bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alteration of liver microsomal monooxygenases and substrate competition with aniline hydroxylase from rats chronically fed low‐fat and high‐fat‐containing alcohol diets
Authors: Winston Gary W. , Narayan Satya 
Published: October 2006

AbstractMale Sprague‐Dawley rats fed ethanol (EtOH) 36% of total calories for four weeks in a liquid diet containing either 34% (HF) or 12% (LF) of calories as fat were studied with respect to induction of microsomal monooxygenases (MFO) and substrate competition with EtOH‐inducible aniline hydroxylase. The specific activity and turnover of aniline hydroxylase were induced to similar extents by HF‐EtOH and LF‐EtOH diets. Whereas, both LF‐EtOH and HF‐EtOH caused a decrease in the turnover of arylhydrocarbon (benzo[a]pyrene) hydroxylase (AHH) and aldrin epoxidase compared to pair‐fed (PF) controls, LF‐EtOH but not HF‐EtOH increased the turnover of ethoxycoumarin and ethoxyresorufin O‐deethylase (ECOD and EROD). The increase in ECOD and EROD and the decrease in AHH by EtOH is contrary to the parallel induction of these activities by J‐methylcholanthrene (3‐MC) and Aroclor 1254 (Aroclor). Benzo(a)pyrene (BaP) stimulated aniline hydroxylase in the HF‐EtOH and PF systems, whereas with LF diet, stimulation was seen only in the EtOH group. Ethoxycoumarin (EC) inhibited aniline hydroxylase by microsomes from EtOH‐ and pyrazole‐treated rats, whereas it stimulated aniline hydroxylase by control microsomes, suggesting that the EC effects were associated with EtOH‐inducible cytochrome P‐450. Ethoxyresorufin (ER) inhibited aniline hydroxylase in EtOH and PF groups, thus the differential effects of EC were not nonspecific O‐deethylase effects. The effects of EtOH feeding on ECOD, EROD, and AHH (ie, substrates for 3‐MC‐inducible cytochrome P‐450) displayed a greater differential between the experimental and control group with the LF‐ than with the HF‐containing diet. The findings suggest that the alteration of certain MFO activities by chronic EtOH ingestion can be modified by the content of dietary fat. Moreover, the competition dynamics of MFO substrates toward EtOH‐inducible aniline hydroxylase are altered by EtOH feeding and, in turn, modified by dietary fat.
Differential Toxicity of Cis and Trans Isomers of Dichlorodiammineplatinum
Authors: Singh Gurmit , Koropatnick James 
Published: October 2006

AbstractNephrotoxicity is the dose‐limiting toxic effect of cis‐dichlorodiammineplatinum (cis‐platin) in humans. Its stereoisomer transplatin does not have any toxicity at equimolar concentrations, and it also possesses little antitumor activity. In this study, subcellular localization of both the platinum isomers was examined in the liver and kidney of the mouse 24 hours following the drug administration. Levels of the platinum isomers were measured using flame‐less atomic absorption. The results showed that higher concentrations of the cis isomer were localized in the liver and kidney, while the concentration of the trans isomer was higher in blood. This indicates that trans isomer is sequestered in the central compartment, whereas cis isomer is distributed in the organs.We also measured metallothionein mRNA and protein levels in both liver and kidney following cisdichlorodiammineplatinum and transdichlorodiammine‐platinum treatment to distinguish if the differential toxicity of the two stereo‐isomers could be related to metallothionein induction. We report here that cisplatin was capable of inducing metallothionein expression in mice in vivo and that there is an inverse relationship between metallothionein expression and the pattern of tissue toxicity induced by the drug.
2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin causes an increase in protein kinases growth hepatic associated with epidermal factor receptor in the plasma membrane
Authors: Madhukar B. V. , Ebner Karl , Matsumura Fumio , Bombick D. W. , Brewster D. W. , Kawamoto T. 
Published: October 2006

