摘要:

AbstractChinese hamster V79 fibroblasts, frequently used as target cells in short‐term tests for mutagenicity, do not possess measurable monooxygenase activity; in particular, enzymatic oxidation of testosterone (T) cannot be demonstrated. If these V79 cells, however, had been transfected with the cDNA‐encoding rat liver cytochromeP‐450IIB1 under control of the SV40 early promoter, they stably expressed monooxygenase activity. These so‐called SD1 cells then oxidatively metabolized T at a rate of 27 pmol/mg protein/min, converting it to 16α‐ and 16β‐hydroxy‐T as well as 4‐androsten‐3,17‐dione as sole metabolites in a ratio of 1.1:1.0:1.6. The regio‐ and stereoselective conversion of T by SD1 cells, as well as the quantitative distribution of the metabolites, corresponds well with the results reported for pure cytochromeP‐450IIB1

ISSN:0887-2082    

DOI:10.1002/jbt.2570040102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe modulation of the phase I and phase II biotransformation enzymes upon treatment with tobacco extract (TE) andN'‐nitrosonornicotine (NNN) was investigated using male Sprague‐Dawley rats fed differential protein diets. It was observed that the animals fed a low protein diet showed an overall decrease in the basal levels of hepatic and pulmonary phase I and II enzymes. TE and NNN significantly decreased the detoxifying system in the low‐proteinfed animals. Animals fed 20% protein, however, showed significant increases in glutathione and glutathioneS‐transferase upon treatment. Furthermore, TE and NNN treatment brought about a significant depletion in the hepatic pool of vitamin A with a concomitant increase in the vitamin C

ISSN:0887-2082    

DOI:10.1002/jbt.2570040103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractTo estimate the potential of small doses of sarin (types I and II) and soman to cause delayed neuropathic effects, 400, 200, 61, and 0 μg/kg of sarin‐I, 280, 140, 70, and 0 μg/kg of sarin‐II, and 14.2, 7.1, 3.5, and 0 μg of soman by gavage were compared with 510 mg/kg tri‐o‐cresyl phosphate (TOCP) in 14‐to 18‐month‐old SPF white leghorn hens (4/dose) protected with atropine (100 mg/kg). The neuropathy target esterase (NTE) activity 24 hr after dosing was determined in brain, spinal cord, and lymphocytes and in plasma and brain for cholinesterase and carboxylesterase. None of the compounds showed statistically significant NTE decreases. Sarin‐II showed a dose‐related trend in the lymphocyte NTE (to 33% of control at 280 μg/kg), suggesting that longer exposure to lower doses might cause a cumulative neurotoxic insult. All of the agents decreased the activity of plasma and brain cholinesterase and carboxylesterase. Using more than 70% inhibition of brain NTE as a biochemical predictor of delayed neuropathy, sarin and soman appear unable to cause delayed neuropathy at nonlethal doses

ISSN:0887-2082    

DOI:10.1002/jbt.2570040104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe mutagenicity of tetrachloroethene (tetra) and itsSconjugate,S‐(1,2,2‐trichlorovinyl)glutathione (TCVG) was investigated using a modified Ames preincubation assay. TCVG was a potent mutagen in presence of rat kidney particulate fractions containing high concentrations of γ‐glutamyl transpeptidase (GGT) and dipeptidases. Purified tetra was not mutagenic without exogenous metabolic activation or under conditions favoring oxidative metabolism. Preincubation of tetra with purified rat liver glutathione (GSH)S‐transferases in presence of GSH and rat kidney fractions resulted in a time‐dependent formation of TCVG as determined by (HPLC) analysis and in an unequivocal mutagenic response in the Ames test. Experiments with tetra in the isolated perfused rat liver demonstrated TCVG formation and its excretion with the bile; bile collected after the addition of tetra to the isolated perfused liver was unequivocally mutagenic in bacteria in the presence of kidney particulate fractions. The mutagenicity was reduced in all cases by the GGT inhibitor serine borate or the β‐lyase inhibitor aminooxyacetic acid. These results support the suggestion that cleavage of the GSHSconjugate formed from tetra by the enzymes of the mercapturic acid pathway and by β‐lyase may be involved in the nephrocarcinogenic effects of this ha

ISSN:0887-2082    

DOI:10.1002/jbt.2570040105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractCyanide detoxification in mammals occurs, in part, by sulfur transfer by rhodanese to form the less toxic thiocyanate. Thiosulfate and nitrite are often used in combination for the treatment of cyanide intoxication. This report shows that nitrite can inhibit the rate of sulfur transfer by rhodanese in vitro. Nitrate, chloride, sulfate, and acetate were also examined as inhibitors. Inhibition by nitrite appeared to be more complex than for the other anions tested. Closer examination showed that nitrite can inactivate the sulfur‐free rhodanese. Our observation leads to the suggestion that, in vivo, either rhodanese is maintained in its more stable sulfur‐substituted form or cellular compartmentalization prevents inactivation by nitr

