RESUMEN
This experiment was carried out to evaluate the possibility of degradation of d-lactate into formate and acetaldehyde. In order to induce hyperproduction of d-lactate in rats. Donryu male albino rats were fed diets containing 0.064% 3'-methyl-4-dimethylaminoazobenzene (3'-MDAB), 4'-methyl-4-dimethylaminoazobenzene (4'-MDAB) or 2-methyl-4-dimethylaminoazobenzene (2-MDAB) for 10 weeks. During the experiment, body mass, food and water intake and volume of urine were documented. Methylglyoxal, D-lactate and formate in the urine samples were determined. On the first day of the eleventh week, methylglyoxal, D-lactate, glutathione and enzymatic activities of demethylation and glyoxalase I and II in liver were measured. Methylglyoxal, D-lactate and clinical chemistry parameters of blood plasma were also measured. The levels of methylglyoxal and D-lactate in livers of rats fed 3'-MDAB were very high, while those of 2-MDAB fed-rats and the control group were the same. The fact that glyoxalase I activity and the level of glutathione, a cofactor of glyoxalase I, were high in the livers of the 3'-MDAB-fed rats can explain the elevated levels of methylglyoxal and D-lactate in the liver. The most striking results were the elevated formate levels in the urine of rats fed 3'- and 4'-MDAB in a precancerous state. The degradation of D-lactate, an end product of the methylglyoxal bypass, into acetaldehyde and formate was suggested as a possible way to explain the results.
Asunto(s)
Formiatos/orina , Ácido Láctico/metabolismo , p-Dimetilaminoazobenceno/metabolismo , Acetaldehído/metabolismo , Administración Oral , Animales , Índice de Masa Corporal , Cisteína/metabolismo , Dieta , Ingestión de Líquidos , Ingestión de Alimentos , Glutatión/metabolismo , Lactoilglutatión Liasa/metabolismo , Hígado/metabolismo , Masculino , Piruvaldehído/metabolismo , Ratas , Ratas Endogámicas , Tioléster Hidrolasas/metabolismo , p-Dimetilaminoazobenceno/administración & dosificaciónRESUMEN
Solid lipid microparticles (SLMs) loaded with the sunscreen agent, octyl-dimethylaminobenzoate (ODAB), were prepared in order to achieve enhanced sunscreen photostability. The microparticles were produced by the melt dispersion technique using glyceryl behenate as lipidic material and poloxamer 188 as the emulsifier. The obtained SLMs showed proper features in terms of morphology, size distribution (1.67-15.81 microm) and ODAB loading (16.15+/-0.11%, w/w). The sunscreen release from the SLMs was slower than its dissolution rate and the photodecomposition of ODAB was markedly decreased (>51.3%) by encapsulation into the lipid microparticles. The efficacy of the SLM carrier system was also evaluated after their introduction in model topical formulations (i.e., hydrogel and oil-in-water emulsion). Further in vitro release measurements, performed using Franz diffusion cells with polycarbonate membranes, indicated that the retention capacity of the microparticles was lost after their incorporation into the emulsion, whereas it was retained in the hydrogel. Moreover, the SLMs achieved a reduction of the sunscreen photodegradation in the hydrogel vehicle (the ODAB loss decreased from 87.4% to 59.1%), whereas no significant photoprotective effect was observed in the emulsion. Therefore, the efficacy of the ODAB-loaded SLMs was markedly affected by the vehicle.
