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At least 217 records · Page 12Linked to original sources
PubMed1986

Biochemical effects and monitoring of exposure of rats to 4-methylcyclohexyl-1,6-dicarboxylic acid anhydride vapour.

Male Wistar rats exposed to 5, 10 or 20 p.p.m. 4-methylcyclohexyl-1,6-dicarboxylic acid anhydride vapour for 2-11 weeks showed dose-dependent blood anhydride concentrations. The maximum concentrations were found after two weeks. At five exposure weeks, they were smaller but they did not decrease further thereafter. The change was coincident with increased epoxide hydrase activity in liver. The excretion of 4-methylcyclohexyl-1,6-dicarboxylic acid was detected in the urine. The excretion was linearly related to the exposure in specimens collected during the 10th and 11th week. Brain acetylcholinesterase activity was transiently inhibited by the exposure at the two higher doses while decreased enzyme activity in the isolated spinal cord axons was only found after 11 weeks. This change was simultaneous with increased creatine kinase activity in the cerebellar homogenate. In the occupational setting, acetylcholinesterase activity might only be significantly inhibited in lungs because of the low exposure levels.

Acetylcholinesterase↗
PubMed1982

Metabolism of acetylene by Nocardia rhodochrous.

A Nocardia rhodochrous strain capable of utilizing acetylene as its sole source of carbon and energy exhibited slow growth on low concentrations of acetaldehyde. Resting cells incubated with acetylene formed a product identified as acetaldehyde, but attempts to demonstrate acetylene hydrase activity in cell-free extracts were unsuccessful. Acetaldehyde dehydrogenase in N. rhodochrous was found to be NAD+ linked and nonacylating, converting acetaldehyde to acetate. Specific activities of acetaldehyde dehydrogenase, acetothiokinase, and isocitrate lyase were enhanced in cells grown on acetylene and ethanol as compared with cells grown on alternate substrates. These results suggest that acetylene is catabolized via acetaldehyde to acetate and eventually to acetyl coenzyme A. Acetylene oxidation in N. rhodochrous appears to be constitutive and is not inhibited in the presence of either ethylene, nitrous oxide, or methane.

Acetaldehyde↗
PubMed1969

Control of fatty acid metabolism. I. Induction of the enzymes of fatty acid oxidation in Escherichia coli.

Escherichia coli grows on long-chain fatty acids after a distinct lag phase. Cells, preadapted to palmitate, grow immediately on fatty acids, indicating that fatty acid oxidation in this bacterium is an inducible system. This hypothesis is supported by the fact that cells grown on palmitate oxidize fatty acids at rates 7 times faster than cells grown on amino acids and 60 times faster than cells grown on a combined medium of glucose and amino acids. The inhibitory effect of glucose may be explained in terms of catabolite repression. The activities of the five key enzymes of beta-oxidation [palmityl-coenzyme A (CoA) synthetase, acyl-CoA dehydrogenase, enoyl-CoA hydrase, beta-hydroxyacyl-CoA dehydrogenase, and thiolase] all vary coordinately over a wide range of activity, indicating that they are all under unit control. The ability of a fatty acid to induce the enzymes of beta-oxidation and support-growth is a function of its chain length. Fatty acids of carbon chain lengths of C(14) and longer induce the enzymes of fatty acid oxidation and readily support growth, whereas decanoate and laurate do not induce the enzymes of fatty acid oxidation and only support limited growth of palmitate-induced cells. Two mutants, D-1 and D-3, which grow on decanoate and laurate were isolated and were found to contain constitutive levels of the beta-oxidation enzymes. Short-chain fatty acids (<C(8)) do not support growth of either the parent strain or the mutants D-1 and D-3. Evidence is also presented to show that decanoate is actively transported by the parent strain and by the mutants.

Acyltransferases↗
PubMed1979

The irreversible binding of benzo[a]pyrene to rat liver macromolecules in vivo and in vitro: effects of agents that influence benzo[a]pyrene metabolism.

