bluuebunny/crossref_metadata_2025_split huggingface dataset:
An examination of the oxidation of mercury vapor by rat brain homogenate
Authors: Sichak S. P. , Mavis R. D. , Finkelstein J. N. , Clarkson T. W. 
Published: October 2006

AbstractThe oxidation of mercury vapor (Hg°) to divalent inorganic mercury (Hg2+) was studied in rat brain homogenates. By using a “degassing” method, it was possible to speciate the mercury present in the homogenate and, for the first time, to measure the rate of oxidation as a function of the substrate (Hg°) concentration. Mercury oxidation was first‐order with respect to substrate concentration at all concentrations tested, and the first‐order rate constant for the oxidation process was proportional to homogenate concentration. The role of catalase compound I in mercury vapor oxidation by brain homogenate was examined by observing the effects of two inhibitors of catalase (catalase compound I) on homogenate mercury‐oxidizing activity and catalase activity. Sodium azide (50 mM) completely inhibited both mercury‐oxidizing activity and catalase activity. Aminotriazole (3‐amino‐1H‐1,2,4‐triazole) (50 mM) completely inhibited only mercury‐oxidizing activity; some residual catalase activity was found in the aminotriazole‐treated homogenate. It was concluded that catalase compound I plays a major role in the oxidation of Hg°, but the possibility that catalase‐independent pathways make a minor contribution cannot be excluded.
Ah receptor for 2,3,7,8‐ tetrachlorodibenzo‐p‐Dioxin: Ontogeny in chick embryo liver
Authors: Denison Michael S. , Okey Allan B. , Hamilton Joshua W. , Bloom Stephen E. , Wilkinson Christopher F. 
Published: October 2006

AbstractAryl hydrocarbon hydroxylase (AHH, cytochrome P1‐450) is induced in chick liver very early during embryonic development if embryos are treated with 3‐methylcholanthrene–type compounds such as 3,4,3′4′‐tetrachlorobiphenyl. In mammals, AHH induction is known to be mediated by the Ah receptor. Liver from embryonic and newly hatched chicks was found to contain a cytosolic receptor for 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) which has properties that are very similar to properties of the Ah receptor previously characterized in mammalian tissues. In chick embryo liver, cytosolic binding sites for TCDD were of high affinity (Kd for [3‐H]‐TCDD = 0.2 nM) and were specific for 3‐methylcholanthrene–type inducers. The specific binding component sedimented at about 9S on sucrose density gradients prepared at low ionic strength. A high level of Ah receptor was detected in chick embryo liver by the fifth day of incubation (5 DI); this is at least 24 hours prior to the onset of AHH inducibility. The Ah receptor concentration increased from 5 DI to 8 DI, the period when chick liver is undergoing early morphological differentiation. After 8 DI, Ah receptor levels dropped substantially and remained low into the posthatching period. In contrast, AHH inducibility was high by 7 DI and remained high throughout embryonic development and into the posthatching period. The discrepancy between Ah receptor levels and the degree of AHH inducibility suggests that only a small fraction of the Ah receptor population is required for maximal AHH induction.
Methoxyacetic acid and ethoxyacetic acid inhibit mitochondrial function in vitro
Authors: Beattie P. J. , Brabec M. J. 
Published: October 2006

AbstractEthylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) have recently been shown to be potent reproductive toxicants in laboratory animals. The toxicity of these compounds is believed to be due to their metabolites, methoxyacetic acid (MAA) and ethoxyacetic acid (EAA). Since the primary targets of EGME and EGEE appear to be tissues with rapidly dividing cell systems and high rates of respiration and energy metabolism, the effects of these compounds and their proposed metabolites on mitochondria were investigated. At concentrations beginning at 3.85 mM, MAA and EAA inhibited state 3 respiration and the respiratory control ratio (RCR) in hepatic mitochondria with either succinate or citrate/malate as substrates. Cytochrome c oxidase activity was also inhibited by both metabolites at similar concentrations. The effects of MAA, the metabolite from the more potent compound, on testicular mitochondria were found to be comparable. Neither EGME or EGEE appeared to affect mitochondrial function at concentrations as high as 238 or 113 mM, respectively. These results support the hypothesis that the toxicity of EGME and EGEE are due to their metabolites, MAA and EAA, and that these metabolites may exert their effects, in part, on mitochondrial function.
Cytochrome P‐450—Mediated denitrification of 2‐nitropropane in mouse liver microsomes
Authors: Marker Elizabeth K. , Kulkarni Arun P. 
Published: October 2006

AbstractEnzymatic denitrification of 2‐nitropropane (2NP) was investigated in an NADPH‐dependent hepatic microsomal system from male CD1 mice. The involvement of cytochrome P‐450 (P‐450) as the catalyst in 2NP denitrification was revealed by the induction of nitrite‐releasing activity following phenobarbital (PB) pretreatment, by a decrease in activity with carbon tetrachloride pretreatment, by the inhibition of the reaction with classical P‐450 inhibitors, and by the observation of a type I binding spectrum. Under optimal conditions, two pH‐dependent peaks of activity were observed at pH 7.6 and pH 8.8, each with its own optimal substrate concentration. Inhibition of the reaction by metyrapone and carbon monoxide (CO) (among others) produced differential responses dependent on pH. These results, along with two pH optima and two substrate optima, suggested the involvement of multiple P‐450 isozymes. Average specific activities were 8.05 nmoles of nitrite released per minute per milligram microsomal protein at pH 7.6 and 6.44 nmoles of nitrite released per minute per milligram microsomal protein at pH 8.8. Acetone was identified as the second product of the reaction by gas chromatography/mass spectrometry (GC/MS). Stoichiometry studies indicated that the acetone production was slightly less than expected (about 70%) from nitrite release. Up to 25% residual activity was observed under anaerobic conditions. These results suggested that though the predominant reaction mechanism was oxidative, oxygen‐independent metabolism of 2NP also occurred to some extent. In contrast to the reported lack of activity in untreated rat, the observed denitrification in uninduced mouse liver microsomes was significant and suggested that major species‐specific differences exist in the in vitro metabolism of 2NP.
Mechanisms of petroleum hydrocarbon toxicity: Destruction of liver microsomal and mitochondrial calcium pump activities by a prudhoe bay crude oil
Authors: Khan S. , Payne J. F. , Rahimtula A. D. 
Published: October 2006

AbstractAdministration of Prudhoe Bay crude oil (PBCO) to rats resulted in an abrupt drop in liver mitochondrial and microsomal ATP‐dependent calcium uptake activity. Also, in vitro incubations of either mitochondria or microsomes in the presence of a dimethyl sulfoxide (DMSO) extract of PBCO resulted in a dose‐dependent inhibition of calcium influx. The release of calcium from calciumloaded mitochondria and microsomes was also observed in the presence of the PBCO extract. At concentrations which effect calcium sequestration, the PBCO extract produced swelling of mitochondria. Microsomal ATPase activity in the presence or absence of calcium was unaffected by PBCO. The results indicate that increased permeability of the membranes to calcium is a contributory factor in the inhibition of calcium uptake by PBCO.
Peroxidase, an alternate pathway to cytochrome P‐450 for xenobiotic metabolism in skin: Partial purification and properties of the enzyme from neonatal rat skin
Authors: Strohm Bradford H. , Kulkarni Arun P. 
Published: October 2006

AbstractPeroxidase activity was partially purified from neonatal (3 to 6 days old) rat skin. The membrane‐bound peroxidase activity was extracted with 0.5 calcium chloride and was monitored spectrophotometrically at 470 nm with 2‐methoxyphenol (guaiacol) and hydrogen peroxide as substrates. Subcellular distribution studies indicated the activity to be highest and comparable in nuclei mitochondria, lowest in microsomes, and absent in cytosol. The peroxidase activity was partially purified by affinity chromatography on concanavalin A‐sepharose 4B and by gel filtration using Bio‐Gel P‐150. Purification factors from these two steps were about 25 and 4, respectively. Peroxidase extraction in the presence of 2mM N‐ethylmaleimide increased activity about twofold. The combination of 2 mM N‐ethylmaleimide and 10% (w/v) glycerol was found to be optimal for preservation of activity. Peroxidase activity increased linearly with increases in protein concentration, time, and guaiacol concentration. Activity was inhibited approximately 75% by 0.1 mM potassium cyanide or 0.05 mM sodium azide. Pyrogallol, hydroquinone, p‐cresol, catechol, benzidine, 3,3′‐dimethoxybenzidine, tetramethyl‐benzidine, and p‐phenylenediamine also acted as substrates for the rat cutaneous peroxidase.
Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans‐4‐OH‐2‐hexenal
Authors: Griffin Donna S. , Segall H. J. 
Published: October 2006