ISSN:0887-2082    

DOI:10.1002/jbt.2570040106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractIn perfused livers from fed rats, rates of glucose production (glycogenolysis) were 133 ± 12 μmol/g/hr. Infusion of 2 μM verapamil into these livers decreased the rates of glucose production significantly to 97 ± 15 μmol/g/hr within 10 min. Conversely, rates of production of lactate plus pyruvate (glycolysis) of 64 ± 6 μmol/g/hr were not significantly altered by verapamil (60 ± 3 μmol/g/hr). When 50 μM verapamil was infused, however, rates of both glycogenolysis and glycolysis were diminished to 56 ± 11 and 43 ± 5 μmol/g/hr, respectively. In perfused livers from fasted rats, infusion of 20 mM fructose increased the rates of production of glucose (gluconeogenesis) significantly from 11 ± 7 to 121 ± 17 μmol/g/hr. These rates reached 138 ± 7 μmol/g/hr upon the simultaneous infusion of verapamil (2 μM). In these livers, fructose also increased rates of production of lactate from 6 ± 2 to 132 ± 11 μmol/g/hr, which were further increased to 143 ± 8 μmol/g/hr when 2 μM verapamil was infused. The results show that calcium‐dependent processes involved in hepatic carbohydrate metabolism respond differently to the calcium channel blocker verapamil. Low concentrations of verapamil inhibited glycogenolysis significantly while having no effect on either glycolysis or gluconeogenesis. These data suggest that these two processes have different sensitivities to changes in intracellular calcium concentrations and/or different sou

ISSN:0887-2082    

DOI:10.1002/jbt.2570040107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe purpose of the study was to identify binding sites of organic arsenic in the erythrocyte and to explain species differences in binding. Washed erythrocytes were exposed to graded concentrations of [U‐14Clphenyldichloroarsine (PDA)] in phosphate‐buffered saline containing 0.1% glucose and 0.1% bovine serum albumin. At low PDA concentrations, all cells bound the arsenical rapidly (within 10 min) and quantitatively. Human, pig, hamster, guinea pig, and mouse erythrocytes approached saturation at 0.02–0.3 μmol PDA/109cells, depending on the species. Saturation points correlated well with each respective species' erythrocyte glutathione content. In contrast, rat erythrocytes showed no sign of saturation at PDA loads as high as 3.0 μmol/109cells. Hemolysates of PDA‐treated erythrocytes were subjected to Sephadex G‐75 gel filtration chromatography.14C from rat hemolysate was distributed between the hemoglobin and small molecular weight (glutathione‐containing) fractions. In all other species, the14C eluted almost exclusively with the glutathione‐containing fractions. In equilibrium dialysis experiments, human hemoglobin did not bind PDA, whereas rat hemoglobin bound 2 PDA/mol withKd∼ 5 μM. In conclusion, glutathione is the principal binding site of phenyldichloroarsine in erythrocytes. In most species, the arsenical does not bind to hemoglobin, even though it has free (titratable) sulfhydryls considerably in excess of the glutathione concentration. In rat erythrocytes, phenlydichloroarsine binds both to glutathione and to hemoglobin. Arsenical binding by rat hemoglobin is presumably due to the unique location of the extra titratable cystei

ISSN:0887-2082    

DOI:10.1002/jbt.2570040108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractPatulin (PAT), a compound produced by certain species ofAspergillus, Penicillium, andByssochlamys, is frequently found associated with agricultural commodities. PAT has many effects on membrane function, including the inhibition of the isolated Na+‐K+ATPase. In this study, a scanning electron microscope equipped with an energy dispersive spectroscopy X‐ray microanalysis system was used to examine individual cultured renal epithelial cells (LLC‐PK1) in order to determine the effects of PAT on the relative intracellular ion concentrations. The estimated EC50(60 min) for both sodium influx and potassium efflux was between 10 and 50 μm for ouabain. For PAT, the EC50(60 min) was 250 μm for sodium influx and 100 μm for potassium efflux. However, 1 mM patulin at 240 min caused complete reversal of the sodium and potassium content of cells, and 1 mM ouabain at 240 min did not. The effect of patulin on sodium and potassium flux was both concentration and time dependent and was reversed by dithiothreitol and glutathione. PAT (250 μM) but not ouabain (250 μM) induced massive blebbing of LLC‐PK1cells. Thus, the interaction of PAT with cellular membranes involves both alterations in the regulation of intracellular ion content and the cyto‐skeleton. We hypothesize that patulin alters intracellular ion content via Na+–K+ATPase and non‐Na+

ISSN:0887-2082    

DOI:10.1002/jbt.2570040109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractChlordecone potentiation of the hepatotoxic and lethal effects of CCl4has 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 CCl4was 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 CCl4alone (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 spermidineN1‐acetyltransferase,N1‐acetylputrescine, putreanine, putrescine, andN1‐acetylspermidine at 6 hr in rats treated with the high dose of CCl4alone 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 CCl4low‐dose combination treatment compared to rats treated with a high dose of CCl4alone. 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 CCl4low‐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

ISSN:0887-2082    

DOI:10.1002/jbt.2570040110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe ability of phenobarbital and β‐naphthoflavone to induce parathion desulfuration, aminopyrineN‐demethylation, and NADPH–cyto‐chrome‐creductase activity in the brain and liver of male and female rats was investigated. Activities of all three enzymes were found in similar levels in both the mitochondrial and microsomal fractions of brain. There were no sex differences in brain activities. Liver activities were from 10‐ to 30‐fold higher than brain activities when computed on a tissue‐wet‐weight‐equivalent basis. Although exposure to both inducers increased all three enzyme activities and cytochromeP‐450 in liver, neither inducer increased the enzyme activities in mitochondrial or microsomal brain fractions of either sex. Thus, these brain monooxygenase activities appear to be refractory to induction by two classical types of cytochromeP‐450 inducers. This lack of inducibility could serve to protect the animal against environmentally enhanced increases in the activation of xenobiotics to neurotoxic metabolites, such as parathion d

ISSN:0887-2082    

DOI:10.1002/jbt.2570040111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY