Toxicological evaluation of dietary fibre.
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Animals↗
Biomedical subjects
M Roberfroid
Publications and source records attributed to M Roberfroid.
Prevention by free radical scavenger AD5 of prooxidant effects of choline deficiency.
This study was designed to explore the possible preventive effects of a novel radicophile, N-p-methoxyphenylacetyl-dehydroalanine (AD5) and three other antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD), butylated hydroxyanisole (BHA) and a water-soluble analogue of vitamin E, trolox C, on the acute effects of the liver of feeding a choline-deficient (CD) diet. It has been suggested that some of the acute effects of a CD diet are related to free radicals, the generation or metabolism of which is disturbed in this acute dietary model. AD5 was found to be very effective in preventing nuclear lipid peroxidation, DNA damage and cell death induced by a CD diet but to have little effect on triglyceride accumulation ("fatty liver"). DPPD, BHA, and trolox C were ineffective. These results add strength to the hypothesis that oxygen free radicals might be an important component in the early events during carcinogenesis induced by feeding a CD diet.
Alanine↗
Peroxisome proliferation and modulation of rat liver carcinogenesis by 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, perfluorooctanoic acid and nafenopin.
Using an initiation--selection--promotion protocol for induction of liver tumors in Wistar rats, the modulating action of various peroxisome proliferators on neoplasia as well as on selected biochemical parameters was studied. After treatment with diethylnitrosamine (DEN), the animals were subsequently subjected to a selection procedure involving feeding of 2-acetylaminofluorene (2-AAF), and in the middle of the 2-AAF treatment, a single necrogenic dose of carbon tetrachloride. Following a recovery period, the rats were fed a diet containing 0.1% nafenopin (NAF), 0.015% perfluorooctanoic acid (PFOA), 0.05% 2,4-dichlorophenoxyacetic acid (2,4-D), 0.05% 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or 0.05% phenobarbital (PB) as a positive control. When the animals were killed, 7 months after initiation, the incidence of hepatocellular carcinoma was 83, 33 and 16% in the animals treated with NAF, PFOA or 2,4,5-T respectively. No cancers were observed in controls, or in the 2,4,-D groups. In comparison with controls, NAF and PFOA caused a 60-and 24-fold increase inthe peroxisomal beta-oxidation of fatty acids respectively, but only about a 2-fold increase in the catalase activity, 2,4-D and/or 2,4,5-T were much less active in this respect, giving approximately a doubling in the rate of fatty acid oxidation. The specific activity of D-amino acid and glycolate oxidases were significantly depressed, whereas the urate oxidase levels were apparently unaffected by the NAF and PFOA treatment. The results suggest that the selective induction of peroxisomal fatty acid oxidation is consistent with the hypothesis that imbalance between H2O2 overproduction and its destruction could play a role in the modulation of hepatocarcinogenesis by peroxisome proliferators.
2,4,5-Trichlorophenoxyacetic Acid↗
[Possible value of variations in the serum alkaline DNAse activity in the prognosis of cancers of the upper respiratory-digestive tract treated by chemotherapy].
Variations in serum alkaline DNase activity before and repeatedly after standardized chemotherapy were examined in patients with head and neck carcinomas. The enzyme activity was measured by way of a modified spectrophotometric method. No variations of such activity observed in patients without therapeutic response or with minor response could be considered as a marker of primary or acquired resistance to chemotherapy. Distinct variations in serum alkaline DNase activity (a steep decrease after therapy followed a few weeks later by a regain of values higher than the initial value) correspond to complete or partial positive responses. Such observations of the variations in enzyme activity in relation to individual initial values measured before therapy could be considered as a reliable prognostic test for the therapy of many head and neck carcinomas.
Adult↗
Modulation of neoplastic development: concepts and examples.
Chemical carcinogenesis is classically considered as a multiphasic process within which one identifies an initiation phase followed by a phase of promotion and finally progression and/or conversion. The concept of modulation of neoplastic development will be proposed. That concept characterizes any treatment able to modify the evolution of a carcinogenic process. Such a modification is either an acceleration or a slowing down of carcinogenesis. It is not fully equivalent to promotion since it is not an obligatory phase of carcinogenesis. After an initiating treatment, the evolution of carcinogenesis can thus be modulated either positively or negatively. Modulating agents of liver carcinogenesis can be chemical carcinogens, non-genotoxic xenobiotics, endogenous factors, food ingredients, surgery, infectious agents. Their effect on the development of preneoplastic lesions can be both quantitatively and qualitatively different from their effect on the appearance of liver cancers. They could act through cellular or systemic metabolic perturbations linked with cell proliferation.
