RESUMEN
Dietary polyunsaturated fatty acid is needed for optimal induction of cytochrome P450. In this study we quantitated cytochrome P450 hemoproteins in male Sprague-Dawley rats that were starved for 36 hr and then refed a fat-free diet (FF) or a diet containing 20% corn oil for 4 days. Some received phenobarbital (Pb) sodium (80 mg/kg, i.p., daily) for 3 days prior to decapitation. Microsomal cytochrome P450 levels were measured by carbon monoxide binding spectra, and the P450 isozymes separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis were quantitated by gel scanner. Cytochrome P450 PB-B was quantitated by a Western blot technique. Rats fed FF diet and administered Pb had only 21% more microsomal P450 than non-induced controls, whereas rats fed 20% corn oil diet had 59% more P450 and Pb-treated rats fed 20% corn oil diet had 181% more P450 than FF controls. Analysis of gels showed 32, 59 and 124% more P450 protein, respectively, in FF Pb, corn oil control or corn oil Pb groups than in FF controls. Cytochrome P450 PB-B was not detected in non-induced groups, but quantitation by Western blot yielded 0.32 and 0.70 nmol/mg protein, respectively, in FF Pb and corn oil Pb groups. Our findings suggest that deprivation of dietary fat reduces the total amount of cytochrome P450 hemoprotein and its inducibility by Pb through decreased P450 hemoprotein synthesis. The limiting factor(s) restricting synthesis of new cytochrome P450 hemoproteins in rats refed a diet devoid of fat may be the inability to respond to the inducer (Pb) or the paucity of utilizable fatty acids needed for synthesis of the phospholipid matrix of the endoplasmic reticulum necessary for the support and proper juxtapositioning of these protein molecules.
Asunto(s)
Aceite de Maíz/farmacología , Sistema Enzimático del Citocromo P-450/biosíntesis , Grasas Insaturadas en la Dieta/farmacología , Isoenzimas/biosíntesis , Microsomas Hepáticos/enzimología , Fenobarbital/farmacología , Aceites de Plantas/farmacología , Animales , Inducción Enzimática/efectos de los fármacos , Privación de Alimentos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Virgin female Sprague-Dawley rats (50 days of age) were administered a single intragastric 10-mg dose of 7,12-dimethylbenz(a)anthracene (DMBA). Twenty-one days later they were placed on diets containing either 20% corn oil (CO), 15% menhaden oil plus 5% corn oil (MO + CO), 20% CO plus 0.5% w/w of the irreversible ornithine decarboxylase inhibitor, D,L-2-difluoromethylornithine (CO + DFMO), 20% CO plus 0.004% w/w of the cyclooxygenase inhibitor indomethacin (CO + INDO), 20% CO + 0.004% INDO + 0.5% DFMO (CO + INDO + DFMO), or 15% MO + 5% CO + 0.5% DFMO (MO + CO + DFMO). The incidence of DMBA-induced mammary tumors was significantly reduced in rats fed diets containing DFMO but not in rats fed the diet containing indomethacin. Incidences of mammary tumors at 16 weeks post-DMBA were 86% in rats fed the CO diet, 83% in rats ingesting the diet containing CO + INDO, 28% in rats fed CO + DFMO, 32% in rats fed diet containing CO + INDO + DFMO, 59% in rats fed the MO + CO diet, and 24% in rats fed the MO + CO + DFMO diet. The average number of tumors and tumor burden per tumor-bearing rat were reduced and tumor latency was increased in all rats fed diets containing DFMO. Body weight gain, but not food intake, of rats fed the 20% fat + 0.5% DFMO diets was significantly less than in rats fed the 20% fat diets. Prostaglandin E and leukotriene (LTB4) syntheses, ODC activity and mammary tumorigenesis were significantly inhibited by feeding the diet containing menhaden oil or by adding 0.5% DFMO to any of the high fat diets. Feeding a 20% CO diet containing 0.004% INDO significantly reduced prostaglandin synthesis and ODC activity and increased LTB4 synthesis of mammary tumors but did not inhibit mammary tumorigenesis. This study suggests that the 5-lipoxygenase product LTB4 may be involved in mammary tumor production. Whereas a decrease in LTB4 appears to be associated with a decrease in tumorigenesis, an increase (as seen in the indomethacin group) was not associated with any change in the tumorigenic response.