AbstractThe pyrrolizidine alkaloid senecionine has been shown to be hepatotoxic, genotoxic, and cytotoxic. However, the biochemical mechanism by which senecionine produces hepatocellular toxicity remains to be elucidated. The role of calcium homeostasis in toxic liver injury was examined in isolated rat hepatocytes treated with senecionine and trans‐4‐OH‐2‐hexenal (t‐4HH), a microsomal metabolite of senecionine, and appropriate cofactors. Hepatocytes treated with senecionine and t‐4HH demonstrated greater cytotoxicity (leakage of lactate dehydrogenase) when incubated in the absence of extracellular Ca2+ than in its presence. Both compounds elicited an increase in cytosolic Ca2+ levels of isolated hepatocytes in the presence of extracellular Ca2+ In the following study, senecionine and t‐4HH depleted intracellular glutathione levels and induced lipid peroxidation and cytotoxicity in isolated hepatocytes. Pretreatment with the thiolgroup reducing agent dithiothreitol prevented depletion of intracellular glutathione and protected hepatocytes against senecionine and t‐4HH‐induced lipid peroxidation and cytotoxicity. Both compounds also depleted intracellular ATP and NADPH levels. These results suggest that hepatotoxocity induced by senecionine and t‐4HH is not dependent on the influx of extracellular Ca2+; however, alterations in intracellular Ca2+, possibly associated with depletion of intracellular glutathione, NADPH, and ATP, may play a critical role.
Short communication effects of six months' feeding of cypermethrin on the blood and liver of albino rats
Authors: Shakoori Abdul Rauf , Ali Syed Shahid , Saleem Mushtaq A. 
Published: October 2006

AbstractA cypermethrin‐mixed diet was fed uninterrupted to male albino rats for six months to evaluate toxicity in nontarget organisms. The rats consumed cypermethrin at a dose of 420 mg active ingredient (AI) per kilogram body weight per day. At the end of the stipulated period, the blood and liver were analyzed for insecticidal toxicity. The hemoglobin content and white blood cell (WBC) count remained unaltered, while the red blood cell (RBC) count and packed‐cell volume (PCV) decreased significantly. The blood serum lactate dehydrogenase (LDH), isocitrate dehydrogenase (ICDH), and amylase activities were elevated 61%, 30%, and 46%, respectively, after six months of insecticide feeding, suggesting liver and possibly pancreas malfunction. The glutamate oxaloacetate transaminase (GOT) and creatine phosphokinase (CPK) activities, on the other hand, decreased 37% and 40%, respectively. The blood serum protein and free amino acids (FAA) content increased 12% and 31%, respectively, while cholesterol content decreased 49%. Consequent to cypermethrin administration the hepatic GOT, LDH, and ICDH activities increased 250%, 20%, and 30%, respectively. The soluble proteins, FAA, and glucose contents exhibited significant increases of 28%, 61%, and 71%, respectively. Histological changes were marked by hypertrophied hepatic cells and nuclei.
Sodium arsenite induced alterations in bilirubin excretion and heme metabolism
Authors: Albores A. , Cebrián M. E. , Bach P. H. , Connelly J. C. , Hinton R. H. , Bridges J. W. 
Published: October 2006

AbstractThe acute administration of sodium arsenite (AsIII) to rats resulted in a biphasic alteration of the hepatic cytosolic “free” heme pool. The first stage was an increase in the cytosolic “free” heme without significant effects on the content of cytochrome P‐450 or on bilirubin excretion. The second stage consisted of a continuous fall of the cytosolic “free” heme and of the content of cytochrome P‐450. These changes were concurrent with an eight‐fold increase in heme oxygenase activity and associated with marked elevations in the biliary excretion of bilirubin. The bile was collected from chronically cannulated rats to avoid artifacts related to anesthesia or post anesthetic effects. The rapid increase in biliary excretion of labeled heme degradation products indicated an increased breakdown of newly synthesized heme. Immunoelectrophoresis of bile proteins showed an altered pattern of bile protein excretion. The increased biliary haptoglobin suggested some hemolysis, while the reduction in the free immunoglobulin A (IgA) secretory component showed an AsIII‐related decreased protein transport across hepatocytes to bile. Further research is required to assess the direct role of an increased heme degradation in the genesis of the hepatotoxic effects of AsIII.
Effects of chronic administration of doxorubicin on myocardial creatine phosphokinase and antioxidant defenses and levels of lipid peroxidation in tissues and plasma of rats
Authors: Robison Timothy W. , Giri Shri N. , Wilson Dennis W. 
Published: October 2006