Animals↗
Serum alkaline DNase activity in normal or nonhospitalised individuals.
According to previous observations, the variations in serum alkaline DNase activity (SADA) appeared to be useful in monitoring malignant disease. In this study, SADA was measured in 625 individuals to explore nontumor-related factors which may influence SADA levels. The overall range in SADA was 0.2-82.3 kU/l. Women aged 50-79 years had higher (p less than 0.001) levels of SADA than younger females. A similar but less consistent effect of age was noticed in men (0.01 less than p less than 0.05). Older men had lower (0.01 less than p less than 0.05) SADA levels than the older women. Old women substituted with estrogens had lower (0.01 less than p less than 0.05) levels of SADA than those not treated with estrogens. SADA levels in pregnancy as well as postparturition were lower (p less than 0.001) than SADA values in nonpregnant females of similar age. In fertile women, no SADA variation was observed during the menstrual cycle and there was no significant effect of contraceptive pills. In males, SADA seemed unrelated to testosterone or cortisol levels but varied during the day. Smoking, alcohol consumption and drug therapy appeared to be without effect on SADA.
Adult↗
Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes.
Tetracycline is known to cause hepatic dysfunction in humans by inducing steatosis. Accumulation of fat in the liver could result from biochemical effects at various levels in the sequence from protein and triglyceride synthesis to lipoprotein secretion. The effects of tetracycline on the synthesis and secretion of triglycerides and proteins were studied in isolated rat hepatocytes surviving in suspension for up to 2.5 hr. Interpretation of the results obtained for tetracycline was made by comparison with results obtained, under the same experimental conditions, for the well-known steatogenic compounds, cycloheximide and colchicine. The data indicate that tetracycline produces a concentration-dependent inhibition of 14C-triglyceride secretion without affecting triglyceride synthesis. This inhibition explains the intracellular triglyceride accumulation. However, tetracycline does not affect protein secretion. Furthermore, it was demonstrated that the effect of tetracycline on protein synthesis was not related to inhibition of triglyceride release. In conclusion, it is proposed that the effect of tetracycline could be at the level of the association between triglycerides and apoproteins to form lipoproteins.
Animals↗
Inhibition of rat liver microsomal lipid peroxidation by N-acyldehydroalanines: an in vitro comparative study.
Captodative substituted olefins are radical scavengers which react with free radicals to form stabilized radical adducts. One of those compounds, N-(paramethoxyphenylacetyl)dehydroalanine (AD-5), may react and scavenge both superoxide anion (O-2) and alk-oxyl radicals (RO.), and in this way prevent the appearance of their mediated biological effects. Nitrofurantoin and tert-butyl hydroperoxide were used as model compounds to stimulate free radical production and their mediated lipid peroxidation in rat liver microsomes. In addition, lipid peroxidation was also initiated by exposure of rat liver microsomal suspensions to ionizing radiation (gamma rays). The microsomal lipid peroxidation induced by these chemicals and physical agents was inhibited by the addition of AD-5. These effects were dose-dependent in a millimolar range of concentration. In addition, AD-5 has no effect on microsomal electron transport, showing that NADPH-cytochrome P450 reductase activity was not modified. These data, together with the comparisons of the effects of AD-5 and some antioxidant molecules such as superoxide dismutase, uric acid, and mannitol, support the conclusion that inhibition of lipid peroxidation by AD-5 is the result of its free radical scavenger activity. In addition, the inhibitory effect of AD-5 on microsomal lipid peroxidation was dependent of the nature of the free radical species involved in the initiation of the process, suggesting that O-2 is scavenged more efficiently than RO.
Alanine↗
Increasing therapeutic effect and reducing toxicity of doxorubicin by N-acyl dehydroalanines.
Doxorubicin toxicity is generally accepted to be free radical-mediated. N-Substituted dehydroalanines (indexed as AD compounds) are capto-dative olefins which react and scavenge free radicals, especially the superoxide anion (O2-) and hydroxyl radical (HO). AD-20, an orthomethoxyphenylacetyl dehydroalanine derivative, decreases the mortality of mice when administered before an acute single dose or multiple non-toxic doses of doxorubicin. Doxorubicin administered to mice induces elevated serum transaminase levels, and the pretreatment of mice with AD-20 decreases significantly these serum enzymatic activities. Preliminary histological examinations suggest that these serum transaminase elevations reflect most likely liver injury. In addition to its cardiotoxicity, doxorubicin induces a severe bone marrow depletion. Although this initial decrease in the peripheral leukocytes induced by doxorubicin is not prevented by the administration of AD-20, it produces a fast recuperation in the white blood cells levels after 1 week, supporting a protective effect at this level. Moreover, the antitumor effect of doxorubicin in L1210 tumor-bearing mice was enhanced when AD-20 was injected before doxorubicin. We postulate that these effects may be related to the free radical scavenging ability of AD-20.