Abstract2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD), administered to male rats at a single intraperitoneal (IP) injection dose of 25 μg/kg causes down‐regulation of epidermal growth factor (EGF) receptor in the plasma membrane of rat liver which starts after two days and continues throughout the experimental period (20 days). Using monoclonal antibody to EGF receptor, it was determined that TCDD‐caused EFG receptor down‐regulation in the rat liver was accompanied by increased protein kinase activity. Such an increase in the protein kinase activity involves, at least in part, an activation of protein tyrosine kinase. Examination of serum samples from control and treated rats revealed no detectable difference in the level of EGF itself or EGF receptor‐reacting substances (eg, hormones and other growth factors). In vivo TCDD caused early eye opening and tooth eruption and poor body weight gain and hair growth in mouse neonates similar to those observed with exogenously administered EGE The results indicate that such EGF receptor–mediated effect of TCDD has some toxocilogical significance in vivo. Although TCDD causes significant reduction in [125I]‐EGF binding in the hepatic plasma membrane in susceptible strains of mice, it has only modest effects in tolerant strains. The results are consistent with the idea that the action of TCDD on the EGF receptor is mediated through the cytosoliclnuclear TCDD receptor, which is known to be regulated by the Ah locus.
Sex and strain differences in the hepatotoxic response to acute cocaine administration in the mouse
Authors: Boyer C. Scott , Ross David , Petersen Dennis R. 
Published: October 2006

AbstractCocaine‐induced hepatotoxicity was examined in vivo in a dose‐responsive manner in C57BL/6Ibg, DBA/2Ibg, C3H/2Ibg, and Balb/cJ mice. Serum glutamic‐pyruvic transaminase (SGPT) activities were determined 24 hours after intraperitoneal (IP) administration of cocaine (20 to 100 mg/kg). Significant elevations (100‐ to 150‐fold) in SGPT were observed in male mice receiving cocaine. Significant differences in sensitivity to cocaine‐induced hepatotoxicity were found among males of the inbred strains, with Balb being most sensitive and C57BL being least sensitive and C3H and DBA strains exhibiting intermediate sensitivity. Female mice of the four inbred strains were more resistant than males to cocainemediated hepatotoxicity, as indicated by only twofold to tenfold elevations in SGPT values. Among the females, sensitivity of the four inbred strains—as indicated by dose response curves—fell into two categories: the sensitive strains (C3H and C57BL) and the resistant strains (Balb and DBA). Pretreatment of males of the four inbred strains with the P‐450 inducer phenobarbital resulted in enhancement of cocaine‐mediated hepatotoxicity in the C57BL and Balb but not the C3H and DBA mice. Phenobarbital pretreatment of females of the four inbred strains resulted in enhancement of the hepatotoxic response to cocaine in the C3H, DBA, and Balb mice. Phenobarbital‐pretreated C57BL females exhibited a 100% mortality rate after the acute cocaine dose, and thus no determination of hepatotoxicity could be established for them. These data demonstrate sex and strain differences in cocaine‐induced hepatotoxicity and suggest that phenobarbital pretreatment does not uniformly enhance the hepatotoxicity of cocaine.
Neonatal phenobarbital imprinting of rat hepatic microsomal testosterone hydroxylations
Authors: Haake J. M. , Safe S. H. 
Published: October 2006

