bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic polyamines and related enzymes following chlordecone‐potentiated carbon tetrachloride toxicity in rats
Authors: Rao Shrinivas B. , Young Robert A. , Mehendale Harihara M. 
Published: October 2006

AbstractChlordecone potentiation of the hepatotoxic and lethal effects of CCl4 has been well established. Recent studies have shown that the suppression of hepatocellular regeneration results in an accelerated progression of liver injury leading to complete hepatic failure. Since polyamines are involved in cell division, these studies were designed to investigate the polyamine levels and associated enzymes in the livers of rats treated with a low‐dose combination of CD and CCl4. For comparison, a large toxic dose of CCl4 was also employed. The extent of liver toxicity in rats fed 10 parts per million chlordecone (CD) for 15 days and subsequently injected with a single dose of CCl4 (100 μL/kg body weight) or a high dose of CCl4 alone (2.5 mL/kg body weight) was similar 6 and 24 hr later as assessed by plasma transaminase levels. There was significant elevation in liver ornithine decarboxylase, S‐adeno‐sylmethionine decarboxylase, and putrescine at 24 hr and spermidine N1‐acetyltransferase, N1‐acetylputrescine, putreanine, putrescine, and N1‐acetylspermidine at 6 hr in rats treated with the high dose of CCl4 alone compared to the combination treatment. Spermidine levels decreased up to 6 hr and then increased up to 24 hr for both treatments. Spermine continuously decreased up to 24 hr for the CD and CCl4 low‐dose combination treatment compared to rats treated with a high dose of CCl4 alone. Spermidine levels were lower than in controls and rose towards control value between 6 and 24 hr after the combination treatment and the high dose of CCl4. Results indicate that the CD and CCl4 low‐dose combination treatment increased liver toxicity, resulting in compromised polyamine metabolism that is coincidental with suppressed hepatocellular regeneration, which leads to an accelerated progressive phase of liver injury and culminates in complete hepatic failure.
Comparison of the formation of benzo[a]pyrene diolepoxide‐dna adducts in vitro by rat and human microsomes: Evidence for the involvement of p‐450IA1 and p‐450IA2
Authors: Vähäkangas Kirsi , Raunio Hannu , Pasamen Markku , Sivonen Päivi , Park Sang‐Shin , Gelboin Harry V. , Pelkonen Olavi 
Published: October 2006

AbstractThe involvement of cytochrome P‐450 isozymes in the activation of benzo[a]pyrene (BP) by human placental and liver microsomes was studied in vitro using monoclonal antibodies (Mab) toward the major 3‐methylcholanthrene (MC)‐inducible and phenobarbital‐inductible rat liver P‐450 isozymes (Mab 1–7–1 and Mab 2–66‐3, respectively). Microsomes from human placenta and liver and rat liver were incubated with BP and DNA, and BP‐diolepoxide‐DNA (BPDE‐DNA) adducts were measured by synchronous fluorescence spectrophotometry (SFS). The only BP metabolite giving the same fluorescence peak as chemically modified BPDE‐DNA was BP‐7,8‐dihydrodiol. Five (smokers) out of 29 human placentas (smokers and nonsmokers), and five out of nine human livers were able to metabolically activate BP to BPDE‐DNA adducts in this system. The Mab 1–7–1 totally inhibited the formation of BPDE‐DNA adducts in placental microsomal incubations. Inhibition using rat or human liver microsomes was 50–60% and about 90%, respectively. The Mab 2–66‐3 had no effect in any of the microsome types. Adduct formation was inhibited more strongly and at lower concentrations of Mab 1–7–1 compared with the inhibition of AHH activity. This study is a clear indication of the major role of P‐450IA1 (P‐450c) in human placenta and probably P‐450IA2 (P‐450d) in human liver in BP activation, while other isozymes also take part in the activation in rat liver. Furthermore, this clearly indicates that AHH activity and BP activation are not necessarily associated.
Covalent binding to proteins of reactive intermediates resulting from prostaglandin h synthase‐catalyzed oxidation of stilbene and steroid estrogens
Authors: Freyberger Alexius , Degen Gisela H. 
Published: October 2006