AbstractTissue and plasma levels of thiobarbituric acid reactive substances (TBARS) were measured in rats treated chronically with doxorubicin. In addition, heart creatine phosphokinase and antioxidant defenses were examined. Male rats received doxorubicin (DXR) 2 mg/kg or vehicle weekly subcutaneously for 13 weeks and were sacrificed at 14 and 19 weeks, 1 and 6 weeks after the last dose, respectively. Histological evaluation in DXR‐treated rats at 14 and 19 weeks found significant and progressive cardiac and renal lesions as compared to controls. Heart TBARS were unchanged from controls. Plasma and kidney levels of TBARS were elevated above controls at both 14 and 19 weeks. Lung levels of TBARS were significantly elevated above controls at 14 weeks. Liver levels of TBARS were elevated at 19 weeks. Heart creatine phosphokinase activity was significantly depressed from controls at both 14 and 19 weeks. Heart glutathione peroxidase and superoxide dismutase activities were unchanged from controls. Heart glutathione, glutathione reductase, glucose‐6‐phosphate dehydrogenase, and catalase were elevated above controls at both 14 and 19 weeks. The lack of change in heart TBARS suggests that changes in TBARS in other organs may be secondary processes. The depression of creatine phosphokinase suggests that levels of adenosine triphosphate may be insufficient to sustain the myocardial function and this may partly be responsible for DXR‐induced cardiac myopathy.
Adverse reactions of imidazole antifungal agents: Computer graphic studies of cytochrome P‐450 interactions
Authors: Lewis D. F. V. , Rodrigues A. D. , Ioannides C. , Parke D. V. 
Published: October 2006

AbstractThe imidazole antifungal agents give rise to adverse reactions and clinically relevant drug interactions. This is due to lack of specificity of the antifungal agents that interact avidly not only with the fungal but also with mammalian cytochrome P‐450 proteins. A computer graphic technique capable of predicting the interaction of these structurally‐related imidazoles with fungal and mammalian cytochrome P‐450 proteins is described. This prediction is achieved by comparing the molecular conformation of these drugs with lanosterol, the substrate of the fungal cytochrome P‐450, and with phenobarbitone, an inducing agent of a family of mammalian cytochrome P‐450, toward which the antifungal agents show highest inhibitory activity.
Niacin attenuates bleomycin‐induced lung fibrosis in the hamster
Authors: Wang Qingjian , Giri Shri N. , Hyde Dallas M. , Nakashima James M. , Javadi Iraj 
Published: October 2006

AbstractBleomycin (BLM)‐induced lung fibrosis has been shown to be accompanied by the activation of poly(ADP‐ribose) polymerase and depletion of nicotinamide adenine dinucleotide (NAD) in the lung. Niacin, a precursor of NAD, was used in the present study to investigate its possible ameliorating effect on BLM‐induced pulmonary fibrosis in hamsters. Niacin (500 mg/kg IP) or saline (IP) was injected daily for 16 or 23 days. On day 3, hamsters were treated with BLM (7.5 U/5 mL/kg) or an equivalent volume of saline intratracheally. BLM alone significantly increased lung hydroxyproline levels, bron‐choalveolar lavage fluid protein concentration, and various inflammatory cell counts in the lavage in both experiments. In addition, BLM alone elevated prolyl hydroxylase and poly(adenosine‐5′‐diphosphate [ADP]‐ribose) polymerase activities in the 3‐week study. Niacin treatment significantly decreased BLM‐elevated lung hydroxyproline, prolyl hydroxylase, and poly(ADP‐ribose) polymerase activities. Histopa‐thology revealed that niacin treatment attenuated BLM‐induced thickened alveolar septa, foci of fibrotic consolidation, and accumulations of inflammatory cells in the parenchyma and air spaces. The ability of niacin to attenuate BLM‐induced lung fibrosis in hamsters suggests that it may have potential as an antifibrotic agent in humans.
Neonatal diethylstilbestrol treatment alters aflatoxin B1‐DNA adduct concentrations in adult rats
Authors: Lamartiniere Coral A. 
Published: October 2006

