RESUMO
Glucogon immunoreactivity (IRG) was measured in plasma of duodenopancreatectomized subjects with a nonspecific (K-4023) and a specific (30-K) glucagon antiserum. After an overnight fast, plasma IRG (K-4023) was significantly (P < 0.05) higher in the subjects without pancreas, averaging 782+/-79 (SEM) pgeq/ml, than in the controls (482+/-80 pgeq/ml). IRG (30-K) of 162+/-68 pg/ml did not change during an infusion of arginine (450 mg/kg per 40 min). Insulin deprivation during 3 d in one patient did not restore the IRG response to arginine as reported in depancreatized dogs.Bio-Gel P-30 column chromatography revealed that virtually all IRG (30-K) measured in whole plasma was of different molecular weight than glucagon, and primarily of a mol wt >/= 40,000. Intravenous arginine did not significantly alter the chromatographic pattern of these plasmas. Thus, as postulated by others, duodeno-pancreatectomized humans have virtually no circulating 3,500-dalton glucagon. Hence, the presence of 3,500-dalton glucagon in plasma is not a condition for the diabetic state. It might, nevertheless, when present in normal or excessive amounts, worsen the metabolic state of diabetic patients. Among 14 amino acids measured in plasma of these patients, the concentrations of alanine, serine, ornithine, and arginine were significantly (P < 0.05) elevated to approximately twice that of normal: alanine and serine are both substrates for gluconeogenesis, whereas ornithine and arginine are involved in the formation of urea, the second product of hepatic gluconeogenesis. As the concentrations of branched chain amino acids were not grossly altered, it is hypothesized that this amino acid pattern is a consequence of glucagon deficiency rather than secondary to the diabetic state of these patients.
Assuntos
Aminoácidos/sangue , Antígenos/análise , Duodeno/cirurgia , Glucagon/imunologia , Pancreatectomia , Adulto , Idoso , Arginina/farmacologia , Glicemia/análise , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/etiologia , Feminino , Glucagon/sangue , Humanos , Insulina/uso terapêutico , Corpos Cetônicos/sangue , Lactatos/sangue , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangueRESUMO
BACKGROUND: Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. Using a novel bioinformatics approach, our group recently described a novel gene fusion in PCa. This fusion involves the androgen-regulated gene TMPRSS2 and so far three members of the ETS family of transcription factors already described as rearranged in the Ewing's family of tumors. By analogy, fusion status in prostate cancer may determine clinical outcome and secondary genetic alterations as witnessed in Ewing's tumors. MATERIAL: These novel gene fusions occur in the majority of prostate cancers identified by PSA screening and are the driving mechanism for overexpression of the three members of the ETS transcription factor family, either ERG (21q22.3), ETV1 (7p21.2), or ETV4 (17q21). Considering the high incidence of prostate cancer and the high frequency of this gene fusion, the TMPRSS2-ETS gene fusion is the most common genetic aberration so far described in human malignancies. RESULTS: So far, this is the only gene rearrangement in any of the most prevalent cancers. As confirmed by other groups, we demonstrated that, within the group of ETS transcription factors, ERG is the most common fusion partner of the ETS genes with TMPRSS2. This gene fusion is considered to be an early event in PCa development. Emerging data suggest that gene fusion PCa demonstrates a distinct clinical course and thus support its use as a diagnostic test and prognostic biomarker. Also similar to the Philadelphia chromosome in chronic myelogenous leukemia (CML), the gene fusion in prostate cancer has potential as an important candidate for the development of targeted therapy.
Assuntos
Biomarcadores Tumorais/genética , Proteínas de Neoplasias/genética , Fusão Oncogênica/genética , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-ets/genética , Serina Endopeptidases/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , PrevalênciaRESUMO
Enzyme induction may be modeled on the basis of four, quantifiable processes that control the rates at which specific gene products accumulate and decay. These processes include synthesis of functional mRNA, translation and degradation of mRNA, and degradation of the protein product. We present a simple computer program that permits mathematical simulation of gene expression on the basis of experimentally determined rates of synthesis and degradation. The program was implemented as a spreadsheet using Microsoft Excel for Macintosh and MS-DOS operating systems and also was adapted for HyperCard on the Macintosh. It contains a formula to account for growth of tissue or cell populations. The program predicts amounts of individual mRNAs and proteins (or enzyme activities) in cells as a function of time after a stimulus alters their rates of synthesis or degradation.