AbstractProstaglandin H synthase (PSH) is known to metabolically activate a variety of xeno‐biotics in vitro by means of its peroxidase activity. Recently, stilbene and steroid estrogens have been found to be cooxidized by ram seminal vesical microsomes, a rich source of PHS, to nonextractable metabolites bound to microsomal protein. To investigate further the nature of this protein binding, different radiolabeled estrogens were incubated with purified PHS, holoenzyme in the presence of various amounts of albumin (BSA), and radioactivity bound to protein was determined after gel electrophoretic separation. Diethylstilbestrol (DES), its analog hexestrol, and the steroid estrogens estrone and 2‐hydroxy‐estrone were cooxidized by PHS in vitro to metabolites that bound covalently to PHS and to BSA. Although a preferential binding of DES to PHS was found in the presence of excess BSA, reactive intermediates derived from DES, or from the other estrogens, were sufficiently stable to react with the competing nucleophile BSA as well.With respect to the metabolic reactions catalyzed by PHS, in addition to one‐electron oxidation of phenolic functions, PHS catalyzed the aromatic hydroxylation of synthetic and steroid estrogens as shown by 3H2O release from regiospecifically labeled compounds and confirmed by product identification. Although DES was extensively metabolized by PHS, its aromatic hydroxylation was minor by comparison to estradiol, a difference possibly related to the compounds' redox potentials.Thus, cooxidation of estrogens in vitro resulted in phenoxy radicals, semiquinones and quinones, reactive intermediates capable of protein binding that may contribute to the adverse effects of stilbene and steroid estrogen observed in vivo and in short‐term assays.
Plasma concentrations of pituitary hormones in 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin‐treated male rats
Authors: Moore Robert W. , Parsons Jonathan A. , Bookstaff Robert C. , Peterson Richard E. 
Published: October 2006

AbstractExperiments were conducted to test the hypothesis that acute TCDD toxicity is associated with pituitary hypofunction. Sexually mature male Sprague‐Dawley rats were given graded doses of TCDD (0–100 μg/kg) and evaluated 7 days later. Despite pronounced hypophagia and body weight loss, plasma concentrations of growth hormone (GH), follicle‐stimulating hormone (FSH), and luteinizing hormone (LH) were not significantly affected by any dose of TCDD. Only prolactin (PRL) concentrations were reduced, while, as previously reported, thyroid‐stimulating hormone concentrations were elevated. Also, plasma LH, PRL, and adrenocorticotropic hormone (ACTH) concentrations were not significantly affected 1, 2, 3, 4, 5, or 7 days after a single dose of TCDD (50 μg/kg). We conclude that (1) pituitary hypofunction is not a major cause of the initial stages of acute TCDD toxicity, (2) growth retardation in TCDD‐treated rats is not the result of a deficiency of GH, (3) alterations in plasma corticosterone concentrations are due to altered responsiveness of the adrenal to ACTH stimulation rather than to changes in plasma ACTH concentrations, and (4) that impaired spermatogenesis is not associated with a decrease in plasma FSH concentrations. In addition, the lack of a consistent effect on plasma PRL concentrations suggests that alterations in plasma PRL concentrations do not play a critical role in the toxicity of TCDD. Finally, because TCDD treatment causes a serious androgenic deficiency without increasing the rates at which androgens are catabolized or excreted, the fact that plasma LH concentrations were unaffected indicates that TCDD treatment must reduce the responsiveness of the testis to LH stimulation. In addition, because the expected compensatory response to low plasma androgen concentrations (a pronounced elevation in plasma LH concentrations) was absent, these observations also indicate that TCDD treatment must interfere with the regulation of plasma LH concentrations.
Covalent interaction of chloroacetic and acetic acids with cholesterol
Authors: Bhat Hari K. , Ansari G. A. S. 
Published: October 2006

AbstractThe covalent interaction of chloroacetic acid with rat liver lipids was studied in vivo. Rats were given a single oral dose (8.75 mg/kg, 50 μCi) of 1‐[14C]chloroacetic acid and sacrificed after 24 hours. Lipids extracted from the livers were separated into neutral lipids and phospholipids by solid‐phase extraction using sep‐pak silica cartridges. The neutral lipid fraction was further fractionated by preparative thin‐layer chromatography followed by reverse‐phase high‐performance liquid chromatography. The fraction corresponding to the retention time of standard cholesteryl chloroacetate gave a pseudomolecular ion peak at m/z 480/482 ratio: (3:1) on ammonia chemical ionization mass spectrometry, and the fragmentation pattern was found to be similar to that of the standard sample. Under similar conditions, acetic acid resulted in the formation of cholesteryl acetate. The effect of such conjugation reactions on the cell membrane and their contribution to toxicity is presently unknown.
Increased susceptibility to pentobarbital following mouse cytomegalovirus infection: Relative roles of viral‐induced interferon and viral infection of the liver
Authors: Catignani Joan C. , Ménache M. G. , Selgrade Maryjane K. 
Published: October 2006