Asunto(s)
Ácidos Grasos/administración & dosificación , Poloxámero/administración & dosificación , Protectores Solares/administración & dosificación , p-Dimetilaminoazobenceno/análogos & derivados , Estabilidad de Medicamentos , Vehículos Farmacéuticos , Fotólisis , Protectores Solares/química , p-Dimetilaminoazobenceno/administración & dosificación , p-Dimetilaminoazobenceno/químicaRESUMEN
BACKGROUND: Chronic injury deregulates cellular homeostasis and induces a number of alterations leading to disruption of cellular processes such as cell cycle checkpoints and apoptosis, driving to carcinogenesis. The stress protein heme oxygenase-1 (HO-1) catalyzes heme degradation producing biliverdin, iron and CO. Induction of HO-1 has been suggested to be essential for a controlled cell growth. The aim of this work was to analyze the in vivo homeostatic response (HR) triggered by the withdrawal of a potent carcinogen, p-dimethylaminoazobenzene (DAB), after preneoplastic lesions were observed. We analyzed HO-1 cellular localization and the expression of HO-1, Bcl-2 and cell cycle related proteins under these conditions comparing them to hepatocellular carcinoma (HC). METHODS: The intoxication protocol was designed based on previous studies demonstrating that preneoplastic lesions were evident after 89 days of chemical carcinogen administration. Male CF1 mice (n = 18) were used. HR group received DAB (0.5 % w/w) in the diet for 78 days followed by 11 days of carcinogen deprivation. The HC group received the carcinogen and control animals the standard diet during 89 days. The expression of cell cycle related proteins, of Bcl-2 and of HO-1 were analyzed by western blot. The cellular localization and expression of HO-1 were detected by immnunohistochemistry. RESULTS: Increased expression of cyclin E/CDK2 was observed in HR, thus implicating cyclin E/CDK2 in the liver regenerative process. p21cip1/waf1 and Bcl-2 induction in HC was restituted to basal levels in HR. A similar response profile was found for HO-1 expression levels, showing a lower oxidative status in the carcinogen-deprived liver. The immunohistochemical studies revealed the presence of macrophages surrounding foci of necrosis and nodular lesions in HR indicative of an inflammatory response. Furthermore, regenerative cells displayed changes in type, size and intensity of HO-1 immunostaining. CONCLUSION: These results demonstrate that the regenerative capacity of the liver is still observed in the pre-neoplastic tissue after carcinogen withdrawal suggesting that reversible mechanism/s to compensate necrosis and to restitute homeostasis are involved.
Asunto(s)
Carcinógenos/toxicidad , Proteínas de Ciclo Celular/genética , Ciclo Celular/efectos de los fármacos , Hemo-Oxigenasa 1/genética , p-Dimetilaminoazobenceno/toxicidad , Animales , Carcinógenos/administración & dosificación , Carcinoma Hepatocelular/enzimología , Esquema de Medicación , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Homeostasis , Neoplasias Hepáticas/enzimología , Masculino , Ratones , Ratones Endogámicos , p-Dimetilaminoazobenceno/administración & dosificaciónRESUMEN
The cytotoxic and genotoxic effects of chronic feeding of the azo-dye p-dimethylaminoazobenzene (p-DAB) during 7, 15, 30, 60, 90 and 120 days have been assessed in mice. The endpoints used for genotoxic analysis were chromosome aberrations (CA), micronuclei (MN) and mitotic index (MI) in bone-marrow cells, and sperm-head abnormality (SHA) in male gonads. The activities of marker enzymes for toxicity, such as glutamate oxalo-acetate transaminase (GOT), glutamate pyruvate transaminase (GPT), acid phosphatase (ACP) and alkaline phosphatase (ALKP) were also assayed periodically, as was lipid peroxidation (LPO). Chronic feeding of p-DAB produced increased numbers of chromosome aberrations, nuclear anomalies and sperm-head abnormalities, as compared with normal untreated controls, generally in a time-dependent manner until 60 days, after which the anomalies persisted, but rather erratically. However, although there was some noticeable modulation in enzyme activities in the corresponding p-DAB-fed mice as well, these were not strictly time-dependent.
Asunto(s)
Carcinógenos/toxicidad , Aberraciones Cromosómicas/inducido químicamente , p-Dimetilaminoazobenceno/toxicidad , Administración Oral , Animales , Ratones , Pruebas de Micronúcleos , Índice Mitótico , Factores de Tiempo , p-Dimetilaminoazobenceno/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: Control of cell proliferation is important for cancer prevention since cell proliferation has an essential role in carcinogenesis. In rodent carcinogenesis models, antioxidant agents suppress carcinogen-induced cellular hyper proliferation in the target organs. Strict control of cell division is an essential process to ensure that DNA synthesis and mitotic division are accurately and coordinately executed. We studied the interplay between cell cycle and heme oxygenase-1 (HO-1) and the effect of the acetylsalicylic acid (ASA) in hepatic carcinogenesis. METHODS: Male CF1 mice pre-treated with dietary p-dimethylaminoazobenzene (DAB; 0.5%, w/w) were fed with ASA (0.16%, w/w). We investigated the hepatic expression of cyclin D1, cyclin E, Cdk2, Cdk4, p21, p27, p53; the level of bcl-2, an antiapoptotic protein and of heme oxygenase-1 (HO-1), a marker of oxidative stress, by Western blot analysis. RESULTS: The treatment with ASA produced an important attenuation in the induction of cyclin E and cyclin D1 provoked by DAB. p21 and p27 levels were increased when animals received both drugs. The administration of ASA to DAB treated animals induced Cdk2 (29%). HO-1 induction (65%) provoked by DAB was diminished by ASA administration reaching lower induction levels (23%). CONCLUSION: The deregulation of cyclin/CDK expression and the up-regulation of p21 and p27 with the administration of ASA, post-treatment of the carcinogen administration, would block the pass through out to the G0/G1 check point to permit the cells to repair their DNA and HO-1 protected the liver from reactive oxygen species produced from DAB.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Transformación Celular Neoplásica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/metabolismo , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Ácido Salicílico/farmacología , Animales , Antiinflamatorios/farmacología , Western Blotting , Proteínas de Ciclo Celular/metabolismo , División Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Hemo-Oxigenasa 1 , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Proteínas de la Membrana , Ratones , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , p-Dimetilaminoazobenceno/administración & dosificación , p-Dimetilaminoazobenceno/farmacologíaRESUMEN
We determined the genotoxicity of synthetic red tar dyes currently used as food color additives in many countries, including JAPAN: For the preliminary assessment, we treated groups of 4 pregnant mice (gestational day 11) once orally at the limit dose (2000 mg/kg) of amaranth (food red No. 2), allura red (food red No. 40), or acid red (food red No. 106), and we sampled brain, lung, liver, kidney, glandular stomach, colon, urinary bladder, and embryo 3, 6, and 24 h after treatment. We used the comet (alkaline single cell gel electrophoresis) assay to measure DNA damage. The assay was positive in the colon 3 h after the administration of amaranth and allura red and weakly positive in the lung 6 h after the administration of amaranth. Acid red did not induce DNA damage in any sample at any sampling time. None of the dyes damaged DNA in other organs or the embryo. We then tested male mice with amaranth, allura red, and a related color additive, new coccine (food red No. 18). The 3 dyes induced DNA damage in the colon starting at 10 mg/kg. Twenty ml/kg of soaking liquid from commercial red ginger pickles, which contained 6.5 mg/10 ml of new coccine, induced DNA damage in colon, glandular stomach, and bladder. The potencies were compared to those of other rodent carcinogens. The rodent hepatocarcinogen p-dimethylaminoazobenzene induced colon DNA damage at 1 mg/kg, whereas it damaged liver DNA only at 500 mg/kg. Although 1 mg/kg of N-nitrosodimethylamine induced DNA damage in liver and bladder, it did not induce colon DNA damage. N-nitrosodiethylamine at 14 mg/kg did not induce DNA damage in any organs examined. Because the 3 azo additives we examined induced colon DNA damage at a very low dose, more extensive assessment of azo additives is warranted.
Asunto(s)
Colorante de Amaranto/farmacología , Compuestos Azo/farmacología , Daño del ADN , Dietilnitrosamina/farmacología , Feto/efectos de los fármacos , Rodaminas/farmacología , p-Dimetilaminoazobenceno/farmacología , Colorante de Amaranto/administración & dosificación , Animales , Compuestos Azo/administración & dosificación , Ensayo Cometa , Dietilnitrosamina/administración & dosificación , Femenino , Edad Gestacional , Masculino , Ratones , Ratones Endogámicos ICR , Naftalenosulfonatos , Embarazo , Rodaminas/administración & dosificación , Distribución Tisular , p-Dimetilaminoazobenceno/administración & dosificaciónRESUMEN
Microsomal preparations from rats treated with 2-acetylaminofluorene (2-AAF) or with 4-dimethylaminoazobenzene (4-DAB), alone or followed by phenobarbital (PB), showed almost complete loss of microsomal proteins of molecular weights higher than 60,000, as shown by Sephadex G-150 gel filtration technique. Induction of a number of microsomal proteins in the lower ranges of molecular weights was also recorded due to the treatment of these two hepatocarcinogens with and without the use of PB as a promoter. These modifications in the protein patterns of microsomes might be due to altered genetic expression resulting in uncontrolled cell division/cell cycle.
Asunto(s)
Carcinógenos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteínas/efectos de los fármacos , Proteínas/metabolismo , 2-Acetilaminofluoreno/administración & dosificación , 2-Acetilaminofluoreno/toxicidad , Administración Oral , Animales , Carcinógenos/administración & dosificación , Femenino , Inyecciones Intraperitoneales , Peso Molecular , Biosíntesis de Proteínas , Ratas , Ratas Wistar , p-Dimetilaminoazobenceno/administración & dosificación , p-Dimetilaminoazobenceno/toxicidadRESUMEN
Attempts by early workers to induce liver tumours by the local implantation of carcinogens had by and large not been successful, so that the liver came to be viewed as being "resistant" to tumourigenesis by this means. A review of these early studies showed not only that fibrosarcomas could be easily induced by the local application of 3-methylcholanthrene (3-M.C.), but that there were also reasons why the apparently low susceptibility of the liver to the localised induction of hepatocellular tumours should not be accepted as established dogma. In an attempt to re-investigate this problem pellets made of cholesterol (CHOL), anthracene (ANT), alpha-naphthylisothiocyanate (ANIT), 3-M.C. or 4-dimethylaminoazobenzene (DAB) were implanted into the livers of male litter-mate weanling rats. The evolution of the response was studied by histological examination of the implantation site at varying intervals. In each instance the liver responded with the formation of a firm, complete connective tissue capsule which, however, did not prevent the gradual degradation of the implants. No tumours or other significant changes were observed with the control implants of CHOL or ANT. ANIT, known to damage biliary ducts, elicited what appeared to be an intense serous exudation which was separated from the adjacent parenchyma by a shell-like deposition of calcium in the connective tissue capsule. No significant biliary changes were observed, however, and no tumours were produced. Attention should be drawn to this reproducible, regularly occurring, in vivo model of extra-osseous calcification. The 3-M.C. induced a high incidence of large solitary bosselated tumours associated with the carcinogenic pellet which was found embedded in the tumour mass. The architectural arrangement and bizarre cytological appearance of the tumours led to the currently widely used diagnosis of malignant fibrous histiocytoma (M.F.H.) rather than the fibrosarcoma or rhabdomyosarcoma of the early workers. Some tumours produced large numbers of implantation metastases in the peritoneal cavity, but no distant metastases were observed in this series. Of particular interest is the fact that it was not possible to determine the site of origin of these tumours despite histological sampling at intervals of the site of implantation of the pellets. In contrast to these pleomorphic, clearly mesenchymal tumours reliably produced by 3-M.C., the implantation of pellets of DAB produced fewer tumours which were classified as large, singly occurring hepatocellular carcinomas (H.C.C.).(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Carcinógenos/administración & dosificación , Neoplasias Renales/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , Animales , Implantes de Medicamentos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/patología , Metilcolantreno/administración & dosificación , Ratas , Sarcoma Experimental/inducido químicamente , Sarcoma Experimental/patología , p-Dimetilaminoazobenceno/administración & dosificaciónAsunto(s)
2-Acetilaminofluoreno/administración & dosificación , Neoplasias Hepáticas Experimentales/inducido químicamente , Hígado/efectos de los fármacos , p-Dimetilaminoazobenceno/administración & dosificación , Administración Oral , Animales , Cricetinae , Combinación de Medicamentos , Femenino , Hígado/patología , Neoplasias Hepáticas Experimentales/patología , Masculino , Mesocricetus , Ratones , RatasRESUMEN
A relatively safe and simple procedure was developed for the induction of hepatomas in the rat by the s.c. administration of powdered 3'-methyl-p-dimethylaminoazobenzene.
Asunto(s)
Carcinoma Hepatocelular/inducido químicamente , Neoplasias Hepáticas/inducido químicamente , p-Dimetilaminoazobenceno , Animales , Métodos , Neoplasias Experimentales/inducido químicamente , Ratas , p-Dimetilaminoazobenceno/administración & dosificaciónRESUMEN
Experiments were performed on male rabbits observing the changes in the fractions of protein, glycoprotein, lipoprotein and lipid of the blood. The effect of scarlet R and p-dimethylamino-azobenzene (methyl yellow) was examined. When a solution of scarlet R or p-dimethylamino-azobenzene in paraffin oil was injected into the testicles of the experimental animals the effect was different from any other route of introduction. p-Dimethylamino-azobenzene caused no significant change in the macromolecular fractions of the blood, while scarlet R injected into the testicles caused a significant increase of the total lipids in the second week after the exposition. This effect did not occur when scarlet R was introduced by any other route. According to the authors, their findings may be viewed as a starting point for new approaches to new ideas and ways of thinking.
Asunto(s)
Preparaciones Farmacéuticas/administración & dosificación , Testículo , Animales , Compuestos Azo/administración & dosificación , Proteínas Sanguíneas/análisis , Colorantes , Inyecciones , Lípidos/sangre , Masculino , Conejos , p-Dimetilaminoazobenceno/administración & dosificaciónRESUMEN
The mutagenicity of N,N-dimethyl-4-aminoazobenzene and N-methyl-4-aminoazobenzene and their derivatives was shown on Salmonella typhimurium TA100 and TA98. S-9 Mix, obtained from rat liver after injection of polychlorinated biphenyl, was abligatory for their mutagenic action. N-Acetoxy-N-methyl-4-aminoazobenzene and N-benzoyloxy-N-methyl-4-aminoazobenzene and their 4'-methoxycarbonyl derivatives were also mutagenic on TA100 and TA98 and did not require metabolic activation by S-9 Mix. It is suggested that the carcinogenic effects of azo dyes may involve modification of DNA.
Asunto(s)
Compuestos Azo/farmacología , Mutágenos , p-Dimetilaminoazobenceno/análogos & derivados , p-Dimetilaminoazobenceno/farmacología , Animales , Compuestos Azo/metabolismo , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Ratas , Salmonella typhimurium/efectos de los fármacos , o-Aminoazotolueno/farmacología , p-Aminoazobenceno/análogos & derivados , p-Aminoazobenceno/farmacología , p-Dimetilaminoazobenceno/administración & dosificación , p-Dimetilaminoazobenceno/metabolismoRESUMEN
The distribution of radioactivity from N-acetyl-9-[114C]-2-aminofluorene and p-[14C]-dimethylaminoazobenzene administered i.v. or p.o. to 18-day-pregnant mice was observed by means of autoradiography of longitudinal section of the whole mouse. Radioactive substances derived from these carcinogens passed through the placenta and were distributed in the fetal organs including the kidney and intestine. Column, thin-layer, and paper chromatography revealed the presence, in while fetuses as well as in maternal livers, of N-acety-9-[14C]-2-aminofluorene. N-hydroxy-N-acetyl-9-[14C]-2-aminofluorene, ring-hydroxy-N-acetyl-9-[14C]-2-aminofluorene, and p-[14C]-dimethylaminoazobenzene. These results establish that N-acetyl-9-[14C]-2-aminofluorene and [14C]-p-dimethylaminoazobenzene are transported, metabolized, and excreted in the mouse fetus.
Asunto(s)
2-Acetilaminofluoreno/metabolismo , Fluorenos/metabolismo , Intercambio Materno-Fetal , p-Dimetilaminoazobenceno/metabolismo , 2-Acetilaminofluoreno/administración & dosificación , Animales , Autorradiografía , Cromatografía en Gel , Cromatografía en Capa Delgada , Femenino , Feto/metabolismo , Inyecciones Intravenosas , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Ratones , Embarazo , p-Dimetilaminoazobenceno/administración & dosificaciónAsunto(s)
Colesterol/biosíntesis , Hígado/metabolismo , Lesiones Precancerosas/metabolismo , p-Dimetilaminoazobenceno/farmacología , Animales , Depresión Química , Dieta , Hígado/efectos de los fármacos , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Masculino , Ratas , Factores de Tiempo , p-Dimetilaminoazobenceno/administración & dosificaciónAsunto(s)
Aciltransferasas/biosíntesis , Carcinógenos/farmacología , Hígado/efectos de los fármacos , Acetamidas/farmacología , Animales , Compuestos Azo/farmacología , Carcinoma Hepatocelular/enzimología , Dieta , Activación Enzimática , Etionina/farmacología , Fluorenos/administración & dosificación , Fluorenos/farmacología , Glutamatos , Hipofisectomía , Hígado/enzimología , Neoplasias Hepáticas/enzimología , Neoplasias Experimentales/enzimología , Nitrosaminas/administración & dosificación , Nitrosaminas/farmacología , Ratas , Factores de Tiempo , Tolueno/farmacología , gamma-Glutamiltransferasa/biosíntesis , p-Dimetilaminoazobenceno/administración & dosificación , p-Dimetilaminoazobenceno/farmacologíaRESUMEN
PIP: A previously reported early appearance of alpha fetoprotein (AFP) in rats fed 3'-methyl-4-dimethylaminobenzene (3-MDAB) which was induced before definite cancers were formed and disappeared on cessation of 3-MDAB administration was further investigated using different doses of 3-MDAB as well as other hepatocellular carcinogens and hepatotoxic agents. AFP was induced after 3 weeks of ingestion of diets with 600 ppm 3-MDAB and appeared after only 2 weeks when higher doses (900 and 1200 ppm) were used. Lower levels of 300 ppm 3-MDAB gave only a transient appaerance of AFP, beginning at the 5th week and remaining detectable for 3 more weeks, but 150 ppm did not induce at all. Immunosuppression with rat lymphocyte globulin extended for 1 week the time during which positive AFP titers were maintained upon cessation of 3-MDAB (600 ppm) intake. A transient appearance of AFP was found when rats were given the carcinogens dimethyl-4-dimethylaminoazobenzene (4-DMAA; 600 ppm), aflatoxin (AFB1; 4 ppm), N-2-fluorenylacetamide (N-2-FAA; 200 and 300 ppm), and N-hydroxy-N-2-fluorenylacetamide (N-OHFAA; 213 and 320 ppm). Lower doses of AFB1 (.2 and 2 ppm), N-2-FAA (150 ppm), N-OHFAA, and diethylnitrosamine (40 ppm) did not induce detectable AFP levels in serum nor did 2'-methyl-4-DMAA (600 ppm) and CCl4 (50 mg intraperitoneally twice a week). Apparently, high levels of liver carcinogens are required to induce the early appearance, within 2-5 weeks, of detectable AFP in serum.^ieng