1.14 mM) and α‐tocopherol (0.08 mM) failed to protect against DES‐induced embryotoxicity, while the antiestrogen tamoxifen (up to 0.85 mM) actually enhanced this effect of DES in culture. The DES analogs Z,Z‐dienestrol (DIES, 0.10 mM) and hexestrol (HES, 0.48 mM) were both embryotoxic in vitro. The presence of an exogenous P‐450‐dependent hepatic biotransforming system appeared to protect against HES‐induced embryolethality but had little effect upon DIES‐induced embryotoxicity. The results were consistent with a direct effect of DES independent of either estrogenicity or exogenously generated metabolites.
Significance of mirex‐caused hypoglycemia and hyperlipidemia in rats
Authors: Jovanovich Lela , Levin Sally , Khan M. A. Q. 
Published: October 2006

AbstractTreatment of rats with mirex (40 ppm in diet) caused hypoglycemia, liver enlargement, and inhibition of adrenal corticosteroid‐synthesizing enzyme activity. At toxic dosages (20,000 ppm mirex in diet, which has a lethal toxicity‐50 [LT‐50] of ten days) poisoned female rats showed severe hypoglycemia, fatty liver, adrenal hyperplasia, hypophagia, lipid mobilization, and body weight (bw) loss. A 50 μg/kg intraperitoneal (IP) dose of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) in male rats caused similar effects two days posttreatment. Hypoglycemia could be overcome by prednisone (which also inhibited adrenocorticoid‐synthesizing enzyme activities) but not by streptozotocin treatment, indicating that hypoglycemia may be related to glucocorticoid deficiency resulting from inhibition of their synthesis and not by direct effects on pancreatic β‐cells. Glucocorticoid deficiency could also cause increased release of adrenocorticoid hormone (ACTH), which may enhance fat mobilization caused by hypophagia.
Allylisopropylacetamide induces rat hepatic ornithine decarboxylase
Authors: Kitchin Kirk T. , Brown Janice L. 
Published: October 2006

AbstractIn rat liver, allylisopropylacetamide (AIA) treatment strongly induced (25‐fold) the activity of rat hepatic ornithine decarboxylase (ODC). By either the oral or the subcutaneous route, AIA produced a long‐lasting induction (30 to 40 hours) of hepatic ODC activity. Three analogs of AIA, propylisopropylacetamide (PIA), allobarbital, and allylbenzene, were active ODC inducers while a fourth, allylacetate, was not. Although induction of hepatic aminolevulinic acid (ALA) synthetase activity and the accumulation of hepatic porphyrins depend on the allyl moiety of AIA, this is not the case with hepatic ODC induction. Allylisopropylacetamide did not elevate serum alanine aminotransferase (SGPT) nor did it cause DNA damage, as measured by the alkaline elution assay. Thus, hepatic cell death is not a likely explanation of AIA's long‐lasting induction of ODC. As AIA does not belong to any of the common categories of ODC inducers, it may be the chemical prototype of a new class of hepatic ODC inducers.
Effects of metal cations on pituitary hormone secretion in vitro
Authors: Cooper Ralph L. , Goldman Jerome M. , Rehnberg Georgia L. , McElroy W. Keith , Hein Joy F. 
Published: October 2006

AbstractIncreased body burdens of metal cations are known to affect adversely reproductive function in several species. The effects of these metals on gonadal function are well documented. In contrast, little is known about their possible direct effects on pituitary hormone release. The purpose of this study was to determine, in vitro, the effects of nickel, cadmium, and zinc (50 μM) on both baseline and potassium chloride (KCl)‐stimulated pituitary luteinizing hormone (LH), prolactin (Prl), and thyroid‐stimulating hormone (TSH) release. Anterior pituitary fragments from adult male Long‐Evans rats were evaluated using a continuous‐flow perifusion system. Baseline and stimulated LH releases were unaffected by nickel and zinc; however, cadmium caused an increase in baseline LH secretion. Baseline Prl release was decreased by zinc, while cadmium resulted in increased release of this hormone. Stimulated Prl release was lower during exposure to zinc but unaltered by nickel and cadmium. Following exposure to zinc, a rebound in stimulated release was noted for all three hormones measured. These results showed that the metal cations tested did have a direct effect on pituitary hormone release at a dose lower than those reported to alter testicular function in vitro. Furthermore, the changes in pituitary hormone secretion varied depending upon the metal and hormone being evaluated.
Desensitization of the nicotinic acetylcholine receptor by diisopropylfluorophosphate
Authors: Eldefrawi Mohyee E. , Schweizer Gordon , Bakry Nabil M. , Valdes James J. 
Published: October 2006

