bluuebunny/crossref_metadata_2025_split huggingface dataset:
The differential hepatotoxicity and cytochrome P450 responses of fischer‐344 rats to the three isomers of dichlorobenzene
Authors: Allis John W. , Simmons Jane Ellen , House Dennis E. , Robinson Barbara L. , Berman Ezra 
Published: October 2006

AbstractThe acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer‐344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho‐DCB (O‐DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three end‐points, meta‐DCB (m‐DCB) exhibited a lesser toxicity. Para‐DCB (p‐DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o‐DCB produced a dose‐dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m‐DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p‐DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o‐DCB and p‐DCB were administered at dosages several times the oral rat LD‐50 (RTECS) without any lethality.
Interactions in vitro of some organophosphoramidates with neuropathy target esterase and acetylcholinesterase of hen brain
Authors: Jokanovic M. , Johnson M. K. 
Published: October 2006

AbstractFor organophosphates or phosphorates to initiate delayed neuropathy two steps are necessary: (1) progressive covalent reaction with neuropathy target esterase (NTE) to produce a form of inhibited NTE which can be reactivated by incubation with aqueous potassium fluoride (KF) and (2) progressive “aging” of inhibited NTE to a form which can no longer be reactivated by KF. However, it has been shown recently that certain N‐unsubstituted organophosphoro‐monoamidates (analogues of methamidophos) cause delayed neuropathy even though the inhibited NTE appeared not to have aged (Johnson et al. (1991). Arch. Tox‐icol., 65, 618–624). In order to study the generality of this phenomenon, we have examined some N‐substituted compounds. We report In vitro studies of inhibition and reactivation and aging of both NTE and acetylcholinesterase (AChE) prior to tox‐icological tests. All the compounds studied were less inhibitory to both NTE and AChE in concentrated rather than in dilute suspensions of EDTA‐washed brain particles without added cofactors. There was an apparent disposal of up to 100 üumoles of test compound by particles from 95 mg hen brain, which is far greater than can be explained by covalent binding. The activity is distinct from calcium‐dependent “A” esterase. Several N‐alkyl phosphoromonoamidates were found to be potent and selective inhibitors of NTE: second‐order rate constant for O‐n‐pentyl N‐benzylphosphoramido‐fluoridate (Cmpd 6) = 5.6×107 M−1 min−1 at 37°, which is about l00% higher than for acetylcholinesterase (AChE). Inhibited NTE and AChE from several chiral phosphoromono‐amidates did not reactivate spontaneously (21 hours at 37°). Virtually 100% reactivation by KF of AChE inhibited by phosphoromonoamidates was achieved at all times tested. Acetylcholinesterase inhibited by 2,5‐dichlorophenyl N,N′‐di‐n‐butylphosphorodiamidate was 42–56% reactivated by incubation with KF (192 mM in pH 5.2 buffer for 30 minutes at 37°rpar;. We believe this is the first report of reactivation of any enzyme after inhibition by a phosphorodi'amidate. For NTE inhibited by tabun (O‐ethyl N‐dimethylphosphoroamidocyanidate), virtually complete and rapid aging (t1/2 = 5.5–8.4 minutes) was observed. Consistent but only partial reactivation by KF was achieved 2 or more hours after inhibition of NTE by Cmpd 6 or by its 2,6‐difluoro‐an‐alogue (Cmpd 7). However, a small but significant aging (approximately 15–20% loss of reactivatability) was measured soon after a 1 minute inhibition by Cmpd 7, but no further change occurred in 21 hours. We conclude that, of the two chiral forms of NTE obtainable from chiral N‐substituted phosphoromonoamidates, one form can and does age rapidly while the enantiomeric form does not. The toxicological significance of these results is discussed.
Immobilized rhodanese: Some aspects of anion inhibition kinetics and modulation by cations
Authors: Nok Andrew J. , Nasir Shuaibu M. , Sa'Adatu Yusuf 
Published: October 2006