AbstractThe purpose of this study was to determine the relative roles of viral‐induced interferon (IFN) and viral infection of the liver in mouse cytomegalovirus (MCMV)‐induced depression of cytochrome P‐450 (cyt P‐450) levels and enhancement of pentobarbital‐induced sleeping time (PEN‐ST). This was done by establishing the temporal relationship among the IFN response, viral infection of the liver, suppression of cyt P‐450 levels, and enhancement of PEN‐ST, by determining the effect of anti‐IFN antibody treatment on all of these responses, and by manipulating factors known to influence viral pathogenesis and host response to virus such as animal age, virulence of the virus, and dose of virus. In general, manipulation of these factors toward increased stimulation of host immune responses resulted in greater depression of cyt P‐450. The data are consistent with the hypothesis that some IFN‐dependent mechanism may have contributed to the effects of MCMV infection on both cyt P‐450 levels and PEN‐ST; however, the temporal relationship among the various responses measured following viral infection suggested that the effect of the IFN response may be indirect and due to modulation of other host defense mechanisms. Use of anti‐IFN antisera to definitively establish a role for IFN in the effects observed here proved unsuccessful. Effects on PEN‐ST and cyt P‐450 levels did not appear to be related to the magnitude of infection in the liver. Because suppression of cyt P‐450 levels and enhancement of PEN‐ST were not always parallel, it is possible that the enhanced sensitivity to pentobarbital observed in infected mice was the cumulative result of effects on cyt P‐450 as well as other components involved in the distribution and metabolism of the drug.
Appendix to the sulfur‐cyanolysis sites of serum albumin: Metabolite competition studies. Tight‐binding inhibitions that yield atypical henderson plots
Authors: Westley John , Jarabak Rebecca 
Published: October 2006

AbstractOrdinary tight‐binding inhibition in steady‐state enzyme systems is conveniently evaluated by means of the Henderson plot. This is a linear plotting form that has an ordinate intercept equal to the total enzyme concentration. However, there are two experimental situations that yield deviations from the common Henderson plot form. These are inhibitor binding in a separate, noninhibitory mode that depletes the concentration of free inhibitor, and partial inhibition, i.e., the retention of partial activity by the enzyme‐inhibitor complex. Noninhibitory depletion results in Henderson plots with elevated ordinate intercepts. Competitive partial inhibition yields a characteristic pattern of parabolic Henderson plots.
Differences in induction of hepatic cytochrome p450 isozymes by mice in eight methylenedioxyphenyl compounds
Authors: Lewandowski Margaret , Chui Y. C. , Levi Patricia E. , Hodgson Ernest 
Published: October 2006

AbstractEight methylenedioxyphenyl (MDP) compounds were examined for their ability to induce cytochrome P450 (P450) in mouse liver. Induction by safrole, isosafrole, and dihydrosafrole was studied in both C57BL/6N (Ah‐responsive) and DBA/2N (Ahnonresponsive) male mice after IP administration of 200 mg/kg/day MDP compound for 3 days. Hepatic P450 content, ethylmorphine N‐demethylase, ethoxy‐resorufin O‐deethylase, and acetanilide hydroxylase activities were induced to the same extent in both strains of mice. Benzo(a)pyrene hydroxylase activity, however, was not induced in either C57 or DBA mice. The similarity of results in both strains of mice indicated induction of these P450 isozymes by these three MDP compounds is not mediated by the Ah receptor. Induction of P450 by butylbenzodioxole (n‐butyl‐BD), tertiarybutylbenzodioxole (t‐butyl‐BD), methylbenzodioxole (methyl‐BD), nitrobenzodioxole (nitro‐BD), and bromobenzodioxole (bromo‐BD) was examined only in C57BL/6N mice. Methyl‐BD, nitro‐BD, and bromo‐BD did not induce hepatic microsomal proteins or selected P450 monooxygenase activities. In contrast, n‐butyl‐BD, and t‐butyl‐BD induced P450 content, ethylmorphine N‐demethylase, acetanilide hydroxylase, and ethoxyresorufin O‐deethylase activities. Benzo(a)pyrene hydroxylase was not induced by any of the treatments. Induction of these P450 activities is consistent with induction of P450 IIB1 and P450 IA2, but not induction of P450 IA1. Western blot analysis with antibodies to P450 isozymes induced with either phenobarbital (Pb) or 3‐methylcholanthrene (3‐MC) confirmed that both IIB1 and IA2 were induced, but that IA1 was not induced.
The effects of soman in vitro on catechol‐o‐methyltransferase and monoamine oxidase activities in rabbit tissues
Authors: Hsu Chia‐Hsuh , Hu Chao‐Yu , Robinson Casey P. 
Published: October 2006