AbstractThe effects of neonatally administered phenobarbital (PB) on adult rat hepatic microsomal metabolism of testosterone were examined in 60‐, 90‐, and 120‐day‐old animals. Phenobarbital‐induced imprinting was evident at all ages; however, female rats appeared to be more susceptible to the neonatal effects of phenobarbital than did male rats. In 60‐day‐old female rats, increased testosterone 2α‐hydroxylase activity was observed in microsomes from noninduced rats, whereas decreased testosterone oxidation at all positions except 2α and 15β was observed in microsomes from Aroclor 1254‐induced rats. The decreased oxidation of testosterone at specific sites in response to Aroclor 1254 induction was quite dramatic, decreasing the activities to near or below control levels. By contrast, phenobarbital‐treated 60‐day‐old males exhibited approximately a twofold increase in Aroclor 1254‐induced 16α and 2α‐hydroxylase activities. The pattern of changes in testosterone metabolism observed in phenobarbital‐treated animals was different at both 90 and 120 days from that at 60 days. Only minor alterations in the oxidation of testosterone were observed in 90‐day‐old animals of either sex. In 120‐day‐old animals the greatest effects of neonatal phenobarbital exposure were on Aroclor 1254–induced 16β‐hydroxylase activities. In induced female rats 16β‐hydroxylase activity was again decreased to noninduced levels, while in induced male rats a fourfold increase in this activity was observed. These results demonstrate that neonatal exposure to phenobarbital can alter both constitutive and Aroclor 1254–induced testosterone metabolism in adult rats and that the effects of neonatal phenobarbital exposure are age and sex differentiated.
The formation of 2‐aminofluorene‐dna adducts in vivo: Evidence for peroxidase‐mediated activation
Authors: Krauss Robert S. , Angerman‐Stewart Julie , Eling Thomas E. , Dooley Kenneth L. , Kadlubar Fred F. 
Published: October 2006

AbstractFormation of DNA adducts in various tissues of dogs fed a single dose of the carcinogen 2‐aminofluorene was investigated. Adduct analysis was performed using a technique that allows measurement of both N‐(deoxyguanosin‐8‐yl)‐2‐aminofluorene, the adduct formed by reaction of N‐hydroxy‐2‐aminofluorene with DNA, as well as the polar 2‐aminofluorene‐DNA adducts formed when 2‐aminofluorene is activated by prostaglandin H synthase‐peroxidase in vitro. Two male beagle (A and B) dogs were examined and a different DNA adduct profile was observed with each dog. For the dog A, N‐(deoxyguanosin‐8‐yl)‐2‐aminofluorene was the major adduct found in hepatic DNA; no peroxidase‐derived adducts were detected in this tissue. In contrast, adducts eluting similarly to peroxidase‐derived adducts were found in urinary tract tissues of this dog with the relative abundance of these adducts in the order urothelium > renal medulla > renal cortex, which correlates with the respective tissues' prostaglandin H synthase activity. N‐(Deoxyguanosin‐8‐yl)‐2‐aminofluorene was detected in the renal tissues, but not in urothelium. For dog B, only the N‐(deoxyguanosin‐8‐yl)‐2‐aminofluorene adduct was observed in all tissues examined, including the urothelium. However, total binding to liver, kidney, and bladder were two‐, two‐, and four‐fold lower, respectively, than dog A. These data indicate that both prostaglandin H synthase‐mediated activation and N‐hydroxylation of 2‐aminofluorene occur in vivo and may be subjected to pharmacodynamic considerations. Furthermore, the tissue distribution of the peroxidase‐mediated 2‐aminofluorene adducts suggests this process may also be of importance in the bladder‐specific carcinogenicity of aromatic amines.
Nonideal behavior of alkoxyphenoxazone compounds (cytochrome P‐450 substrates) in aqueous solution
Authors: Rabovsky J. , Heflin E. , Judy D. J. , Sapola N. A. 
Published: October 2006