AbstractThe rat liver rhodanese (thiosulphate: cyanide sulfurtransferase EC 2.6.1.1) has been immobilized on polyacrylamide gels. The immobilized enzyme had a pH optimum of 7.4 and Km values of 3.25 mM and 1.12 mM for S2O2−3 and KCN, respectively. The enzyme was competitively inhibited by NaNO2 and CH3COONa and noncompetitively by amyl‐nitrite. A modulation of activity was observed in the presence of Ca2+, Zn2+, and Cu2+. The results are discussed in line with the detoxicating function of liver rhodanese.
The effect of the cytochrome P‐450 system inducers on the development of drosophila melanogaster
Authors: Fuchs S. Yu. , Spiegelman V. S. , Belitsky G. A. 
Published: October 2006

AbstractD. melanogaster development was markedly retarded and its survival decreased by larvae treatment with compounds being strong inducers of the cytochrome P‐450 2B in mammals— phenobarbital (PB*), perfluorodecaline (PFD), transstilbene oxide (TSO), and triphenyldioxane (TPD). At the same time, the weak inducer hexobarbital or the selective cytochrome P‐450 inducer in mice but not in rats 1,4‐bis[2‐(dichloropyridyl‐oxy)]‐benzene (DPB) did not affect the larvae development. The cytochrome P‐450 1A1 inducers benzo(a)anthracene (BA) and β‐naphtoflavone (BNF) were also not effective. The toxicity of phenobarbital was shown to be decreased by the cytochrome P‐450 inhibitor piperonyl butoxide by adding 20‐hydroxyecdysone or by treatment with aminophylline—the indirect enhancer of ecdysone production in the larval prothoracic gland. The hypothesis of the moulting hormone degradation as the cause of elevated larvae mortality resulting from the induced high mixed function oxidase activity has been discussed.
Effects of piperine on enzyme activities and bioenergetic functions in isolated rat liver mitochondria and hepatocytes
Authors: Jamwal Deshvir S. , Singh Jaswant 
Published: October 2006

AbstractThe influence of piperine on the enzymes and bioenergetic functions in isolated rat liver mitochondria and hepatocytes was studied. Piperine at lower concentrations (<50 μM) did not affect the RCR and ADP:O ratios, state 4 and 3 respirations supported by site‐specific substrates, viz. glutamate + malate, succinate, and ascorbate + TMPD. The site‐specific effects became significantly apparent only at higher concentrations. Only the state 3 respiration supported by NAD‐linked substrates was impaired equipotently in mitochondria and permeabilized hepatocytes; the effect appeared to be localized at energy‐coupling site 1. In hypotonic treated mitochondria, respiration supported by three kinds of substrates was not affected.Among the respiratory chain‐linked enzymes, the activity of NADH‐dehydrogenase registered a significant decrease of about 25, 42, and 53% at 100, 150, and 180 μM piperine, respectively. The activity of Mg++‐ATPase, however, was stimulated at concentrations above 150 μM. Among the matrix enzymes, only malate and succinate dehydrogen‐ases were studied. Malate dehydrogenase only showed a strong concentration‐related inhibition in both the forward and backward directions. Enzyme kinetics indicated noncompetitive inhibition with a very low Ki of 10 μM. The presence of unsaturated double bonds in the side chain of piperine appeared essential for producing this strong inhibition. The studies suggested that piperine produces concentration related site‐specific effects on mitochondrial bioenergetics and enzymes of energy metabolism.
Controversial role of intracellular iron in the mechanisms of chemically‐induced hepatotoxicity
Authors: Badr Mostafa Z. 
Published: October 2006

AbstractHepatotoxicity induced by various therapeutic agents, industrial chemicals and environmental pollutants is a well‐recognized phenomenon. These chemicals are known to cause liver damage that is localized to either periportal or centrilobular regions of the liver lobule (1–3). Depending on dose, duration, and route of exposure, the resultant liver injury may regress or progress and becomes irreversible (1). Mechanisms involved in this selective, localized toxicity have been the target of extensive research efforts, and many Studies produced conflicting results. As depicted in Figure 1, although many investigators implicate iron and lipid peroxidation in this process (4‐9), others dispute such assertions (10–12).
Ozone increases amino‐ and carboxy‐terminal atrial natriuretic factor prohormone peptides in lung, heart, and circulation
Authors: Vesely David L. , Giordano Amy T. , Raska‐Emery Patricia , Montgomery Mark R. 
Published: October 2006