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Eflornitina/farmacología , Indometacina/farmacología , Neoplasias Mamarias Experimentales/prevención & control , 9,10-Dimetil-1,2-benzantraceno , Animales , Femenino , Leucotrieno B4/biosíntesis , Neoplasias Mamarias Experimentales/inducido químicamente , Ornitina Descarboxilasa/análisis , Prostaglandinas E/biosíntesis , Ratas , Ratas EndogámicasRESUMEN
The comparative effects of high-fat diets (20%, w/w) on eicosanoid synthesis during mammary tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-induced rats were studied using diets containing 20% primrose oil (PO), 20% menhaden oil (MO) or 20% corn oil (CO). Sprague-Dawley rats fed the PO or MO diet had 21% of 24% fewer adenocarcinomas, respectively, than rats fed the CO diet. Histologically (i.e., mitotic figures, inflammatory cell infiltration and necrosis), the CO-fed rats exhibited the highest frequency of changes within tumors. Plasma fatty acid composition was significantly altered by diet, reflecting the composition of the oils which were being fed. Only the plasma of PO-fed rats contained detectable levels of gamma-linolenic acid (GLA). Arachidonic acid (AA) levels were significantly higher (p less than 0.05) in PO-fed than in CO- or MO-fed rats. MO-fed rats had significantly higher levels of plasma palmitic acid, while palmitoleic, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids were detected only in MO-fed rats. As expected, linoleic acid (LA) and AA levels were lower (p less than 0.05) in the MO-fed rats than in PO- or CO-fed groups. The plasma of the CO-fed rats contained significantly higher levels of oleic acid. Eicosanoid synthesis in mammary carcinomas of rats fed the 20%-fat diets was 2-10 times higher than in mammary fat pads of control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Aceite de Maíz/farmacología , Grasas de la Dieta/farmacología , Ácidos Eicosanoicos/biosíntesis , Ácidos Grasos Esenciales/farmacología , Aceites de Pescado/farmacología , Neoplasias Mamarias Experimentales/metabolismo , Aceites de Plantas/farmacología , 9,10-Dimetil-1,2-benzantraceno , Animales , Ácidos Grasos/sangre , Femenino , Ácidos Linoleicos , Neoplasias Mamarias Experimentales/inducido químicamente , Modelos Biológicos , Oenothera biennis , Ratas , Ratas Endogámicas , Ácido gammalinolénicoRESUMEN
Female rats receiving a diet containing 20% menhaden oil beginning at 10 weeks of age and continuing for 13 weeks had hepatic benzo(a)pyrene [B(a)P] hydroxylase activity significantly higher than similar rats fed diets containing 20% corn oil or 20% oil of evening primrose. Compared to microsomes recovered from rats fed the corn oil diet, a significant increase in microsomal cytochrome P-450 content along with an increase in the activity of cytochrome P-450 mediated ethoxycoumarin O-dealkylase was evident in rats fed menhaden oil. Glutathione S-transferase activity of the cytosol of hepatocytes was increased twofold by the feeding of 20% menhaden oil, compared with the feeding of corn or primrose oil. Administration of 7,12-dimethylbenz(a)anthracene (DMBA) 21 days before instituting the diets enhanced B(a)P hydroxylase in all animals, with the activity greatest in those fed the menhaden oil. DMBA also caused a significant increase in ethoxycoumarin O-dealkylase in rats fed menhaden oil.
Asunto(s)
9,10-Dimetil-1,2-benzantraceno/farmacología , Grasas Insaturadas en la Dieta/farmacología , Hígado/enzimología , Oxigenasas de Función Mixta/metabolismo , Animales , Aceite de Maíz/farmacología , Ácidos Grasos Esenciales/farmacología , Femenino , Aceites de Pescado/farmacología , Ácidos Linoleicos , Oenothera biennis , Aceites de Plantas , Ratas , Ratas Endogámicas , Ácido gammalinolénicoRESUMEN
Hepatic microsomes from rats starved 48 hours and refed diets containing zero, 3 or 20% corn oil metabolized benzo(a)pyrene, aniline and N-nitrosodimethylamine in proportion to the quantity of corn oil in the diet. No diet-related changes in apparent Km for these reactions were evident. The content of microsomal cytochrome P-450 was also clearly dependent upon the content of corn oil in the refed diets. When metabolism of these three substrates is expressed as product formed per unit of cytochrome P-450, the activities are least in microsomes from rats fed the 20% corn oil diet, suggesting that P-450 species responsible for metabolizing substrates other than these are enhanced preferentially. Cytosolic glutathione S-transferase activities are also increased with increasing corn oil in the diet. The administration of 3-MC increased cytochrome P-448 content of microsomes from all rats, regardless of diet, however highest content was present in microsomes from rats fed the 20% corn oil diet. Induction of benzo(a)pyrene hydroxylase was not influenced by dietary corn oil and, as anticipated, 3-MC caused significant repression of DMN N-demethylase in microsomes from rats fed the 20% corn oil diet. In like manner, 3-MC induced glutathione S-transferase only in cytosol from rats fed the fat-free diet.
Asunto(s)
Carcinógenos/metabolismo , Aceite de Maíz/administración & dosificación , Grasas de la Dieta/administración & dosificación , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/biosíntesis , Aceites de Plantas/administración & dosificación , Animales , Citocromo P-450 CYP1A2 , Sistema Enzimático del Citocromo P-450/biosíntesis , Citocromos/biosíntesis , Inducción Enzimática/efectos de los fármacos , Cinética , Masculino , Metilcolantreno/farmacología , Microsomas Hepáticos/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
It is well established that dietary polyunsaturated omega-6 fatty acids promote tumorigenesis and support the activity of mixed-function oxidases (MFO), which are responsible for carcinogen activation. This study was undertaken to determine if increased levels of dietary menhaden fish oil (rich in omega-3 fatty acids) would affect in vivo binding of [3H]benzo[a]pyrene (BP) to rat liver DNA. The effects of dietary menhaden oil on the activities of phase I and phase II drug-metabolizing enzymes were also studied to determine the possible relationships between the activity of these enzymes and the binding of [3H]BP metabolites to liver DNA. Following a single intraperitoneal injection of [3H]BP, more BP was bound to liver DNA recovered from rats fed diet containing 20% menhaden oil for 11 days at all time intervals tested (16, 24, 48, and 192 hours) than was bound from rats fed 0.5% menhaden oil. The increased binding of [3H]BP to liver DNA of rats fed the high level of menhaden oil may be due, in part, to increases in the MFO responsible for BP activation (as suggested by increased cytochrome P-450 level and total BP hydroxylase activity). The higher concentrations of radioactivity extracted from blood of rats fed 20% menhaden oil diet at the initial time periods (16 and 24 hours) may be a reflection of the greater capacity of the liver to metabolize BP to more water-soluble metabolites. The maximum velocity (Vmax) for ethoxycoumarin O-dealkylase, expressed as nanomoles per milligram protein or per gram liver, was increased three- to fourfold by feeding the high level of menhaden oil. The differences in these enzymatic responses suggest that certain form(s) of cytochrome P-450 are preferentially increased by feeding the omega-3 fatty acids of menhaden oil.