AbstractAflatoxin B1‐DNA adduct concentrations were measured in the livers of adult Sprague‐Dawley CD rats treated on days 2, 4, and 6 postnatally with 1.45 μmol of diethylstilbestrol and in adulthood with phenobarbital, 3‐methylchlanthrene, or vehicle prior to treatment with aflatoxin B1. Aflatoxin B1 (1 mg/kg) was injected 5 hr prior to killing the rats. Female rats exposed neonatally to diethylstilbestrol had significantly higher aflatoxin B1‐DNA adduct concentrations (three‐ to sixfold) than adult female rats treated neonatally with propylene glycol. Liver aflatoxin B1‐DNA adduct concentrations were slightly higher in control males as compared to adduct concentrations in neonatally diethylstilbestrol‐treated males, as compared to adduct concentrations in control females (not significant [NS]). Phenobarbital and 3‐methylcholanthrene treatment followed by aflatoxin B1 injection resulted in decreased aflatoxin B1‐DNA adduct concentrations in all rats. Our results demonstrate that neonatal exposure to diethylstilbestrol alters the capacity of adult female rats to form and/or dispose of carcinogen‐DNA adducts following a single dose of aflatoxin B1 (increased adduct concentration). This alteration may be a consequence of altered imprinting mechanisms with diethylstilbestrol causing developmental modifications early in life. The animals were, however, able to respond to cytochrome P‐450 and P‐448 inducers as evidenced by decreased aflatoxin B1‐DNA adduct concentrations.
Metabolism of methacrylonitrile to cyanide: In vitro studies
Authors: Farooqui Mohammed Y. H. , Diaz Rolando G. , Cavazos Rogelio 
Published: October 2006

AbstractIn liver fractions from male Sprague‐Dawley rats, the metabolism of methacrylonitrile (MeAN) to cyanide (CN−) was localized in microsomal fraction and required reduced nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen for maximal activity. The biotransfomation of MeAN to CN− was characterized with respect to time, microsomal protein concentration, pH, and temperature. Metabolism of MeAN was increased in microsomes obtained from phenobarbital‐treated rats (310% of control) and decreased with CoCl2 and SKF 525 A treatments (55% and 61%, respectively). Addition of the epoxide hydratase inhibitor, 1,1,1‐trichloropropane 2,3‐oxide, decreased the formation of CN− from MeAN. Addition of glutathione, cysteine, D‐penicillamine, and 2‐mercaptoethanol enhanced the released of CN− from MeAN. These findings indicate that MeAN is metabolized to CN− via a cytochrome P‐450‐dependent mixed‐function oxidase system.
Activation of benzo(a)pyrene‐7,8‐dihydrodiol in rat uterus: An in vitro study
Authors: Byczkowski Janusz Z. , Kulkarni Arun P. 
Published: October 2006

AbstractPeroxidatic metabolism of benzo(a) pyrene‐7,8‐dihydrodiol by calcium containing extracts of rat uteri was investigated. Covalently bound and soluble metabolites of benzo(a)pyrene‐7,8‐dihydrodiol were quantitated by radiometry and high performance liquid chromatography, respectively

Uterine extracts incubated with benzo(a)pyrene‐7,8‐dihydrodiol activated this proximate mutagen to protein binding metabolite(s).
Hydrogen peroxide increased the protein binding and yielded a substantial amount of benzo(a)pyrene‐trans‐anti‐tetrahydrotetrol, suggesting the peroxyl‐type free‐radical epoxidation process.
The results indicate that rat uterine peroxidase is able to catalyze free‐radical activation of benzo (a)pyrene‐7,8‐dihydrodiol by epoxidation to its 9,10‐dihydrodiolepoxide, a known ultimate mutagen and carcinogen.
The effect of TCDD on Acyl CoA: Retinol acyltransferase activity and vitamin a accumulation in the kidney of male sprague‐dawley rats
Authors: Jurek Maria A. , Powers Robert H. , Gilbert Linda G. , Aust Steven D. 
Published: October 2006

AbstractPrevious studies have shown that rats treated with 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) show signs of toxicity that are similar to the responses of animals to a vitamin A‐deficient diet. These include hypophagia, loss of body weight, loss of hepatic vitamin A, and accumulation of renal retinoids. Male Sprague‐Dawley rats treated with 10, 30, or 100 nmol/kg of TCDD accumulated renal vitamin A, with retinyl palmitate concentrations reaching 8 times those of control animals, similar to that of male rats fed a vitamin A‐free diet for 26 days. Acyl CoA:retinol acyltransferase (ACARAT) activities in both TCDD‐treated rats and rats fed a vitamin A‐free diet for 26 days were similarly elevated, and were strongly and positively correlated with the renal retinyl palmitate concentrations. Retinol concentrations in the kidneys of rats treated with TCDD or fed a vitamin A‐free diet were only slightly elevated when compared to control rats. We suggest that accumulation of retinyl esters in the kidneys of rats treated with TCDD or fed a vitamin A‐free diet occurs as a result of increased rates of retinol esterification.