AbstractOzone can cause pulmonary edema and simultaneously decrease blood pressure. Atrial natriuretic peptides may mediate both of these effects in that they increase pulmonary capillary permeability resulting in edema formation and are potent vasodilating peptides. To examine this possibility, the lungs of Fischer 344 rats were exposed to ozone (0.5 ppm) for 8 hours which resulted in a three‐ to fourfold increase in atrial natriuretic peptides. Ozone also increased atrial natriuretic peptides in the heart two‐ to fivefold from 266 ± 25, 226 ± 22, and 288 ± 40 ng/g (room air) to 716 ± 26, 471 ± 14, and 1473 ± 235 ng/g recognized by the proANFs 1–30 and 31–67 and atrial natriuretic factor radioimmunoassays, respectively. Ozone also doubled the concentrations of proANFs 1–30, 31–67, and 1–98 and ANF in the circulation. This study demonstrates that ozone increases atrial natriuretic peptides within the heart, lung, and circulation, suggesting that atrial natriuretic peptides may mediate the decreased blood pressure and pulmonary edema observed with ozone exposure. Since the proANF 31–67 radioimmunoassay exclusively recognizes the ANF prohormone within the heart, this study further indicates that ozone can increase the synthesis of the ANF prohormone.
Long‐lasting effects of chronic ethanol administration on the activity of antioxidant enzymes
Authors: Almeida Vǎnia D' , Monteiro Maristela Goldnadel , Oliveira Maria Gabriela M. , Pomarico Ana Cristina , Bueno Orlando Francisco Amodeo , da Silva‐Fernandes Maria Eugěnia 
Published: October 2006

AbstractThe aim of this study was to investigate the long‐lasting effects of prolonged administration of ethanol doses on oxidative processes of aged rats. We determined the activity of superox‐ide dismutase (SOD), catalase (CAT), and gluta‐thione peroxidase (GPx) in erythrocytes of rats 15, 20, and 24 months old treated with an average daily dose of 1.5 g/Kg of ethanol or saline administered intraperitoneally for 13 weeks and after a 2 month period of withdrawal from treatment. The activity of all three enzymes decreased significantly with aging in the controls, while no age‐related changes were found among treated rats. These findings are important since they are the first to show a long‐lasting toxic effect of low ethanol doses observed in association with the aging process.
The effects of ricin on the sympathetic vascular neuroeffector system of the rabbit
Authors: Christiansen Victoria J. , Hsu Chia‐Hsuh , Robinson Casey P. 
Published: October 2006

AbstractRicin is a toxic lectin that inhibits protein synthesis. Because ricin decreases arterial pressure and causes cardiovascular collapse, its effects on the vascular neuroeffector system were investigated. Rabbits were given either of two doses of ricin, and then norepinephrine (NE) release from aorta to transmural stimulation, NE uptake into aorta, NE content of aorta, monoamine oxidase activity, and catechol‐O‐methyl transferase activity in aorta were determined 18 hours, 4 days or 7 days later. Norepinephrine uptake and enzyme activities in the aorta were not altered by ricin administration. Norepinephrine release and content of aorta were increased at most time periods following ricin administration, significantly so for NE content at 4 days and for release at 18 hours following the lower dose of ricin. We conclude that the mechanisms involved in the release of NE from sympathetic nerves in the vasculature are not impaired by ricin administration, but rather show changes that indicate increased compensatory activity.
A kinetic analysis of hepatic microsomal activation of parathion and chlorpyrifos in control and phenobarbital‐treated rats
Authors: Ma Tangeng , Chambers Janice E. 
Published: October 2006

AbstractA kinetic analysis of cytochrome P450‐mediated desulfuration (activation) or dearylation (detoxication) showed that rat hepatic microsomes have a greater capacity to detoxify and a lower capacity to activate chlorpyrifos compared to parathion. Kinetic curves for the desulfuration of both parathion and chlorpyrifos were biphasic; K s of 0.23 and 71.3 μM were calculated for parathion, and 1.64 and 50.4 μM for chlorpyrifos. While phenobarbital (PB) exposure seemed to generally lower the Kmapp s for desulfuration except for the low Km activity on chlorpyrifos, the results were not statistically significant. While the low Km activity contributed 44 and 60% of the control Vmax for parathion and chlorpyrifos, respectively, it contributed 50 and 17% in PB‐treated rats. These studies have indicated the presence of a low Km activity capable of functioning at very low substrate concentrations. A single dearylation K was calculated, 56.0 and 9.8 μM for parathion and chlorpyrifos, respectively. Phenobarbital exposure seemed to raise the Ks of dearylation; however, again, the results were not statistically significant. While numerous biochemical factors contribute to the overall toxicity levels of phosphorothionate insecticides, the in vitro efficiencies of hepatic microsomal desulfuration and dearylation of parathion and chlorpyrifos correspond to the acute toxicity levels.
Effect of thyroid hormone administration on the depletion of circulating glutathione in the isolated perfused rat liver and its relationship to basolateral γ‐glutamyltransferase activity
Authors: Videla Luis A. , Fernández Virginia 
Published: October 2006

AbstractThe influence of thyroid hormone administration on liver glutathione (GSH) extraction in the isolated perfused liver was studied in fed rats for a period of 1–7 days following a single dose of 0.1 mg 3,5,3′‐triiodothyronine (T3)/kg. T3 treatment led to an early and transient calorigenic response, as well as an enhancement in liver GSH removal, reaching a maximal effect at 2 days after hormone administration, which was normalized in the 3‐ to 7‐day period studied. Addition of the γ‐glutamyltransferase (γ‐GT) inhibitor DL‐serineborate (4 mM) to the perfusate abolished the increase in the hepatic removal of GSH elicited by T3, and enhanced the sinusoidal concentration of GSH, studied at 2 days after hormone administration. These data support the role of hepatic basolateral γ‐GT ectoactivity in the depletion of portally added and liver‐derived GSH as an adaptive response to recover GSH levels after reduction by T3‐induced oxidative stress.
Ah receptor involvement in mediation of pyruvate carboxylase levels and activity in mice given 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin
Authors: Ryu Byung‐Woo , Roy Shukla , Sparrow Barney R. , Selivonchick Daniel P. , Schaup Henry W. 
Published: October 2006

AbstractThe arylhydrocarbon receptor (AhR) plays a central role in mediating 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) toxicity in animals. The investigations described here provide evidence that support a role for the AhR in TCDD‐mediated pyruvate carboxylase (PC) level/activity reductions in mice. Pyruvate carboxylase plays a pivotal role in gluconeogenesis and in supplying carbon units for the citric acid cycle. Delivered ip in a corn oil carrier, TCDD suppresses PC activity/amount at doses as low as 1 μg/kg in responsive C57BL/6J(Ahb/b) mice. Corn oil alone injected ip into mice at 4 mL/kg appears to be an inducer that increases the amount and activity of PC. However, TCDD suppresses this induction. In the Ahb/b mouse, PC levels and activity are reduced to 10% of control values at a dose of 75 μg/kg. A time‐course experiment shows that the PC reductions are apparent within 16 hours post‐TCDD exposure. Here we report investigations on the PC/TCDD response using a congenic C57BL/6J(Ahd/d) mouse strain having an AhR with a low affinity for TCDD. If the PC/TCDD response is AhR mediated, the congenic mouse strain (Ahd/d) would require much higher doses of TCDD to suppress PC. In the Ahd/d mice, we observe that an approximately 60‐fold increase in TCDD dose is necessary to produce a PC/TCDD effect. We also find that in Ahd/d mice, corn oil does not induce an increase in PC activity/amounts, as reported for Ahb/b mice.
Paradoxical effect of sudan III on the in vivo and in vitro genotoxicity elicited by 7,12‐dimethylbenz(a)anthracene
Authors: Hatakeyama Shigeki , Hayasaki Yayoi , Masuda Makihiko , Kazusaka Akio , Fujita Shoichi 
Published: October 2006

AbstractEffect of the induction of drug metabolizing enzymes by Sudan III on the in vivo and in vitro genotoxicity elicited by 7,12‐dimethyl‐benz(a)anthracene (DMBA) was investigated. A significant suppression of DMBA‐induced micronucleated reticulocytes was observed in C57BL/6 mice treated with Sudan III intraperitoneally for 3 or 5 days before injection of the DMBA. However, the preincubation of DMBA with hepatic microsomes from Sudan III‐treated rats caused a marked increase in the in vitro mutagenicity in the Ames assay, paradoxically. Sudan III was found to induce CYP 1A1, 7‐ethoxycoumarin O‐deethylase activity as well as both UDP‐glucuronyl transferase and glutathione S‐transferase activities. The increase of mutagenicity of DMBA observed in the Ames assay using hepatic microsomes from Sudan III‐treated rats was inhibited by the addition of uridine 5′‐diphosphoglucuronic add or reduced glutathione with cytosol. Mutagenic metabolites of DMBA formed by CYP1A1 appeared to be effectively detoxified by these phase II enzymes.The results of this study suggest that Sudan III‐induced prevention of in vivo mutagenesis is due to the induction of both CYP 1A1 and detoxifying phase II enzymes. The induced CYP1A1 may accelerate formation of active metabolic intermediates, but phase II enzymes are also induced and detoxify these intermediates to inactive metabolites. This would reduce residence time of the carcinogen in the body and the time of exposure to active metabolites for target organs.
Alteration of Ca2+ homeostasis of sea urchin embryos by retinoid CD 367, dual effect on egg cleavage and embryonic development
Authors: Espagnet S. , Delescluse C. , Pesando D. , Graillet C. , Michel S. , Girard J.‐P. 
Published: October 2006

AbstractThe effect of a light stable retinoid (CD 367) was studied on sea urchin embryos. CD 367 did not affect sperm‐egg interaction. In a range of concentrations between 10 and 100 μM, CD 367 delayed the first and the second cleavages. When added after fertilization, micromolar amounts of CD 367 delayed hatching and produced embryonic abnormalities in a dose‐dependent manner. Mesodermal cells, primary (PMC) and secondary (SMC) mesenchyme cells migration was particularly disturbed, leading to exogastrulations and calcified spicules malformations. Concentrations of CD 367 higher than 8 μM were embryolethal. Micromolar amount of CD 367 increased plasmalemma Ca2+ permeability of fertilized eggs but not of unfertilized eggs. CD 367 inhibited ATP‐dependent intra‐cellular sequestration of Ca2+ in a range of concentrations similar to those affecting egg cleavage and embryonic structures. Since we were unable to detect nuclear receptors for CD 367 in sea urchin eggs and ovocytes, these effects probably are not related to interaction of the retinoid with members of the RAR family, to which CD 367 has a high affinity, but rather to its toxicity by the means of some unknown mechanisms.
Altered glycine transport by cerebral tissue and decreased Na+ and Ca++ pump activities during organophosphorus‐ester–induced delayed neurotoxicity development period
Authors: Sharma Shri Krishna , Bhattacharya Bijoy K. 
Published: October 2006

AbstractUptake of [U‐14C] glycine during the organophosphorus‐ester‐induced delayed neurotoxicity (OPIDN) development period was studied. Diisopropyl fluorophosphate (DFP), a delayed neurotoxic organophosphorus ester was administered to adult rats and hens. Results showed a decreased accumulation of glycine in hen cerebral cortex slices during the delayed neurotoxicity development period. An altered sensitivity toward transport inhibitors 2,4‐dinitrophenol and ouabain was observed in DFP‐treated hens. An altered neuronal membrane function during the OPIDN development period is reported in the present work. Brain Na+, K+‐ATPase and Ca++‐ATPase activities decreased during the neurotoxicity development period. The decrease in Ca++‐ATPase activity persisted in hens until the complete development of neurotoxic symptoms. Decreased Ca++ pump activity is correlated with altered membrane function during OPIDN. © 1996 John Wiley & Sons, Inc.