The present study was carried out to determine the effects of agents that influence benzo[a]pyrene (BP) metabolism in vitro on the irreversible binding of BP to rat hepatic macromolecules in vivo. The irreversible binding of [3H]BP was found to be both dose and time dependent after its intraperitoneal administration to male Wistar rats. The SKF 525-A, at doses of 50 and 75 mg/kg, ip 3 h before BP, decreased the level of binding from control by 31 and 34%, respectively. At 35 mg/kg, SKF-525-A had no effect. Diethyl maleate (0.6 mL/kg, ip) and cysteine (150 mg/kg, ip), 30 and 5 min before BP, respectively, did not alter the binding of BP from control. Oral methadone treatment, previously shown to increase selectively epoxide hydrase activity in male Wistar rats, also failed to alter the amount of BP bound to hepatic macromolecules. 3-Methylcholanthrene (20 mg/kg per day, ip, for 2 days) administered 24 h before BP, decreased the level of binding from control by 30%. Parallel in vitro studies were carried out with the various agents used in vivo.

Animals↗
PubMed1975

Drug conjugation in Gunn rats: reduced UDP-glucuronosyl transferase and UDP-glucosyl transferase activities with increased glycine-N-acyltransferase activity.

Glucuronyl, glucosyl, glutathione, glycine conjugations and epoxide hydration were studied in livers of Wistar and Gunn rats. The activities of bilirubin UDP-glucuronosyl transferase and UDP-glucosyl transferase were reduced in microsomes of homozygous and heterozygous Gunn rats compared to Wistar rats (over 90 and 55-65%, respectively). Conjugation of 4-methylumbelliferone by UDP-glucuronosyl transferase was also reduced (30-35%) in Gunn rats. Treatment of microsomes in vitro with membrane perturbating agents increased the measurable activities but did not change the activity relationships between Wistar and Gunn rats. Microsomal epoxide hydrase and soluble glutathione-S-epoxide transferase activities occurred in Gunn rats at the Wistar level, but mitochondrial glycine-N-acyltransferase activity was elevated in homozygous and heterozygous Gunn rats (66 and 47%, respectively). The reciprocal velocity plots of UDP-glucuronosyl transferase activity were similarly concave in Gunn and Wistar rats.

Acyltransferases↗
PubMedDate not supplied

Effects of L-proline on phase I and phase II xenobiotic biotransformation capacities of rat and human hepatocytes in long-term collagen gel cultures.

L-Proline supplementation of the medium for collagen gel cultures of hepatocytes has been shown to improve albumin secretion. A study was made as to whether L-proline is also essential for the maintenance of xenobiotic biotransformation capacities in collagen gel sandwich and immobilisation cultures of rat and human hepatocytes. Key phase I (cytochrome P450-dependent monooxygenase [CYP)] and microsomal epoxide hydrase [mEH]) and phase II (glutathione S-transferase [GST]) biotransformation enzyme activities and the secretion of albumin in the culture medium were assessed in the absence and presence of L-proline. CYP and mEH activities were not affected by the addition of L-proline, whereas phase II alpha-Class GST activity of rat hepatocytes in collagen cultures was decreased. Species differences were demonstrated, as human hepatocytes showed a better maintenance of GST activities than their rat counterparts in the presence of L-proline. Albumin secretion, often considered to be a marker for differentiated cell function, does not parallel the biotransformation capacities of the hepatocytes in culture. Additional results demonstrated an L-proline-mediated enhancement of the proliferation rate of contaminating stellate cells in conventional monolayer culture. Transdifferentiation of stellate cells to proliferating myofibroblasts, along with an increased albumin secretion and collagen synthesis, are characteristic of fibrotic liver. Since the last two phenomena have been observed in L-proline-supplemented collagen gel cultures, it can be concluded that when stable collagen gel cultures of rat hepatocytes are needed for long-term pharmacotoxicological studies, it is preferable to use an L-proline-free culture medium. Further studies on medium optimisation are required for hepatocytes from species other than rat.

Adult↗
PubMed1977

1,1-Dichloroethylene hepatotoxicity: proposed mechanism of action and distribution and binding of 14C radioactivity following inhalation exposure in rats.