Asunto(s)
Benzo(a)pireno/metabolismo , ADN/metabolismo , Grasas de la Dieta/farmacología , Aceites de Pescado/farmacología , Hígado/metabolismo , Oxigenasas de Función Mixta/metabolismo , 7-Alcoxicumarina O-Dealquilasa , Animales , Benzopireno Hidroxilasa/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Cinética , Hígado/efectos de los fármacos , Masculino , Oxigenasas/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The influence of phenobarbital on the activity of hepatic mixed function oxidases responsible for benzo[a]pyrene hydroxylation was studied in rats fed diets containing menhaden fish oil (rich in n-3 fatty acids). Male rats were starved for 2 days and refed diet devoid of fat or containing 0.5, 10, or 20% menhaden oil for 4 days. Phenobarbital increased the apparent Km value as well as Vmax for benzo[a]pyrene hydroxylase in microsomes from rats fed the 20% menhaden oil diet. The increased Km was due to a progressive decrease in benzo[a]pyrene metabolism at the lower substrate concentrations, even in the presence of increased cytochrome P-450 content. The phenobarbital-induced increase in Km and the decreases in benzo[a]pyrene hydroxylation were not observed in rats fed 0.5% menhaden oil or a diet devoid of fat.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/análisis , Benzopireno Hidroxilasa/análisis , Grasas de la Dieta/administración & dosificación , Aceites de Pescado/farmacología , Microsomas Hepáticos/enzimología , Fenobarbital/farmacología , Animales , Aceites de Pescado/administración & dosificación , Masculino , Metilcolantreno/farmacología , Compuestos Policíclicos/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The fact that nutriture affects drug metabolism and drug action in laboratory animals is undisputable. Activation or detoxification of drugs and potential carcinogens can also be modified by diet. The quantity and quality of dietary fat affects lipid composition and physical characteristics of biological membranes and enzymatic activity of several components of the drug metabolizing enzyme system. These changes have been associated with alterations in the physiological response to drugs and to the resulting mutagenicity and carcinogenicity of procarcinogens. It is suggested by these data that dietary fat, by altering fatty acid composition of biological membranes, alters the physical and biochemical characteristics of these membranes, thereby directly affecting drug entrance into the membrane; the stability of the membrane; the potential for lipid peroxidation; and the activity of the phospholipid dependent enzymes associated with these membranes. The fact that these membrane associated changes can occur rapidly and that brief periods of fatty acid deprivation can profoundly affect the inducibility of these enzymes by xenobiotics suggests that the potential for drug-nutrient interactions exists in the absence of frank nutrient deficiency states.
Asunto(s)
Grasas de la Dieta/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Benzo(a)pireno/metabolismo , Biotransformación , Carcinógenos/metabolismo , Sistema Enzimático del Citocromo P-450/análisis , ADN/metabolismo , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/análisis , Dimetilnitrosamina/metabolismo , Inducción Enzimática , Ácidos Grasos/análisis , Ácidos Grasos/metabolismo , Femenino , Glucuronosiltransferasa/análisis , Humanos , Masculino , Metilcolantreno/farmacología , Ratones , Oxigenasas de Función Mixta/biosíntesis , Oxigenasas de Función Mixta/fisiología , NADPH-Ferrihemoproteína Reductasa/análisis , Fosfolípidos/análisis , Fosfolípidos/fisiología , Medicina Preventiva , Ratas , Esteroides/metabolismoRESUMEN
Dietary polyunsaturated fatty acids enhance activation of constitutive and induced forms of enzymes of endoplasmic reticulum responsible for drug and carcinogen metabolism. The current report demonstrates that diets containing 10% or 20% refined menhaden fish oil that contains high concentrations of omega-3 fatty acids also supports these enzymes in a manner similar to that of oils that contain high concentrations of the omega-6 fatty acid linoleate. Cytosolic glutathione S-transferase was unaffected by dietary menhaden oil. However, ingestion of increasing concentrations of menhaden oil increased hepatic microsomal cytochrome P-450 content and the apparent Vmax for ethylmorphine N-demethylase, N-nitrosodimethylamine (DMN) N-demethylase, and benzo(a)pyrene [B(a)P] hydroxylase. Feeding menhaden oil increased the Km for ethylmorphine N-demethylase, and decreased Km's for DMN N-demethylase and B(a)P hydroxylase. Phenobarbital induced glutathione S-transferase activity only in rats fed 10% or 20% menhaden oil. Ethylmorphine N-demethylase was induced by only 25% by phenobarbital in rats refed the fat-free diet compared to 128% in rats refed the 20% menhaden oil. In contrast, DMN N-demethylase was induced only in rats fed the fat-free diet. B(a)P hydroxylase was induced in all rats regardless of the level of dietary fat. The specific activity of cytochrome P-450 for the metabolism of DMN and B(a)P, however, was significantly reduced in menhaden oil-fed animals by phenobarbital. This coupled with the increased Km for these reactions may have significant effects on the in vivo activation of these carcinogens in animals fed menhaden oil and subjected to dietary inducers of the mixed function oxidases.
Asunto(s)
Carcinógenos/metabolismo , Grasas de la Dieta/farmacología , Aceites de Pescado/farmacología , Oxigenasas de Función Mixta/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Técnicas In Vitro , Cinética , Masculino , Microsomas Hepáticos/enzimología , Ratas , Ratas EndogámicasAsunto(s)
Biotransformación , Carcinógenos/metabolismo , Animales , Transformación Celular Neoplásica , ADN/metabolismo , Grasas de la Dieta/efectos adversos , Oxigenasas de Función Mixta/metabolismo , Pruebas de Mutagenicidad , Neoplasias Experimentales/etiología , Prostaglandina-Endoperóxido Sintasas/metabolismoRESUMEN
Dietary unsaturated fat is required for maximum induction of the hepatic mixed function oxidases (MFO) responsible for activating carcinogens to forms that may bind covalently to DNA. The aim of this study was to assess the influence of dietary fat type and content on the activities of some enzymes involved in activation and detoxification of the carcinogen benzo[a]pyrene (B[a]P). Modification of these changes by pretreatment with phenobarbital (PB) was also evaluated. Male rats were fed diet devoid of fat or containing 20% corn oil (CO) or 20% menhaden fish oil (MO) for 4 days. PB induced soluble glutathione S-transferase, a detoxifying enzyme, only in rats fed dietary fats. Microsomes from rats fed both types of dietary fat had increased levels of cytochrome P-450 (P-450) and PB induced P-450 only in rats fed these fats. Although ethoxycoumarin O-dealkylase was significantly elevated in the MO group, the induction by PB was not dependent on dietary fat type or level. Dietary fat increased microsome-catalyzed in vitro binding of [3H]-B[a]P to calf thymus DNA, especially in response to PB. Menhaden oil depressed B[a]P hydroxylation and PB treatment depressed this activity to the greatest extent in rats fed this diet. When calculated as B[a]P metabolized per unit of P-450, PB seems to induce a P-450 in fat fed animals having lower affinity and capacity for B[a]P hydroxylation and activation than in rats fed the fat-free diet.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/biosíntesis , Benzopireno Hidroxilasa/biosíntesis , Benzopirenos/metabolismo , Aceite de Maíz/farmacología , ADN/metabolismo , Aceites de Pescado/farmacología , Oxigenasas/biosíntesis , Aceites de Plantas/farmacología , 7-Alcoxicumarina O-Dealquilasa , Animales , Peso Corporal , Sistema Enzimático del Citocromo P-450/metabolismo , Inducción Enzimática/efectos de los fármacos , Glutatión Transferasa/metabolismo , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Fenobarbital/farmacología , Ratas , Ratas EndogámicasRESUMEN
Male rats were starved 0-48 hr, and then refed diets containing 0% (F.F.) to 20% corn oil (C.O.) lab chow or 20% coconut oil (C.C.O.) for 1-4 days. Some received phenobarbital sodium (80 mg/kg, i.p. daily) for 1-3 days prior to decapitation. Five cytochrome P-450-dependent indicators were assayed as measures of altered hepatic microsomal function: ethylmorphine N-demethylase (EMDM), N-nitrosodimethylamine (DMN)-N demethylase, aniline hydroxylase (AH), benzo[a]pyrene hydroxylase (AHH) and CO-difference spectra (P-450). Increasing dietary corn oil (0, 0.5, 10, 20%) in control rats resulted in a progressive increase in the activities of these five enzymes. Dietary fat influenced phenobarbital (Pb) inducibility of all mixed-function oxidase (MFO) enzymes measured except AHH. Pb induced the remaining enzymes only 11-22% in animals fed fat-free diet as compared to 119-246% in animals fed coconut oil and corn oil. Rats fed fat-free diet for 21 days without prior food deprivation and administered Pb had 79% more EMDM, 34% more AH and 120% more P-450 than non-induced controls, whereas rats fed 20% corn oil diet had 227% more EMDM, 143% more AH and 128% more P-450. A requirement of dietary fat for induction of MFO by Pb was demonstrated by these starvation-refeeding experiments. Coupled with data recovered from the 21-day studies, these experiments suggest that a compensatory mechanism may be operative during chronic feeding of the fat-free diet to partially return inducibility to the drug-metabolizing system.
Asunto(s)
Grasas de la Dieta/farmacología , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/biosíntesis , Inanición , Anilina Hidroxilasa/biosíntesis , Animales , Benzopireno Hidroxilasa/biosíntesis , Citocromo P-450 CYP2E1 , Sistema Enzimático del Citocromo P-450/biosíntesis , Inducción Enzimática/efectos de los fármacos , Etilmorfina-N-Demetilasa/biosíntesis , Plomo/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Oxidorreductasas N-Desmetilantes/biosíntesis , Fenobarbital/farmacología , Ratas , Ratas EndogámicasRESUMEN
Bluegill (Lepomis macrochirus R.) were acclimated to 12, 22 or 32 degrees C for 5 or 14 days. Liver weight to body weight ratio and the rate of metabolism of benzo[alpha]pyrene by liver microsomes varied inversely with the acclimation temperature of the fish. Concentration of microsomal cytochrome P-450, as determined by CO-difference binding spectra, was not significantly affected by acclimation temperature. There were no qualitative or quantitative differences in the electrophoretic patterns of proteins with molecular weights similar to those reported for cytochrome P-450. There were no shifts in the temperature optima of the microsomal benzo[alpha]pyrene hydroxylase activity.
Asunto(s)
Aclimatación , Sistema Enzimático del Citocromo P-450/metabolismo , Peces/fisiología , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/metabolismo , Animales , Benzopireno Hidroxilasa/metabolismo , Peso Corporal , Hígado/anatomía & histología , Tamaño de los Órganos , Temperatura , TermodinámicaRESUMEN
The effects of temperature acclimation at 10, 20 and 30 degrees C on the concentration and activity of the mixed function oxidase system in bluegill are as follows. Liver weight/body weight varied inversely with temperature. Significant (P less than 0.05) differences in concentration of cytochrome P-450 of hepatic microsomes were seen and varied inversely with temperature. Benzo(a)pyrene hydroxylase activity tested in vitro at incubation temperatures of 10, 20 and 30 degrees C showed significant differences in Km, but no differences in Vmax. SDS polyacrylamide gel electrophoresis revealed some quantitative differences in cytochrome P-450 isozymes between groups.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Peces/metabolismo , Microsomas Hepáticos/enzimología , Aclimatación , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Benzopireno Hidroxilasa/metabolismo , Peso Corporal , Electroforesis en Gel de Poliacrilamida/métodos , Técnicas In Vitro , Cinética , Hígado/enzimología , Hígado/fisiología , Tamaño de los Órganos , TemperaturaRESUMEN
The subject of chemical carcinogenicity is reviewed with discussions of the involved environmental factors, proposed mechanisms of mutagenesis and carcinogenesis, dose-response considerations, secondary tumor development, and an emphasis on the potential carcinogenicity of antineoplastic agents. Although the causes of various cancers are complex, 70-90% of human cancers are thought to be caused by environmental factors. The factors that have been strongly implicated are excessive cigarette use, heavy alcohol consumption, and disordered dietary practices. Of the minor possible causes of cancer, the administration of prescribed pharmaceutical agents such as the antineoplastic drugs accounts for a suspected 1% of total cancer deaths in the United States. Chemical carcinogenesis involves a multistep process of initiation, promotion, and progression. The development of cancer in man usually takes several years and may be associated with specific tissue susceptibility. Although antineoplastic agents have been recognized for their potential ability to cause cancer, it is difficult to assess from the literature their actual carcinogenic effects in man. Important determinants that modify the ability of the host to deal with carcinogenic substances and the subsequent effects have not been fully evaluated. The control of chemical carcinogenesis must involve reduction of exposure to potential hazards wherever possible. To reduce the risks involved in handling antineoplastic agents, health-care professionals should follow a method of systematic avoidance by adhering to appropriate procedures.
Asunto(s)
Antineoplásicos/toxicidad , Carcinógenos/toxicidad , Animales , Carcinógenos Ambientales/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Mutágenos , Metástasis de la NeoplasiaRESUMEN
Administration of a single dose of the potent interferon inducer poly rI:rC to Swiss Webster mice depressed hepatic cytochrome P-450 to 75% of control, ethylmorphine N-demethylase to 56% of control and DMN N- demethylases I and II to about 80% of control. Although each enzyme responded in a unique manner, maximum depression occurred at 24 hours after poly rI:rC administration and the concurrent administration of inhibitors of protein synthesis (actinomycin D or cycloheximide) prevented this depression. These data suggest that poly rI:rC effects on the mixed function oxidases are not species specific although depression follows a time course shorter than that reported in the rat (maximum depression at 40 hours after poly rI:rC administration) and that depression occurs through the stimulation of a protein responsible for degrading cytochrome P-450.
Asunto(s)
Cicloheximida/farmacología , Dactinomicina/farmacología , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/antagonistas & inhibidores , Poli I-C/farmacología , Animales , Inhibidores Enzimáticos del Citocromo P-450 , Femenino , Ratones , Ratones Endogámicos ICR , Oxidorreductasas N-Desmetilantes/antagonistas & inhibidores , Poli I-C/antagonistas & inhibidoresRESUMEN
Feeding a thiamin-deficient diet to male and female rats for 3 weeks alters the mixed function oxidases responsible for metabolizing benzo(a)pyrene and enhances the response of these enzymes to induction by phenobarbital or 3-methylcholanthrene. The caloric restriction observed in thiamin deprivation may be partially responsible for the enhanced metabolism in this condition but, as established in pair-feeding studies, was not responsible for the enhanced response to enzyme inducers seen in these animals. The degree of altered response was also seen to depend on the sex of the rat and on the substrate concentration of the incubation mixture.
Asunto(s)
Benzo(a)pireno/metabolismo , Deficiencia de Tiamina/metabolismo , Animales , Benzopireno Hidroxilasa/metabolismo , Biotransformación , Carcinógenos/metabolismo , Dieta , Femenino , Cinética , Masculino , Metilcolantreno/farmacología , Microsomas Hepáticos/metabolismo , RatasRESUMEN
Tamoxifen (Nolvadex; TAM) and its major metabolites, N-desmethyl- (DMT) and 4-hydroxy-tamoxifen (HT), were shown to be potent inhibitors of hepatic cytochrome P-450-dependent mixed function oxidations. From in vitro experiments, all three were found to be potent inhibitors of oxidation of Type-I substrates (ethylmorphine and aminopyrine) and less potent, non-competitive inhibitors of Type-II substrates (aniline and dimethylnitrosamine). TAM, DMT and HT were of essentially equal potency and had a much more pronounced effect on Type-I substrates than on Type-II compounds studied. Their action appears to parallel SKF-525A in type and potency of inhibition produced. Spectral binding studies suggest that TAM and its metabolites exert their effects by occupying the Type-I binding site of cytochrome P-450 and thus limiting the accessibility of other substrates to the active site of the enzyme. TAM (and its metabolites) also inhibits its own metabolism, altering the distribution and elimination half-lives of tamoxifen-derived species. In addition, tamoxifen metabolism was found to be sensitive to the presence of other drugs. These results raise concern regarding the role that continued administration of tamoxifen plays in changing its own disposition as well as in the detoxification of drugs administered with it.
Asunto(s)
Microsomas Hepáticos/enzimología , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Aminopirina N-Demetilasa/metabolismo , Anilina Hidroxilasa/metabolismo , Animales , Etilmorfina-N-Demetilasa/metabolismo , Femenino , Cinética , Microsomas Hepáticos/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Partially purified fractions of cytochrome P-450 were prepared from hepatic microsomes recovered from male rats 12 h after administration of either saline or polyriboinosinic:polyribocytidylic acid (poly I:C). Poly I:C reduced the microsomal concentration of cytochrome P-450 by 19% and decreased the maximal binding spectrum (delta Amax) resulting from addition of the type-II substrate 2,4-dichloro-6-phenylphenoxyethylamine to one fraction (B2) while increasing the affinity of that fraction for this substrate. Poly I:C also reduced the microsomal hydroxylation of benzo(a)pyrene and the N-demethylation of benzphetamine by the other fraction (B1). Since 14C-leucine incorporation into cytochrome P-450 was increased in poly I:C-treated rats, it is suggested that poly I:C depresses hepatic mixed-function oxidase activity by increasing the rate of degradation of specific cytochrome P-450s.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Poli I-C/farmacología , Animales , Benzo(a)pireno , Benzopirenos/metabolismo , Benzfetamina/metabolismo , Radioisótopos de Carbono/metabolismo , Electroforesis en Gel de Poliacrilamida , Hidroxilación , Leucina/metabolismo , Masculino , Microsomas Hepáticos/enzimología , Oxigenasas de Función Mixta/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Male ICR Swiss mice, weighing 16-20 g, were fed ad libitum either a fat-free diet or a diet containing 10% corn oil. After three weeks on these diets, the rates of benzo[a]pyrene (B[a]P) metabolite formation and metabolism to products which covalently bind with macromolecules were compared using hepatic nuclei and microsomal preparations. The maximum activity of B[a]P hydroxylase in microsomes from untreated animals was increased 50% by feeding the corn oil diet, however, B[a]P hydroxylase in microsomes from 3-methylcholanthrene (3-MC)-treated mice was unaffected by diet. In animals treated with phenobarbital, B[a]P metabolism and B[a]P-DNA adduct formation were greater in microsomes from corn oil fed mice compared to those fed the fat-free diet. At a B[a]P concentration of 96 microM, microsomes from corn oil fed untreated mice produced 26% more extractable metabolites and covalent binding to exogenous DNA was increased 46%. At lower substrate concentrations (0.94-15.0 microM B[a]P), B[a]P-DNA and B[a]P-protein binding were 300-400% greater when incubated with microsomes from corn oil fed mice than when incubated with microsomes from mice fed fat-free diet. The apparent Vmax's determined for the formation of each extractable metabolite were increased 1.5-3.0 times by the corn oil diet. Hepatic nuclear B[a]P hydroxylase and nuclear activation of B[a]P to products which covalently bind to DNA in both non-induced and 3-MC-pretreated animals fed the corn oil diet were greater than that observed in animals fed the fat-free diet. B[a]P hydroxylase activities in the lungs of these animals were unaltered by diet.