Assuntos
Simulação por Computador , Expressão Gênica , Modelos Genéticos , Animais , Divisão Celular , Indução Enzimática , Cinética , Fígado/enzimologia , Fígado/metabolismo , Substâncias Macromoleculares , Biossíntese de Proteínas , Proteínas/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/metabolismo , RatosRESUMO
A single oral or intraperitoneal application of 2-(3-phenylpropoxyimido)-butyrate (BM 13.677) resulted in a dose-dependent blood-glucose-lowering effect in fasted guinea-pigs. The threshold dose and the EC50 were estimated as 25 mg/kg and 63 mg/kg, respectively, which is between that of the biguanides phenformin and metformin. A rise in blood lactate concentrations was observed only at high doses of BM 13.677, but was not related to an irreversible metabolic inhibition. Among several rodent species studied the potency of the drug decreased in the order guinea-pig much greater than mouse greater than rat = rabbit. Inhibition of hepatic gluconeogenesis by the drug was demonstrated in the perfused liver or hepatocytes of guinea-pigs. Inhibition of glucose production by the perfused liver in the presence of 0.1 mM BM 13.677 was dependent on the substrate and decreased in the order: lactate greater than pyruvate greater than alanine much greater than propionate greater than glycerol = fructose. This suggests a specific interaction of the drug with a mitochondrial key reaction of gluconeogenesis. Stimulation of glucose oxidation in rat diaphragm by the compound (EC50 = 0.85 mM) suggests that besides inhibition of gluconeogenesis also extrahepatic effects contribute to the blood-glucose-lowering effects of the drug.
Assuntos
Gluconeogênese/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Iminoácidos/farmacologia , Fígado/efeitos dos fármacos , Animais , Células Cultivadas , Jejum , Cobaias , Iminoácidos/administração & dosagem , Masculino , Metformina/farmacologia , Camundongos , Fenformin/farmacologia , Coelhos , RatosRESUMO
The effect of the piperazine derivative BM 15.766 (4-(2-[1-(4-chlorocinnamyl)piperazin-4-yl]ethyl]-benzoic acid) on the biosynthesis of sterols was investigated in adult rat hepatocytes in primary monolayer culture. The substance led to a dose-dependent reduction of cholesterol in the serum of various species of animals such as rat, dog and marmoset. BM 15.766 showed a dose-dependent action on the incorporation of 14C-acetate in neutral, nonsaponifiable lipids. The inhibition of the overall incorporation was 10-12% (10(-5) M). No inhibition was observed in the hepatocytes over the entire dose range of 10(-8) M to 2 X 10(-5) M, while the release of the neutral lipids from the hepatocytes into the culture medium was reduced by up to 40%. The biosynthesis of cholesterol could be reduced by more than 90%. Simultaneously, 7-dehydrocholesterol levels rose in the cells and, to a less marked extent, in the medium. This can be interpreted as an indication that 7-dehydrocholesterol is incorporated into the cell membrane, which results in a lower release of 7-dehydrocholesterol into the medium in comparison with controls. The site of attack is the inhibition of the delta 5.7-sterol delta 7-reductase. The formation of desmosterol and cholestatrienol as well as other 7-dehydrocholesterol precursors could also be demonstrated. After longer incubation, there was an additional accumulation of squalene and lanosterol with simultaneous reduction of 7-dehydrocholesterol by BM 15.766, whereas the total 14C-acetate incorporation in neutral lipids was increased.
Assuntos
Colestadienóis/metabolismo , Colesterol/biossíntese , Desidrocolesteróis/metabolismo , Fígado/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Oxirredutases/antagonistas & inibidores , Piperazinas/farmacologia , Acetatos/metabolismo , Ácido Acético , Animais , Radioisótopos de Carbono , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Cinética , Fígado/efeitos dos fármacos , Masculino , RatosRESUMO
A new compound, 2-(3- methylcinnamylhydrazono )-propionate (BM 42.304), showed a dose dependent hypoglycemic effect in starved guinea pigs after both oral and intraperitoneal administration. In contrast to biguanides (phenformin and metformin) the new compound produced only a moderate increase in blood lactate concentration and did not alter the content of adenine nucleotides in the freeze-clamped liver in vivo. Gluconeogenesis from a variety of precursors in the perfused guinea-pig liver was also inhibited by BM 42.304. These properties suggest that the compound deserves further investigation in connection with its potential usefulness for the treatment of diabetes.