AbstractSoman (pinacolyl methylphosphonofluoridate) not only increases acetylcholine levels by inhibiting cholinesterases, it also alters the levels of some other neurotransmitters including norepinephrine, dopamine, and serotonin. Soman also causes an alteration in the activities of the enzymes metabolizing norepinephrine when it is administered to animals. Because these alterations may result from indirect effects on the enzymes, the effects of in vitro application of soman on catechol‐O‐methyl‐transferase (COMT) and monoamine oxidase (MAO) activities in rabbit tissues were investigated. Enzyme activities were determined in rabbit lung, liver, cerebellum, cerebrum, brain stem, mesenteric artery, pulmonary artery, renal artery, central ear artery, thoracic aorta, and diaphragm. MAO and COMT activities were not affected by soman in any tissues tested, except the lung and liver, where the activity of COMT was increased (p < 0.05). Thus, reported effects of soman in vivo on norepinephrine, dopamine, or serotonin concentrations, and MAO and COMT activities do not seem to result from direct effects on the activities of these aminemetabolizing enzymes.
Role of inducer binding in cytochrome P‐450 IA2‐mediated uroporphyrinogen oxidation
Authors: Jacobs Judith M. , Sinclair Peter R. , Lambrecht Richard W. , Sinclair Jacqueline F. , Jacobs Nicholas J. 
Published: October 2006

AbstractThe oxidation of uroporphyrinogen, an intermediate of the heme biosynthetic pathway, by methylcholanthrene‐inducible isozyme(s) of cytochrome P‐450 has been proposed to play a role in the development of chemically induced uroporphyria. Prior work from this laboratory [10] indicated that although addition of 3,4,3′,4′‐tetrachlorobiphenyl is required for uroporphyrinogen oxidation by methylcholanthrene‐induced chick embryo liver microsomes, this biphenyl is not required for the oxidation catalyzed by hepatic microsomes from methylcholan‐threne‐induced rodents. Here we investigated whether rodent microsomes catalyze uroporphyrinogen oxidation without addition of 3,4,3′,4′‐tetrachlorobiphenyl because the chemical used as an inducer remains bound to cytochrome P‐450. Hepatic microsomes containing almost no residual inducer were isolated from rats treated with a low dose of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). These microsomes oxidized uroporphyrinogen at high rates without addition of 3,4,3′,4′‐tetrachlorobiphenyl. Inducerfree microsomal cytochrome P‐450 was also obtained by inducing cytochrome P‐450 in rats and mice with isosafrole, which was then removed from the isolated microsomes by butanol treatment. This procedure resulted in microsomes with high activity for uroporphyrinogen oxidation. Furthermore, addition of chlorobiphenyl to these inducer‐free microsomes was inhibitory. Hepatic microsomes from isosafroleinduced C57BL / 6 and DBA mice, rendered inducerfree by butanol treatment, oxidized uroporphyrinogen at the same rate even though these two strains differ markedly in their susceptibility to chemically induced uroporphyria. We conclude that uroporphyrinogen oxidation is catalyzed by cytochrome P‐450 that is free of inducer.
Tissue distribution, metabolism, and elimination of perfluorooctanoic acid in male and female rats
Authors: Heuvel John P. Vanden , Kuslikis Benedict I. , Van Rafelghem Marc J. , Peterson Richard E. 
Published: October 2006