1,1-Dichloroethylene is reported to produce renal tumors in male mice. It is an hepatotoxin in fasted rats after inhalation. We found that trichloropropane epoxide, an inhibitor of epoxide hydrase, enhances hepatic injury as measured by serum sorbitol dehydrogenase elevation. A significant elevation of hepatic citric acid concentration was seen in fasted but not fed rats. We hypothesized that mitochondrial injury was associated with inhibition of the tricarboxylic acid cycle and postulated that monochloroacetic acid was a toxic metabolite of 1,1-DCE. Fluoroacetic acid and chloroacetic acid were similar in their ability to inhibit oxygen uptake when pyruvic and malic acids were substrates in isolated mitochondria supplemented with adenosine diphosphate. In experiments where 1,1-DCE metabolism was estimated, no difference between the rate of uptake in a 2-hr period was detected between fed and fasted animals. Urinary output of radioactivity at 26 hr for fed and fasted rats was similar. Water-soluble (i.e. TCA-soluble) 1,1-DCE metabolites were found in tissues of fasted rats in excess of that seen in fed rats. The kidney had the largest concentration of total metabolites. Tissue-bound, or TCA-insoluble, radioactivity was associated with the mitrochondrial and microsomal fraction of fasted rats in excess of that seen in fed rats. The disappearance of TCA-insoluble radioactivity from the mitochondrial and microsomal fractions was comparable in rate between fed and fasted rats respectively. These results suggest that 1,1-DCE is metabolized quite rapidly in the organism to TCA-soluble components which are excreted by the kidneys. Metabolites of 1,1-DCE may enter the metabolic pool, since a reasonably short turnover of (14)C-labeled, bound material was observed. The metabolite of 1,1-DCE appears to inhibit the mitochondria so that citric acid accumulates. This may occur by a process of lethal synthesis.

Acetates↗
PubMed1977

Acute hepatotoxicity of ethylene and halogenated ethylenes after PCB pretreatment.

Previous studies from our laboratory have shown that ethylene, vinyl fluoride monomer (VFM), vinyl chloride monomer (VCM), and vinyl bromide monomer (VBM) are all acutely hepatotoxic in rats pretreated with polychlorinated biphenyl (PCB). The time course of hepatic injury development after exposure and several parameters, environmental and chemical, affecting this toxicity were evaluated in the work reported here. Liver injury, as measured by serum alanine-alpha-ketoglutarate transaminase (SAKT) or sorbitol dehydrogenase (SDH), develops progressively over a 24-hr period following a 4-hr inhalation exposure of PCB-pretreated rats to ethylene or VCM. Environmental temperature during exposure to VCM does not affect hepatotoxicity or mortality below 30.3 degrees C. At 33.8 degrees C, however, mortality and SAKT are dramatically increased. Overnight fasting, which depletes hepatic glutathione (GSH) of PCB-pretreated rats before exposure to ethylene or VCM, significantly increases the hepatotoxicity of these compounds as measured by SDH. The combined effects of fasting and of trichloropropane epoxide (TCPE), an inhibitor of epoxide hydrase (EH), were also examined. TCPE treatment of fasted PCB-pretreated rats immediately before exposure was synergistic in increasing the acute toxicity of ethylene and VCM. TCPE increased mortality in fed or fasted rats exposed to VFM, but there was no effect of fasting alone. Both fasting and TCPE increased the sensitivity of PCB-pretreated rats to VBM, but there was not a clearly synergistic effect of fasting plus TCPE. These data suggest that the acute toxicity of these compounds is mediated through epoxide intermediates.

Animals↗
PubMed1988

Comparative biology of test species.

This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, beta-glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated.

Animals↗
PubMed1979

The formation of phenylethane-1,2-diol 2-acetate in the metabolism of styrene oxide by rabbit liver microsomes in vitro.

1. Phenylethane-1,2-diol 2-acetate has been isolated from the incubation of styrene oxide or styrene diol with liver microsomes of phenobarbital-pretreated rabbits. 2. Observed ratios of phenylethane-1,2-diol to its 2-acetate in the incubation mixtures ranged between 19 : 1 and 5 : 1 with different microsomal preparations and different periods of incubation. 3. The formation of phenylethane-1,2-diol 2-acetate may be a source of errors in the radiometric determination of epoxide hydrase activity in microsomes.

Acetylation↗
PubMed1981

Effect of aflatoxin B1 on hepatic drug-metabolizing enzymes in female rats. Interaction with a contraceptive agent.