Assuntos
Cinamatos/farmacologia , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Animais , Glicemia/análise , Ácidos Graxos/metabolismo , Feminino , Gluconeogênese/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Lactatos/sangue , Ácido Láctico , Fígado/metabolismo , MasculinoRESUMO
Treatment of rats by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) resulted in a dose- and time-dependent increase in liver peroxisomal enoyl-CoA hydratase and cyanide-insensitive palmitoyl-CoA oxidation with a concomitant increase in the volume density of peroxisomes as determined by morphometry. The induced peroxisomal proliferation was sustained as long as treatment was maintained and was accompanied by an increase in liver weight. Incubation of cultured rat hepatocytes in the presence of MEDICA 16 added to the culture medium resulted in a dose-dependent increase in peroxisomal beta-oxidation activities with a concomitant elevation of the volume density of peroxisomes. The induction of peroxisomal proliferation by MEDICA 16 in culture could be prevented in the presence of carnitine palmitoyltransferase inhibitors added to the culture medium, e.g. 2-bromopalmitate, 2-tetradecylglycidic acid or 2-[5-(4-chlorophenyl)-pentyl]oxirane-2-carboxylate. The induction of liver peroxisomes by MEDICA 16 conforms to the previously defined requirement for an amphipathic carboxylate in initiating peroxisomal proliferation. The prevention of peroxisomal proliferation by carnitine acyltransferase inhibitors may implicate the involvement of this acyltransferase in the induction of peroxisomal proliferation by xenobiotic or native amphipathic carboxylates.
Assuntos
Hipolipemiantes/farmacologia , Fígado/efeitos dos fármacos , Microcorpos/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Animais , Carnitina O-Acetiltransferase/biossíntese , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Indução Enzimática/efeitos dos fármacos , Feminino , Masculino , RatosRESUMO
A new hypoglycemic agent, 2-(3-methylcinnamylhydrazono)-propionate MCHP (BM 42.304) was shown to be an inhibitor of the transfer of long-chain fatty acids across the mitochondrial inner membrane. The following data support this conclusion: the drug, at already 5 microM, inhibited ketogenesis from oleate but not from octanoate in the perfused guinea-pig liver; likewise, ketogenesis from L-(-)-palmitoylcarnitine and palmitoyl-CoA + L-(-)-carnitine, but not from octanoate, was depressed in isolated guinea-pig liver mitochondria. Oxigraphic measurements of the oxygen uptake by isolated mitochondria showed that the drug impaired oxygen uptake with the long-chain fatty acid derivatives but not with octanoate. Finally, in vivo effects of the drug such as hypoketonemia and an increased concentration of free fatty acids in blood are in agreement with the above formulated mechanism of action. A comment is given on the relationships between fatty acid oxidation and gluconeogenesis in the guinea-pig liver.
Assuntos
Cinamatos/farmacologia , Fígado/metabolismo , Animais , Caprilatos/metabolismo , Feminino , Gluconeogênese/efeitos dos fármacos , Cobaias , Hipoglicemiantes/farmacologia , Corpos Cetônicos/biossíntese , Fígado/efeitos dos fármacos , Masculino , Mitocôndrias Hepáticas/metabolismo , Ácido Oleico , Ácidos Oleicos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Fosfoenolpiruvato/biossínteseRESUMO
Comparative data on the incidence of ectopic pregnancy among accidental pregnancies associated with failure of a contraceptive or sterilization procedure are shown in Table 16. The practical clinical significance of the data in this review is predicated upon a number of related factors. One of the most important of these is the realistic failure rate (or success rate) of each contraceptive or sterilization method. The reported efficacy of various contraceptive methods has such a wide range that we have not attempted to calculate the likelihood that a woman may experience an ectopic pregnancy within a particular time period while using a specific method. The success or failure rate of each method is influenced by such variables as (1) the conscientiousness and ability of the patient to follow instructions, (2) the true failure rate of the method itself, (3) the experience of the clinician prescribing a method or performing a surgical procedure, and (4) other factors less clearly defined. Because of these many variables, the data shown in Table 16 were calculated on the basis of the number of reported accidental pregnancies which occurred coincidentally with, or subsequent to, a specific contraceptive or sterilization modality. (formula: see text). These data do not reflect the actual rate of occurrence of ectopic pregnancy with respect to woman-months of experience. We recognize the significant influence that age, race, gravidity, and socioeconomic factors have upon the incidence of ectopic pregnancy, but were unable to control for these factors in the data presented in this review. These data reprresent only what has occurred under specific circumstances and cannot logically be extrapolated to any specific future case or study series. It is important to emphasize the necessity of constant awareness by the medical and paraprofessional personnel of the potentially increased risk to the patient of an extrauterine pregnancy should one or another of these contraceptive or sterilization procedures fail. Complacency or a false sense of security on the part of responsible medical personnel concerning women who are "protected against conception" can quickly lead to a life-threatening situation in case of an ectopic pregnancy. Prompt diagnosis and definitive treatment of the extrauterine pregnancy is vital for the successful management of this serious complication of conception.
Assuntos
Anticoncepcionais Femininos , Dispositivos Anticoncepcionais , Gravidez Ectópica/epidemiologia , Anticoncepcionais Femininos/efeitos adversos , Dispositivos Anticoncepcionais/efeitos adversos , Feminino , Humanos , Injeções , Dispositivos Intrauterinos/efeitos adversos , Medroxiprogesterona/administração & dosagem , Gravidez , Gravidez Ectópica/etiologia , Congêneres da Progesterona/efeitos adversos , Esterilização Reprodutiva , Reino Unido , Estados UnidosRESUMO
BM 13.177 (4-[2-(benzenesulfonamido)-ethyl]-phenoxyacetic acid) is a representative of a new class of sulfonamidophenylcarboxylic acids which possess platelet-inhibitory and anti-thrombotic activity and inhibits the contraction of rabbit aorta stimulated by PG endoperoxides and TXA2. BM 13.177 5 mg/kg body weight p.o. protected rabbits from arachidonate-induced sudden death and greater than or equal to 10 mg/kg dose-dependently reduced the experimental thrombus formation induced in the rabbit aorta by perivascular administration of silver nitrate. In guinea-pigs, the collagen-induced bronchoconstriction was inhibited in a dose- and time-dependent fashion. The formation of TXA2 and the TXA2-induced platelet aggregation and smooth muscle contraction are probably crucial events in these experimental models. The protective effect of BM 13.177 may, therefore, be due to the TXA2-antagonizing effect of BM 13.177, which has been conclusively demonstrated in human platelets (PATSCHEKE and STEGMEIER, Thrombosis Res., 33, 277-288 (1984). The antagonism of TXA2 is supported by the observation that BM 13.177 also specifically inhibits the contraction of isolated arterial strips from rabbits which were stimulated with the thromboxane A2 mimetic U 46619. Schild-plot with a slope close to unity suggests a competitive type of antagonism. BM 13.177 exhibited neither anti-inflammatory nor ulcer-inducing activity of cyclooxygenase inhibitors. Furthermore it did not block the TXB2 formation in spontaneously clotting blood from rabbits and did not inhibit the release of prostacyclin-like activity from rabbit aortas. The lack of toxicological effects in long-term toxicity studies in rat and dog, together with the absence of objective and subjective side effects in the first human studies have encouraged us to initiate clinical trials in order to evaluate the therapeutic benefit of this new approach in humans.