AbstractSpectral properties of the cytochrome P‐450 substrates, methoxy‐, ethoxy‐, pentoxy‐, and benzyloxyphenoxazone (MeOPx, EtOPx, PeOPx, and BzOPx, respectively) were investigated from 350 to 600 nm in ethanol and aqueous buffer. In ethanol, each alkoxyphenoxazone displayed a λ max at 460 nm and a shoulder around 390 nm. Extinction coefficients (EmM) in ethanol were calculated as MeOPx, 20.5; EtOPx, 20.4; PeOPx, 24.7; and BzOPx, 22.4. In aqueous buffer, only MeOPx obeyed the Lambert‐Beer law (λmax =480 nm, EmM =22.1). Three substrates, EtOPx, PeOPx, and BzOPx, displayed anomalous behavior in aqueous solution, wherein the λmax shifted to lower wavelengths (480–430 nm) and EmM(apparent) decreased as the alkoxyphenoxazone concentration increased. This behavior was dependent on the side chain, and the concentrations at which the spectral changes took place were estimated as: BzOPx, 2 μM. PeOPx, 5 μM; EtOPx, 17 μM; and MeOPx, > 20 μM. The blue shift and decreased EmM (apparent) observed for PeOPx at high concentration in aqueous buffer was reversed at high temperature. Unlike EtOPx, PeOPx, and BzOPx, and like MeOPx, hydroxyphenoxazone (resorufin) and unsubstituted phenoxazone obeyed the Lambert‐Beer law in aqueous buffer and ethanol. The data suggest that the pentoxy and benzyloxy substituents facilitated a self‐association process among the phenoxazones in aqueous solution. The data further show that aqueous solutions should be avoided when spectral data are used to determine alkoxyphenoxazone concentrations.
Selective inhibition of cytosolic epoxide hydrolase activity in vitro by compounds that inhibit catalase
Authors: Guenthner Thomas M. , Thomas Hjelle J. , Whalen Robert 
Published: October 2006

AbstractThe ability of a number of known inhibitors of catalase activity to affect cytosolic and microsomal epoxide hydrolase activities in vitro, measured as enzymatic trans‐stilbene oxide hydrolysis and styrene oxide hydrolysis, respectively, was investigated. Catalase and cytosolic epoxide hydrolase activities are inhibited by hydroxylated metabolites of 2‐amino‐4,5‐diphenylthiazole (DPT). The metabolite hydroxylated on the 4‐phenyl ring (4OH‐DPT) and the metabolite hydroxylated on both phenyl rings (4,5‐DIOH‐DPT) are potent inhibitors of both enzymes; the metabolite hydroxylated on the 5‐phenyl ring (5OH‐DPT) is less potent. Unmetabolized DPT has no effect on either enzyme. 4OH‐DPT inhibits, but 5OH‐DPT enhances, microsomal epoxide hydrolase activity. 4,5‐DIOH‐DPT and DPT have no effect on this enzyme. Other compounds that inhibit both catalase and cytosolic epoxide hydrolase activities, but do not inhibit microsomal epoxide hydrolase activity, are nordihydroguaiaretic acid and 2‐aminothiazole. Microsomal epoxide hydrolase activity is enhanced by 2‐aminothiazole and levamisole in vitro. Thus these inhibitors of catalase are selective epoxide hydrolase inhibitors in that they inhibit cytosolic epoxide hydrolase activity in vitro, but have either no effect on, or increase the activity of, microsomal epoxide hydrolase in vitro. Conversely, the selective cytosolic epoxide hydrolase inhibitors 4‐phenylchalcone oxide and 4′‐phenylchalcone oxide do not inhibit catalase activity, nor does trichloropropene oxide, a selective microsomal epoxide hydrolase inhibitor.
Age‐related difference in bioenergetics of lung and heart mitochondria from rats exposed to ozone
Authors: Zychlinski Lech , Raska‐Emery Patricia , Balis John U. , Montgomery Mark R. 
Published: October 2006

AbstractBioenergetics of isolated lung and heart mitochondria from adult and aged rats were examined in the presence of glutamate (NAD‐linked substrate) or succinate + rotenone (FAD‐linked substrate) following ozone exposure (3.0 ppm, 8 hr). In controls, several differences were observed between adults and aged in both organ preparations. Following exposure, all bioenergetic parameters were decreased significantly in lung preparations from both adult and aged rats. In heart mitochondria, the respiration rates in state 3 and in uncoupled state, and the ADP/O ratio were decreased significantly in both exposed age groups. The respiratory control ratio (RCR) was decreased significantly only in the aged exposed rats. These results suggest that acute exposure to high levels of ozone alters energy production in both lung and heart mitochondria of adult and aged rats.
Differential enzyme induction of mouse liver and lung following a single low or high dose of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD)
Authors: Beebe L. , Park S. S. , Anderson L. M. 
Published: October 2006

AbstractThe induction response of cytochrome P‐450‐dependent enzyme activities to a single low (5 nmol/kg) or high (50 nmol/kg, intraperitoneal [ip] dose of TCDD was examined in liver and lung homogenates over a 12‐week time course in an outbred, Ah‐responsive strain of mice (National Institutes of Health [NIH] Swiss). Total hepatic cytochrome P‐450 was quantified, and the dealkylation of ethoxy‐ and benzyloxyresorufin (activities of P‐450 IA1 and IIB1, respectively) were measured in both tissues at 48 and 96 hr and at 1, 4, and 12 weeks post‐TCDD administration. Western immunoblotting with monoclonal antibody 1–7–1 was conducted to confirm the specific IA1‐inductive effects of each dose of TCDD over the same time course. Following the low dose, specific IA1 induction was apparent in liver at the earliest time point, was maximal at 1 week, and declined to control values at 12 weeks. Pulmonary IA1 was near‐maximally induced at 48 hr, and remained at that level for 4 weeks. In contrast, a tenfold higher dose of TCDD elicited similar IA1 induction profiles for both tissues, with a maximum at 1 week and a progressive loss at 4 and 12 weeks postexposure. P‐450 IIB1 activity was elevated in TCDD‐treated animals by enzymatic assay; however, Western immunoblotting did not confirm this finding. These data demonstrate persistent dose‐dependent P450 induction over many weeks by a single TCDD dose, with significant organ‐specific differences: (a) lung is more sensitive than liver to a nonmaximal inducing dose of TCDD, and (b) at a maximally inducing dose of TCDD, lung is very similar to liver in both the level and time course of IA1 induction.
Localization of the sulfur‐cyanolysis site of serum albumin to subdomain 3‐ab
Authors: Jarabak Rebecca , Westley John 
Published: October 2006

AbstractThe results of kinetic experiments measuring the effects of a variety of ligands on the sulfur‐cyanolysis reaction catalyzed by serum albumin point to the conclusion that the active site for cyanolysis is on subdomain 3‐AB. Relationships among the inhibition by short‐chain fatty acids, the activation by p‐nitrophenyl acetate, and the influence of bilirubin and L‐tryptophan on these effects indicate that the cyanolysis active site and the known primary binding site for indoles are both near, but on opposite sides of, tyrosine‐409 of bovine albumin (tyrosine‐411 of human albumin).
Effect of ascorbic acid esters on hepatic glutathione levels in mice treated with a hepatotoxic dose of acetaminophen
Authors: Mitra Ashoke , Kulkarni Arun P. , Ravikumar Vinnavadi C. , Bourcier Denis R. 
Published: October 2006

AbstractAcetaminophen (APAP) with or without ascorbyl stearate (AS) or ascorbyl palmitate (AP) was administered by gavage to male Swiss‐Webster mice at a dose of 600 mg/kg for each chemical. The biochemical markers of hepatotoxicity, serum transaminases (serum glutamate pyruvate transaminase [SGPT], serum glutamate oxaloacetic transaminase [SGOT]) and serum isocitrate dehydrogenase (SICD) activities were monitored after APAP and APAP + AP or AS dosing. There were significant reductions in serum transaminase and SICD activities in the APAP‐ + ascorbate ester‐treated animals as compared to APAP‐positive controls. Oral coadministration of APAP with AP or AS did not prevent the initial hepatic GSH depletion (15 min‐4 hr postdosing). However, hepatic GSH content began to rise in the APAP + AS or AP‐treated animals at 4 hr and reached control values within 12 hr postdosing. Urinary mercapturate conjugates were also significantly higher in the APAP + AP or AS‐treated animals as compared to APAP alone when measured over a 60‐min postdosing period. Plasma sulfobromophthalein (BSP) retention was approximately eight times higher in APAP‐treated animals as compared to the APAP + ascorbate ester treatments indicating maintenance of hepatic excretory functions in presence of AP or AS. Prior depletion of hepatic GSH by diethyl maleate (DEM) did not alter hepatoprotective effects of AP or AS in the presence of APAP. Hepatic ascorbate levels also peaked at 4 hours after APAP + AP or AS treatments. The possible role of L‐ascorbic acid esters in GSH regeneration following co‐administration of a hepatotoxic dose and APAP is discussed.
Effect of different amino acidic pretreatments that protect the kidney against papillary necrosis induced by bromoethylamine on differential distribution of renal nonprotein sulfhydryls
Authors: Thielemann L. E. , Rosenblut G. , Cerda M. C. , Oberhauser E. W. , De Geyter M. A. , Videla L. A. 
Published: October 2006

AbstractContent of nonprotein sulfhydryls (NPSH) was found to be higher in rat renal cortex than in external medulla and papilla. Administration of bromoethylamine (BEA), at a dose that produces extensive papillary necrosis and minor effects in the other renal segments, induced a significant reduction in NPSH levels of renal cortex and external medulla, with no changes in the papilla. Treatment with N‐acetyl‐L‐cysteine (NAC) elicited an increase in papillary NPSH and a decrease in the cortex, with opposite changes being observed with an amino acid mixture of glutamine, glycine, and cystine (AM). Similar results were found in animals pretreated with NAC or AM prior to BEA intoxication. These pretreatments protect the cortex, external medulla, and papilla from the necrosis induced by BEA. It is suggested that protection of BEA‐induced renal necrosis by NAC or AM pretreatments might be due to different mechanisms, with NPSH playing direct or indirect roles, respectively.
Calcium channel blocking agents protect against acetaminophen‐induced cytotoxicity in rat hepatocytes
Authors: Thibault N. , Peytavin G. , Claude J. R. 
Published: October 2006

AbstractThe effect on acetaminophen‐induced cytotoxicity of three calcium channel blocking agents‐diltiazem, verapamil and gallopamil‐was studied in primary cultures of rat hepatocytes and compared with the chelating agent EGTA. Using the measurement of cytosolic lactate dehydrogenase (LDH) as an index of cytotoxicity, it was demonstrated that a 1‐hr pretreatment with calcium channel blocking agents protected cells against acetaminophen cytotoxicity, but were less effective than EGTA. These data suggest that influx of extracellular Ca2+ into the cells could have a role in the genesis of hepatocyte injury by acetaminophen.
Effects of carbon tetrachloride, menadione, and paraquat on the urinary excretion of malondialdehyde, formaldehyde, acetaldehyde, and acetone in rats
Authors: Bagchi D. , Bagchi M. , Hassoun E. , Moser J. , Stohs S. J. 
Published: October 2006

AbstractExcretions of the lipid peroxidation products, formaldehyde (FA), acetaldehyde (ACT), malondialdehyde (MDA), and acetone (ACON), were simultaneously identified and quantitated in the urine of female Sprague‐Dawley rats by gas chromatography‐mass spectroscopy (GC‐MS) and high pressure liquid chromatography (HPLC) following the acute administration of carbon tetra‐chloride, a model alkylating agent that does not induce glutathione depletion, and the redox cycling compounds paraquat and menadione. All three xenobiotics are well‐known inducers of oxidative stress. Oxidative stress was induced by oral administration of single doses of 2.5 mL of carbon tetrachloride/kg, 60 mg menadione/kg, and 75 mg paraquat/kg. These doses are approximately 50% of the LD50's for the three xenobiotics. Urinary excretion of FA, ACT, MDA, and ACON increased relative to control animals following treatment with all xenobiotics. Over the 48 hours of the study, the greatest increases in the excretion of MDA, FA, ACT, and ACON occurred after paraquat administration, with increases of approximately 2.7‐, 2.6‐, 4.3‐, and 11.0‐fold, respectively. This technique may have wide‐spread applicability as an effective biomarker for investigating altered lipid metabolism in disease states and exposure to environmental pollutants/xenobiotics.