1. The effect of a contraceptive on aflatoxin B1 toxicity has been studied in female rats treated for 15 consecutive days with repeated doses of aflatoxin (0.40 mg/kg/day), norethindrone (0.60 mg/kg/day) and ethynylestradiol (0.012 mg/kg/day). 2. Increases occurred in hepatic microsomal cytochrome P-450 content (31%), and in the activities of epoxide hydrase (77%), UDP-glucuronyltransferase (67%) and gamma-glutamyltransferase (78%). 3. Aflatoxin alone caused a 22% increase in GSH S-epoxide transferase activity, whereas the contraceptive given alone or combined with aflatoxin increased the hepatic reduced glutathione. 4. The effect of aflatoxin plus contraceptive was not additive. 5. The effects caused by aflatoxin and the contraceptive were similar, and the contraceptive (depending on its progestogen/estrogen ratio), may modify aflatoxin toxicity by increasing the drug-metabolizing enzyme activities and the concentration of hepatic glutathione.

Aflatoxin B1↗
PubMed1994

Bromobenzene detoxification in the human liver-derived HepG2 cell line.

1. The applicability of the human hepatoma cell line, HepG2, as a cell culture model for studying xenobiotic liver toxicity has been investigated using the well-characterized hepatotoxic chemical, bromobenzene. 2. Bromobenzene caused a concentration- (0-10 mM) and time-dependent (0-180 min) decrease in HepG2 cell viability. The degree of toxicity was dependent upon the culture medium composition and the state of cell growth. Toxicity in Modified Earle's and Williams' E Media was maximal at 7 days growth compared with 3 and 10 days, and was greater in Williams' than in Earle's medium. Toxicity in Dulbecco's medium was apparent only at 10 days growth and was less than the maximum toxicity in the other media. 3. Bromobenzene was detoxified by epoxide hydrase. The question of metabolic activation by P450 remained unresolved, but any involvement of P450 was by forms not inhibited by ketoconazole. 4. The mechanism of bromobenzene toxicity did not appear to involve lipid peroxidation, depletion of reduced glutathione, calcium-mediated proteolysis or metabolic activation by prostaglandin synthetase, but may have involved direct solvent-induced cell damage. 5. This study demonstrates the potential usefulness of HepG2 cells in toxicity testing and highlights the importance of standardizing culture conditions.

Antipain↗
PubMed1979

Nuclear activation of polycyclic hydrocarbons.

In this report the ability of nuclei to carry out mixed function oxidase activity has been discussed. The properties of the nuclear system have been contrasted with those of microsomes and the localization of the nuclear mixed function oxidase has been definitively established. In addition, the nuclei have been shown to contain an inducible O-deethylase and epoxide hydrase(s). Finally, nuclei have been demonstrated to catalyze the formation of benzo[a]pyrene syn- and anti-diolepoxides, ultimate carcinogenic forms of this polycyclic hydrocarbon.

Aryl Hydrocarbon Hydroxylases↗
PubMed1976

The direct spectrophotometric observation of benzo(a)pyrene phenol formation by liver microsomes.

Optical spectral repetitive scan analysis during the oxidative metabolism of benzo(a)pyrene by liver microsomal suspensions reveals the time-dependent formation of an intermediate(s) of which the visible spectra resemble those of several benzo(a)pyrene phenols. Liver microsomes from 3-methylcholanthrene-treated rats showed a greater rate of formation of the phenols than did microsomes from control animals; the rate of formation catalyzed by liver microsomes from phenobarbital-pretreated rats was intermediate. When 3-hydroxybenzo(a)pyrene was used as a standard for comparison of activity, the rates of formation of phenols were compared when measured by fluorometric, spectrophotometric, or high-pressure liquid chromatographic analytical techniques. An epoxide hydrase inhibitor, 1,1,1-trichloropropene-2,3-oxide, enhanced phenol formation regardless of the source of liver microsomes, and 7,8-benzoflavone inhibited control and 3-methylcholanthrene-induced microsomal metabolism of benzo(a)pyrene, 7,8-Benzoflavone did not effect benzo(a)pyrene metabolism by liver microsomes from phenobarbital-pretreated rats. The effect of inhibitors on the spectrophotometric assay correlates well with the results obtained from benzo(a)pyrene metabolite analysis using high-pressure liquid chromatography.

Adenosine Monophosphate↗
PubMedDate not supplied

[Effect of trace elements on the hydroxylation of benzo(a)pyrene].

The trace elements are surrounding factors which are able to act on the yield of benzo(a)pyrene hydroxylation reaction of the hepatic tissue. This action was studied for each element and for various concentrations. The action of these elements may occurred to arylhydrocarbon hydroxylase by activating or inhibiting it, to epoxyde hydrase or to glutathione S epoxydase, favouring or inhibiting the way epoxyde dihydrodiol, and finally to arylhydrocarbon hydroxylase induction. Our results, obtained in vitro on hepatic tissue with many metallic salts, showed that some trace elements may have a cocarcinogenic action.