AbstractThe interaction of diisopropylfluorophosphate (DFP) with the nicotinic acetylcholine (ACh) receptor of Torpedo electric organ was studied, using [3H]‐phencyclidine ([3H]‐PCP) as a reporter probe. Phencyclidine binds with different kinetics to resting, activated, and desensitized receptor conformations. Although DFP did not inhibit binding of [3H]‐ACh or 125I‐α‐bungarotoxin (BGT) to the receptor recognition sites and potentiated in a time‐dependent manner [3H]‐PCP binding to the receptor's high‐affinity allosteric site, it inhibited the ACh or carbamylcholine‐stimulated [3H]‐PCP binding. This suggested that DFP bound to a third kind of site on the receptor and affected receptor conformation. Preincubation of the membranes with DFP increased the receptor's affinity for carbamylcholine by eightfold and raised the pseudo‐first‐order rate of [3H]‐PCP binding to that of an agonist‐desensitized receptor. Accordingly, it is suggested that DFP induces receptor desensitization by binding to a site that is distinct from the recognition or high‐affinity noncompetitive sites.
Investigations on the role of free radical processes in hexachlorobenzene‐induced porphyria in mice
Authors: Rizzardini M. , Graziani A. , Carugo C. , Cantoni L. 
Published: October 2006

AbstractMale C57BY/10 mice were chronically fed hexachlorobenzene (HCB) (0.02% of the diet) alone or in combination with a single subcutaneous dose of iron (12.5 mg iron per mouse). After eight weeks the group of mice pretreated with the iron overload was highly sensitized to the porphyrogenic effect of HCB, as shown by liver porphyrin accumulation. A synergistic effect of iron was evident on other parameters too, such as HCB‐induced hepatic damage, activation of type O of xanthine oxidase, and decreased activity of copper zinc superoxide dismutase and glutathione peroxidase(s). None of these parameters was affected by iron alone.Iron alone and in association with HCB markedly raised the level of lipid peroxides, the increase in the HCB group being smaller. The combined treatment resulted in a significant reduction of HCB's inductive effects on microsomal heme and cytochromes P‐450 and b5 and on the activity of aryl hydrocarbon hydroxylase. The content of nonprotein sulfhydryl groups was reduced to the same extent in mice treated with HCB or HCB plus iron.The results suggest that reactive intermediates such as are formed by lipid peroxidation are not sufficient on their own to create the conditions for uroporphyrinogen decarboxylase impairment, as evident in the group of mice receiving iron overload alone. Conversely, HCB administration induced a specific condition of imbalance in the liver between formation and inactivation of reactive intermediates which was associated with hepatic porphyrin accumulation and was potentiated by concomitant administration of iron.
Cyclosporin‐mediated increase in kidney glutathione and effects on γ‐glutamyl‐cycle enzymes
Authors: Mayer Robert D. , Cockett Abraham T. K. 
Published: October 2006

AbstractThe unprecedented ability of cyclosporin A, when given for six days at a dose of 25 mg/kg/d or 50 mg/kg/d, to cause a marked and sustained increase in renal glutathione (GSH) concentration in rat kidney is described. This response was particular to the kidney insofar as the GSH concentration in the liver was not increased in response to a lower dose of cyclosporin and was decreased in the liver of animals treated with the higher dose of the drug. The increase in kidney GSH concentration did not appear to be due to an increased rate of production or to an inhibition of the degradation of the tripeptide. This suggestion is based on the finding that the activities of the GSH synthesis pathways, GSSG‐reductase and γ‐glutamylcysteine synthetase, were unchanged or decreased, respectively, and those of the catabolic enzymes, GSH‐peroxidase and γ‐glutamyltranspeptidase, were unchanged or increased, respectively.It is suggested that the elevation of renal GSH content in the face of diminished synthetic capacity and an apparent increased utilization may result from an enhanced uptake of GSH as the result of alterations caused by cyclosporin in the renal transport system.
Toluene‐induced alterations in rat synaptosomal membrane composition and function
Authors: Le Bel Carl P. , Schatz Robert A. 
Published: October 2006

AbstractToluene is a widely used organic solvent that can produce acute central nervous system (CNS) effects. Since toluene reaches relatively high concentrations in the CNS and is extremely lipophilic, we investigated its effects on rat brain membrane composition and function. Toluene (1 g/kg, lh) did not alter total brain microsomal phospholipid (PL) or cholesterol (CL) content. However, synaptosomal PL was decreased (24%), while synaptosomal CL was unaltered. The PL/CL ratio, an indirect index of membrane fluidity, did not change, suggesting that toluene did not affect membrane fluidity. Fluorescence polarization studies employing 1,6‐diphenyl‐1,3,5‐hexatriene (DPH) showed that toluene did not alter synaptosomal membrane fluidity after administration in vivo (1 g/kg) or in vitro (0.5 to 5.0 mM). Dose‐response and time‐course studies showed that toluene maximally decreased synaptosomal PL after 1 g/kg, 1 h. The dose‐response and time‐course studies also showed that the toluene‐induced decreases in PL were a result of specific decreases in phosphatidylethanolamine (PE). Since PE was decreased, we assessed whether toluene altered synaptosomal membrane function by investigating phospholipid methylation, a reaction which uses PE as its initial substrate. Toluene decreased the incorporation of methyl groups into lipid when [3H]‐methionine was used as the methyl donor, but did not affect methylation when [3H]‐adenosylmethionine was the methyl donor. These data suggest that toluene‐induced specific decreases in synaptosomal PE and inhibition of phospholipid methylation may alter normal synaptic function and play a critical role in the mechanism(s) of action of toluene's CNS effects.
Sensitivity of selected drug biotransformation enzymes to dietary protein levels in adult F344 male rats
Authors: Butler L. E. , Dauterman W. C. 
Published: October 2006

AbstractAdult male Fischer 344 rats were fed inadequate, adequate, and excessive quantities of dietary protein (8, 12, and 22%, respectively) for a period of 14 days. An increase in dietary protein did not increase liver weight but resulted in an increase in cytochrome P‐450 content and 7‐ethoxycoumarin O‐deethylase activity. No significant difference in glutathione S‐transferase activity was observed at the three protein levels. The in vivo hepatotoxicity of bromobenzene increased with an elevation in dietary protein intake from 12 to 22%. These data from mature rats follow trends similar to findings we have reported previously with juvenile rats.
TCDD (2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin) is a tight binding inhibitor of cytochrome p‐450D
Authors: Voorman Richard , Aust Steven D. 
Published: October 2006

AbstractBased on data indicating that compounds which induce cytochrome P‐450d also bind to the enzyme (R. Voorman and S. D. Aust (1987). Toxicol. Appl. Pharmacol. 90, [69–78], we investigated the inhibition of cytochrome P‐450d‐dependent estradiol 2‐hydroxylase by (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin TCDD), using ligand‐free cytochrome P‐450d from isosafrole‐treated rats. Since maximum inhibition of estradiol 2‐hydroxylase occurred at TCDD concentrations comparable to the concentration of enzyme (50 nM), a modified form of steady‐state kinetic analysis was used. Using I50 =Et/2 + Ki where Et =total enzyme concentration), we showed that TCDD inhibited cytochrome P‐450d‐dependent estradiol 2‐hydroxylase activity with Ki equal to 8 nM. Association of TCDD with P‐450d occurred within 2 min of inhibitor addition. Therefore, TCDD can be considered a tight binding inhibitor of cytochrome P‐450d.
Effects of hyperthermia on xanthine oxidase activity and glutathione levels in the perfused rat liver
Authors: Skibba Joseph L. , Stadnicka Anna , Kalbfleisch John H. , Powers Robert H. 
Published: October 2006

AbstractThe hepatotoxic effects of hyperthermic liver perfusion were investigated in male Fischer 344 rat livers. Perfusions were carried out at 37, 41, 42, 42.5, and 43°C for 2 hr. During the 2 hr, the perfusate was analyzed for activity of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), N‐acetyl‐β‐glucosaminidase (NAG), and glutathione (GSH), oxidized glutathione (GSSG), allantoin, and potassium. After perfusion, each liver was homogenized and analyzed for total xanthine oxidase (XO) activity, percentage type‐D and type‐O XO, and total GSH content. Perfusate AST, LDH, NAG, and potassium levels were increased significantly with time and were significantly different in all hyperthermic perfusions from the 37°C perfusion values by the end of the perfusion. Perfusate GSH + GSSG levels were increased significantly in all hyperthermic perfusions after 60 min. Liver GSH levels were significantly lowered following perfusion at hyperthermic temperatures. There was a temperature‐dependent increase in the percentage of XO in the type‐O form following perfusion at hyperthermic temperatures, which was strongly and positively correlated with the loss of hepatic GSH. These data support the hypothesis that hyperthermic toxicity to the liver is the result of oxidative stress brought about by conversion of XO to the type‐O form.
Carbon tetrachloride metabolism in partially hepatectomized and sham‐operated rats pre‐exposed to chlordecone (kepone)
Authors: Young Robert A. , Mehendale Harihara M. 
Published: October 2006

AbstractThe potentiation of CCl4 toxicity by pre‐exposure to chlordecone (CD) is well established. Chlordecone‐induced metabolism of CCl4 and suppressed hepatocellular repair have been offered as possible mechanisms for this potentiation. Recent work using the partially hepatectomized (PH) rat as a model for an actively regenerating liver has provided supportive evidence for the latter hypothesis. The present study was initiated to determine if metabolism and disposition of 14CCl4 is altered in the PH rat, and if this is a contributing factor to the reported protective effect afforded by the PH procedure. Male Sprague‐Dawley rats (150–175 g) maintained on dietary CD (10 ppm) for 15 days were partially hepatectomized or sham‐operated (SH) on day 15. Another group of CD‐pretreated rats received 0.9% CoCl2 (60 mg/kg, sc, qd for 2 days) in lieu of the surgical procedure. On day 16 the rats were challenged with a single dose of CCl4 (100 μL/kg, ip) containing 20 μCi 14CCl4. A radiolabel inventory consisting of exhaled 14CCl4, 14CO2 production, total hepatic 14C, free 14CCl4 and covalently bound 14C was taken over a 6‐hr time period. Lipid peroxidation and serum enzyme activities [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were measured as indices of toxicity. Neither CD pretreatment alone nor CoCl2 treatment alone produced significant alterations in metabolism of low dose (100 μl/kg) CCl4. No significant difference in 14CCl4 recovery or 14CO2 production was detected for PH versus SH rats. Hepatic 14CCl4‐derived 14C (per gram tissue) was greater in PH rats. Values for free 14CCl4, covalently bound 14C, and lipid peroxidation were similar for SH and PH rats. The data suggest that metabolism and disposition of CCl4 are not altered by PH. Thus the PH rat is a valid model for studying the CD + CCl4 interaction in an actively regenerating liver, and the protection afforded by partial hepatectomy is not due to a reduction in hepatic uptake or bioactivation of CCl4.
Feprazone: An inducer of the P450 II B family of proteins in the rat
Authors: Smith Jonathan N. , Ayrton Andrew D. , Chown Janice , Lewis David F. V. , Ioannides Costas 
Published: October 2006

AbstractThe ability of feprazone to induce the hepatic microsomal mixed‐function oxidases was investigated in the rat, with emphasis being placed on the nature of the cytochrome P‐450 family induced. Treatment with feprazone enhanced the p‐hydroxylation of aniline and the dealkylations of benzphetamine and pentoxyresorufin but had no effect on the O‐deethylation of ethoxyresorufin. The same treatment had no major effect on total cytochrome P‐450 levels but increased the spectral interaction of metyra‐pone with reduced cytochrome P‐450. Immunoblots employing monospecific polyclonal antibodies revealed that feprazone induces the apoprotein levels of the P450 II B, but not of the P450 I, family. It is concluded that feprazone is an inducer of the rat hepatic mixed‐function oxidase system showing selectivity toward the P450 II B family.
Exposure of Pulmonary Artery Endothelial Cells to Nitrogen Dioxide Activates Phospholipase A1
Authors: Bhat G. B. , Patel J. M. , Block E. R. 
Published: October 2006