Alanine↗
N-acyl dehydroalanines protect from radiation toxicity and inhibit radiation carcinogenesis in mice.
N-Acyl dehydroalanines have shown free radical scavenging activity. They react with and scavenge mainly oxygen-derived free radicals such as the superoxide anion (O2-.) and the hydroxyl radical (HO.). Ortho-methoxyphenylacetyl dehydroalanine (AD-20) protects total-body irradiated mice against the toxicity induced by X-rays when delivered as a single dose of 700 rads in a short period of time. This degree of protection was of the same order of magnitude as that obtained with the aminothiol S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR-2721). The radioprotection of AD-20 is extended to all other doses of X-rays tested (from 600 to 800 rads). Furthermore, AD-20 inhibits the development of thymic lymphomas in C57Bl/Ka mice undergoing a leukaemogenic course of irradiation (4 x 175 rads applied at weekly intervals). We postulate that AD-20 may act as a radioprotector and anticarcinogenic agent, most probably by inactivating the oxygen-derived free radicals formed during water radiolysis.
Alanine↗
Variations in serum alkaline DNase activity: a new means to assess early detection of relapse in patients treated for acute nonlymphoblastic leukemia.
Our previously published clinical results on various malignancies indicated that the variations in serum alkaline DNase activity (SADA) could be a sensitive test for therapeutic monitoring of human malignancies. In the present study, the clinical efficacy of SADA detecting relapse in 32 acute nonlymphoblastic leukemia (ANLL) patients in remission was tested. The observation period ranged from 3 to 17 months. A simple and rapid biochemical technique based on spectrophotometric measurements was used to assay SADA. Of the 32 patients, 17 remained in remission and had less than a 15% variation in SADA levels. They had no clinical symptoms of recurrence at any time. In the remaining 15 patients, after a period of stability, a progressive decrease in SADA, with variations of more than 15%, was observed without any treatment. At that time, no abnormalities of clinical parameters were detected in these patients. A recurrence of disease as evidenced by routine examinations was found relatively late after the first decrease in SADA in all 15 patients (range 1.5 to 5.5 months). These results suggest that periodic measurements of SADA during the posttherapeutic course can be used as a means to assess early detection of an eventual recurrence.
Biomarkers, Tumor↗
A new class of free radical scavengers reducing adriamycin mitochondrial toxicity.
Beef heart mitochondria were incubated with ADM and NADH. An adriamycin semiquinone radical was detected using ESR spectroscopy. The semiquinone radical production rate is decreased upon addition of a scavenger (AD 20) in the reaction medium. NMRI mice were treated with AD 20 (70 mg/kg, i.p.) 15 min prior ADM injection (20 mg/kg, i.p.) or with ADM alone. Heart mitochondria were isolated 48 hr later. The enzymatic activities of complex I-III and complex IV of the mitochondrial respiratory chain were strongly depressed in animals receiving ADM alone, whereas these activities were almost completely restored in animals receiving AD 20 and ADM. Fluorescence depolarization measurements indicated that only mice treated with ADM alone presented a decreased fluidity of their cardiac mitochondrial membrane.
Alanine↗
Variations in serum alkaline DNase activity. A new means for therapeutic monitoring of malignant lymphomas.
Our previously published clinical results suggest that the variations in serum alkaline DNase activity (SADA) could be a reliable marker for the therapeutic monitoring of different human malignancies. The aim of the study documented in this was to determine SADA variations in 27 patients suffering from malignant lymphomas (Hodgkin's and non-Hodgkin's). Patients continued to be observed after therapy. The blood samples were collected before treatment (Time 0), during several days from the onset of each treatment (Phase I), and weeks after the last therapy (Phase II). A decrease in the serum alkaline DNase activity during the first treatment indicates a good clinical response; no decrease indicates a nonresponse to treatment (Phase I). The Phase II data can be used to predict the long-term evolution of the disease. In patients who respond to therapy three types of variations of SADA are observed during this phase. A progressive regain of SADA up to a value exceeding the level of initial value (T0) correlates with a complete remission. An incomplete regain of activity corresponds to a partial remission. No regain of SADA precedes death.
Adolescent↗
Histochemical detection of the in vivo produced cellular aldehydes by means of direct Schiff's reaction in CCl4 intoxicated rat liver.
A histochemical technique for detection of the in vivo induced cellular aldehydes based on the direct Schiff's reaction is reported in this paper. CCl4-intoxicated rat liver was used as an experimental model. Fresh and non-pretreated rat liver cryostat sections fixed in 10% formol calcium solution and washed in distilled water were exposed to Schiff's reagent. The sections were then immersed in two baths of sodium bisulphite solution, then in water, dehydrated in ethanol, cleared in xylene and mounted in a synthetic anhydrous mounting medium. As Schiff positive areas presented well circumscribed foci which increased with time following intoxication, semi-quantitative planimetric measurements were feasible. The direct Schiff's reaction detects cellular aldehydes in a sensitive, rapid, histologically and topographically estimable way. The appearance of these aldehydes precedes distinctly morphological alterations detectable by other histochemical or histological techniques. No positive results were obtained in control, non-intoxicated rat livers. Inhibition of this direct Schiff's reaction was obtained in positive control rat liver sections preincubated in solutions of aldehyde blockers. Histochemical detection of aldehydes may give useful information on different aspects of tissue and organ intoxication such as their topography, appearance, evolution, extension, consequences and effects of treatment. The direct Schiff's reaction can be considered as a valuable tool in fundamental and applied research dealing with various toxicological, environmental, pathological, cancer-related and therapeutic problems.
Aldehydes↗
Analysis of antioxidant defense systems during rat hepatocarcinogenesis.
To better understand the role of free radicals in liver carcinogenesis, endogenous antioxidant defense systems and the susceptibility of membranes to lipid peroxidation were evaluated in early lesions and in malignant tumors induced by the Solt-Farber resistant hepatocyte protocol. These parameters were also measured in the liver surrounding these tumors. In comparison with the normal liver, both nodules and carcinomas show a different biochemical pattern consisting of decreased glutathione peroxidase (GSH peroxidase) and catalase activities plus increased glutathione reductase (GSSG reductase) activity. In contrast, 1 week after the application of the initiation-selection protocol, the liver displays a high level of glutathione (GSH), high GSSG reductase activity, a reduced production of malondialdehyde and no changes in superoxide dismutase and GSH peroxidase activities. These data suggest that the liver is well protected against reactive oxygen species. During the carcinogenic process, the liver parenchyma surrounding the altered foci recovers from most of the modifications induced by the initiation-selection treatment. These results add additional support for the hypothesis that the appearance of early alterations in the liver, after a carcinogenic treatment, might be an adaptive response to a hazardous environment in which selected cell populations are transformed into nodules and/or carcinomas.
Animals↗
Partial hepatectomy of rats ten weeks before carcinogen administration can enhance liver carcinogenesis: preliminary observations.
Partial hepatectomy (PH) is known to enhance liver carcinogenesis when it is performed several hours before or after administration of a hepatocarcinogen. This effect has been attributed to cell proliferation, which is induced by PH and is a necessary step for fixation of DNA damage leading to initiated cancer cells. We now report for the first time that PH can also increase the tumour incidence, and decrease the latency period, when it is performed 8-10 weeks before treating rats with the hepatocarcinogen N-nitrosodiethylamine. This animal model may offer a tool for investigating the underlying mechanism of the 'memory effect' and increased tumour susceptibility of liver cells after PH. Additionally, it could be explored as a more sensitive rodent bioassay for testing putative carcinogens.
Animals↗
Inhibition of O2-.- and HO.- mediated processes by a new class of free radical scavengers: the N-acyl dehydroalanines.
N-phenylacetyl dehydroalanines are captodative olefins. They inhibit two processes mediated by superoxide anion (O2-.) in a concentration dependent manner: reduction of NBT to blue formazan and oxidation of epinephrine to adrenochrome. They also inhibit in a dose related way the degradation of deoxyribose produced during either the Fenton reaction or the radiolysis of water, which are the two experimental sources of hydroxyl radical (HO.) production. Based on the results obtained with superoxide dismutase, mannitol, thiourea, and uric acid, we postulate that these competitive inhibitory effects suggest a reaction between the dehydroalanine derivatives and the two oxygen derived radicals. Hydroxyl free radical is scavenged more efficiently than superoxide anion. Substitution of the phenyl ring by methoxy groups does not modify significantly the activity. These molecules possess three target active sites which can react with free radicals.
Alanine↗
Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment.
The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.
Animals↗