Animals↗
PubMed1979

Comparison of metabolism-mediated binding to DNA of 7-hydroxymethyl-12-methylbenz(a)anthracene and 7, 12-dimethylbenz(a)anthracene.

Comparison of the binding to DNA of 7-hydroxymethyl-12-methylbenza(a)anthracene and 7, 12-dimethylbenz(a)anthracene (DMBA) catalyzed by mouse embryo cells in culture or by rat liver microsomes indicates that the products formed are different for the two hydrocarbons. Thus, the hydroxy compound is not an intermediate in the binding of DMBA to DNA in these systems. Binding of the hydroxy compound to DNA in mouse embryo cells is less efficient than for DMBA and is inhibited by 1,1,1-trichloropropylene 2,3-oxide, an inhibitor of epoxide hydrase. This and the fluorescence spectra of the hydroxy compound-DNA adducts indicate that the hydroxy compound is activated for DNA binding through the formation of a diol-epoxide in the 1,2,3,4-ring. As previously found for DMBA, this is consistent with the activation of this compound through a bay-region diol-epoxide.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1975

The benzo(alpha)pyrene deoxyribonucleoside products isolated from DNA after metabolism of benzo(alpha)pyrene by rat liver microsomes in the presence of DNA.

Rat liver microsomes (induced by 3-methylcholanthrene) were used to catalyze the binding of tritium-labeled benzo(alpha)pyrene to DNA. Enzymic degradation of this DNA to deoxyribonucleosides, followed by separation of the products by Sephadex LH20 column chromatography, revealed two major products. One of these was shown to be the same as that obtained from DNA with benzo(alpha)pyrene bound following treatment of mouse embryo cells in culture with the carcinogen. Neither product resembled those obtained from DNA that had been caused to react with benzo(alpha)pyrene 4,5-oxide (K-region eposide). The aryl hydrocarbon hydroxylase activity of the microsome preparations was determined and related to the extent of microsome-catalyzed hydrocarbon binding. Inhibitors of the enzyme epoxide hydrase increased this binding but caused the loss of one of the two major products. On the basis of the results obtained, a model is proposed of the mechanism of benzo(alpha)pyrene metabolism and DNA binding.

Aryl Hydrocarbon Hydroxylases↗
PubMed1975

Inhibition of benzo(alpha)pyrene metabolism catalyzed by mouse and hamster lung microsomes.

Induced and constitutive microsomal enzymes of mouse and hamster lungs catalyze both the hydroxylation of benzo(alpha)pyrene and reactions that lead to its irreversible binding to macromolecules. For mouse and hamster, the induced lung hydroxylases have Km values of 1.10 and 0.52 muM, respectively. The induced hydroxylases are strongly inhibited by 7,8-benzoflavone and are stimulated by cyclohexene oxide, an inhibitor of epoxide hydrase. Formation of the macromolecular product by the induced "binding" enzyme follows. Michaelis-Menten kinetics, except for substrate inhibition, and has Km values of 0.52 and 0.25 muM for lung microsomes from mouse and hamster, respectively. These reactions are also inhibited by 7,8-benzoflavone. The reaction catalyzed by the constitutive hydroxylase of mouse lungs is characterized by a brief lag period but proceeds in a linear fashion after the lag. The enzyme requires 60 muM benzo(alpha)pyrene to achieve maximum reaction velocity. Above this concentration, strong substrate inhibition is observed; accurate values for Vmax and Km cannot be derived. The constitutive hydroxylases are moderately inhibited by butylated hydroxytoluene, retinol, cyclohexene oxide, and 7,8-benzoflavone. The product of the constitutive "binding" enzyme is formed in a reaction that follows Michaelis-Menten kinetics. The Km value for enzymes from mouse and hamster lungs are 11.8 and 4.9 muM, respectively. Formation of this product is strongly inhibited by butylated hydroxytoluene and by retinol but not strongly by 7,8-benzoflavone or cyclohexene oxide. Since other evidence indicates that a constitutive enzyme may be involved in carcinogenesis by benzo(alpha)pyrene and since this reaction is inhibited by two known anticarcinogens, we suggest that it may be involved in this process.

Animals↗