AbstractPhospholipase A1, A2, and C and diacylglycerol lipase activities were measured in cell sonicates after exposing confluent monolayers of porcine pulmonary artery endothelial cells to 5 ppm NO2, a toxic constituent of environmental pollution, for 24 and 48 hr. There was a significant increase (2.25‐fold) in phospholipase A1 activity in 24 and 48 hr NO2‐exposed cells, whereas activities of phospholipases A2 and C and diacylglycerol lipase were comparable to control cells at both time points. When endothelial cells were prelabeled with [3H]‐arachidonic acid and then exposed to NO2 for 48 hr, increased counts were recovered from cell lysophospholipids with concomitant decreased recovery of counts from cell phosphatidylcholine and phosphatidylethanolamine. These results demonstrate that NO2 exposure results in specific activation of phospholipase A1.
Metabolism and toxicity of xenobiotics in the adrenal cortex, with particular reference to 7,12‐dimethylbenz(a) anthracene
Authors: Hallberg Einar 
Published: October 2006

AbstractThe adrenal cortex contains high amounts of detoxifying enzymes, as well as generators and protectors of reactive oxygen species. The high content of cytochrome P‐450 enzymes in the adrenal cortex together with its remarkable tendency to accumulate hydrophobic substances probably contributes to the extraordinary vulnerability of the gland to a number of xenobiotics. The best studied adreno‐corticolytic compounds are the potent carcinogen 7, 12‐dimethylbenz(a)anthracene (DMBA) and its liver metabolite 7‐hydroxymethyl‐12‐methylbenz (a)anthracene (7‐OHM‐12‐MBA). Adrenocorticolysis generated by these agents in vivo as well as in vitro demonstrates high regioselective requirements and is strongly influenced by the presence of ACTH, steroids, cytochrome P‐450 inhibitors and antioxi‐dants. Furthermore, 7‐OHM‐12‐MBA has been demonstrated to uniquely generate selective and massive oxidation of mitochondrial glutathione in cultured rat adrenal cells.The DMBA‐induced adrenocorticolysis is thoroughly discussed in this review with particular emphasis on the metabolism of DMBA and the influence of various effectors. A working hypothesis involving a possible peroxidative mechanism is also presented.
The effects of haloalkene cysteine conjugates on cytosolic free calcium levels in suspensions of rat renal proximal tubules
Authors: Groves Carlotta E. , Lock Edward A. , Schnellmann Rick G. 
Published: October 2006

AbstractDisturbances in intracellular calcium homeostasis may play a role in the injury induced by various haloalkene cysteine conjugates. The effects of S‐(1,2,3,4,4‐pentachloro‐1,3‐butadienyl)‐L‐cysteine (PCBC), S‐(1,2‐dichlorovinyl)‐L‐cysteine (DCVC), and S‐(1,1,2,2‐tetrafluoroethyl)‐L‐cysteine (TFEC) on cytosolic free calcium levels were examined in suspensions of rat renal proximal tubules. Cytosolic free calcium levels, measured with fura 2, in control tubules, were 112 ± 3 nM and increased more than 200% within 1 minute after exposure to the calcium ionophore ionomycin (0.005 mM). PCBC (0.1 mM) increased cytosolic free calcium levels 18% after 5 minutes, while tubular oxygen consumption was unaffected. DCVC (1 mM) did not alter tubular cytosolic free calcium levels or oxygen consumption under similar conditions. TFEC (1 mM) increased cytosolic free calcium levels 36%, had no effect on basal oxygen consumption, and decreased nystatin‐stimulated oxygen consumption 30% after 5 minutes. TFEC increased cytosolic free calcium levels in tubules incubated in a nominally calcium‐free buffer but not in a calcium containing buffer in the presence of EGTA. The data suggest that the TFEC‐induced increase in cytosolic free calcium levels may result from an influx of extracellular calcium or from inhibition of calcium efflux. The increase in cytosolic free calcium levels preceded changes in basal oxygen consumption in tubules exposed to PCBC and TFEC. This study shows that an increase in cytosolic free calcium levels is an early event following PCBC and TFEC but not DCVC exposure.