AbstractThe elimination, tissue distribution, and metabolism of [1‐14C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 μmol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA‐derived 14C was observed. Female rats eliminated PFOA‐derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered 14C in the urine. The sex‐related difference in urinary elimination resulted in the observed difference in the whole‐body elimination half‐life (t1/2) of PFOA in males (t1/2 = 15 days) and females (t1/2 < 1 day). Analysis of PFOA‐derived 14C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6‐hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA‐containing lipid (i.e., a PFOA‐containing mono‐, di‐, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA‐glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to formation of a PFOA metabolite.
Effects of hydroxylated polychlorinated biphenyls on mouse liver mitochondrial oxidative phosphorylation
Authors: Narasimhan T. R. , Kim H. L. , Safe S. H. 
Published: October 2006

AbstractThe effects of three tetrachlorobiphenylols [2′,3′,4′,5′‐tetrachloro‐2‐biphenylol (1); 2′,3′,4′,5′‐tetrachloro‐4‐biphenylol (2); and 2′,3′,4′,5′‐tetrachloro‐3‐biphenylol (3)]; three monochlorobiphenylols [5‐chloro‐2‐biphenylol (5), 3‐chloro‐2‐biphenylol (6); and 2‐chloro‐4‐biphenylol (7)] and a tetrachlorobiphenyldiol [3,3′,5,5′‐tetrachloro‐4,4′‐biphenyldiol (4) on respiration, adenosine triphosphatase (ATPase)] activity, and swelling in isolated mouse liver mitochondria have been investigated. Tetrachlorobiphenylols (1–3) and the tetrachlorobiphenyldiol (4) inhibited state‐3 respiration in a concentration‐dependent manner with succinate as substrate (flavin adenine dinucleotide [FAD]‐linked) and the tetrachlorobiphenyldiol (4) caused a more pronounced inhibitory effect on state‐3 respiration than the other congeners. The monochlorobiphenylols 5–7 were less active as inhibitors of state‐3 mitochondrial respiration and significant effects were observed only at higher concentration (≥0.4 μM). However, in the presence of the nicotinamide adenine dinucleotide (NAD)‐linked substrates (glutamate plus malate), hydroxylated PCBs (1–7) significantly inhibited mitochondrial state‐3 respiration in a concentration‐dependent manner. Compounds 5, 6, and 7 uncoupled mitochondrial oxidative phosphorylation only in the presence of FAD‐linked substrate as evidenced by increased oxygen consumption during state‐4 respiratory transition, stimulating ATPase activity, releasing oligomycin‐inhibited respiration, and inducing mitochondrial swelling (5, 6, and 7). Tetrachlorobiphenylols 1, 2, and 3 had no effect on mitochondrial ATPase activity while the tetrachlorobiphenyldiol, 4, decreased the enzyme activity. The possible inhibitory site of electron transport by these compounds and their toxicologic significance is discussed.
Selective erythrocyte potassium efflux following pulse treatment with tellurite
Authors: Klug Robert K. , Kurantsin ‐Mills Joseph 
Published: October 2006

AbstractHuman erythrocytes exposed to 0.1 mM tellurite (K2TeO3) in an isotonic buffered choline chloride medium for 15 min at 37°C, washed, and incubated further in the absence of the chemical in the buffer, exhibited selective leakiness for potassium within minutes. The potassium efflux curve was sigmoidal, with an initially slow leakage followed by a sharp rise (first‐order kinetics) and a plateau by 60 min. After 15 min, 30–50% of the total potassium concentration had leaked from the cells, although less than 1% lysis had occurred. The control cells incubated in buffer with no K2TeO3 exhibited no potassium leakage. The mean volume of the K2TeO3‐treated erythrocytes increased and their median density decreased, indicating changes in the colloid osmotic state and physical characteristics of the cells. However, cells pretreated with K2TeO3 exhibited no significant change in glutathione (GSH) concentration and no membrane lipid peroxidation, unlike cells pretreated with t‐butylhydroperoxide (Deuticke et al., Biochim. Bio phys. Acta, 899, 125–128, 1987). The enhanced potassium permeability of the K2TeO3‐treated erythrocytes preceded the increase in cell volume, intracellular hydration, and a decrease in median density. We suggest that perturbation of the lipid‐protein interaction in the membrane by the oxidant alters the potassium permeability and results in the selective leakage with eventual hemolysis.