Assuntos
Fibrinolíticos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Sulfonamidas/farmacologia , Tromboxano A2/antagonistas & inibidores , Tromboxanos/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Epoprostenol/sangue , Feminino , Cobaias , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Coelhos , Trombose/sangue , Trombose/tratamento farmacológico , Tromboxano B2/metabolismoRESUMO
The effects of mevinolin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor and bezafibrate, a modulator of lipoprotein metabolism, were measured on BM 15.766-induced 7-dehydrocholesterol (7-DHC) accumulation in liver and serum of rats. BM 15.766, an inhibitor of delta 7 sterol reductase, leads to an accumulation of 7-DHC, which can be used as a measure of cholesterol (CH) synthesis de novo. The investigations were carried out to evaluate the usefulness of this new non-isotopic in vivo method for testing compounds that affect directly and indirectly the CH-biosynthetic pathway. Mevinolin showed a dose-dependent reduction of BM 15.766-induced 7-DHC accumulation after a single oral dose. The dose range for reduction of 7-DHC in the liver of rats was comparable with that for serum CH-lowering in humans. Bezafibrate reduced the BM 15.766-induced 7-DHC accumulation in liver in a dose- and time-dependent manner. These findings agree with the reported reduced activity of HMG-CoA reductase and support the view, that bezafibrate reduces CH biosynthesis by modulation of lipoprotein metabolism. The 7-DHC levels in serum do not reflect those in the liver and cannot be used as a measure of CH biosynthesis. The investigations show that BM 15.766-induced 7-DHC accumulation in liver of rats is an appropriate measure for CH de novo synthesis and can be used for testing compounds that interfere directly and indirectly with the CH-biosynthetic pathway. In contrast to previously described methods, no radiolabelled precursors are necessary.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticolesterolemiantes/farmacologia , Bezafibrato/farmacologia , Colestadienóis/metabolismo , Colesterol/biossíntese , Desidrocolesteróis/metabolismo , Lovastatina/farmacologia , Piperazinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos EndogâmicosRESUMO
Using two different assay systems to distinguish between overt and inner forms of carnitine palmitoyl transferase (CPT, EC 2.3.1.21) of intact guinea-pig liver mitochondria, we have shown that the hypoglycemic agent 2-(3-methylcinnamylhydrazono)-propionate (BM 42.304) inhibits the activity of carnitine-acylcarnitine translocase of liver mitochondria. The results offer an explanation for the inhibitory effect of the compound on ketogenesis with oleate but not with octanoate in the perfused guinea-pig liver, previously reported by us (Biochem. Pharmacol. 32, 3405-3412, 1983).
Assuntos
Aciltransferases/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Cinamatos/farmacologia , Hipoglicemiantes/farmacologia , Mitocôndrias Hepáticas/metabolismo , Transferases/antagonistas & inibidores , Animais , Transporte Biológico/efeitos dos fármacos , Carnitina/metabolismo , Carnitina Aciltransferases , Compostos de Epóxi/farmacologia , Ácidos Graxos/farmacologia , Cobaias , Membranas Intracelulares/efeitos dos fármacos , Membranas Intracelulares/metabolismo , Cinética , Masculino , Malonil Coenzima A/farmacologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Palmitoilcarnitina/metabolismoRESUMO
The central cornea obtains its glucose by diffusion through the cornea from the aqueous humor to the epithelium. The diffusion of glucose in the cornea is analogous to the flow of current in an electrical resistance network. The cellular consumption of glucose can be compared to shunting a portion of the charge to electrical ground. An electrical analog model of the cornea was developed to predict the availability of glucose to the epithelium and the distribution of glucose in the stroma. The glucose constant concentration lines in the normal stroma are parallel to the corneal surface and have decreasing values from 880 to 580 micrograms/ml. The effects on epithelial glucose concentration by implanting an intracorneal lens (ICL) of varying diameter, depth, permeability and thickness can be modeled. Glucose permeability through the intracorneal lens has the most significant effect on glucose availability. The ICL profile i.e. power, can also be an important fact in determining glucose availability. A minus power design requires a thin central lens zone with a thick peripheral zone. The design results in relatively more glucose flux through the optical zone of the lens and thus improves central epithelial glucose availability.
Assuntos
Córnea/metabolismo , Glucose/metabolismo , Substância Própria/metabolismo , Epitélio/metabolismo , Humanos , Matemática , Modelos Biológicos , Permeabilidade , Próteses e ImplantesRESUMO
The rate of glucose consumption in cultured epithelium, endothelium, and keratocytes was measured; and the effect of reduced glucose availability on the consumption rate of these three cell lines was delineated. All three cell types exhibited an asymptotic decrease of glucose over time while being incubated in Krebs-Ringers solutions of varying glucose concentrations. At a concentration resembling that of the aqueous, epithelium (EPI), endothelium (ENDO), and keratocytes (K) consumed 6.7, 7.4, and 9.0 micrograms/cm2/hr respectively. Each cell type consumed glucose at a rate that was related to the amount of available glucose. As glucose concentration was reduced from 90 to 30 mg%, which was a 66% reduction in available glucose, the consumption of EPI, ENDO, and K dropped 74%, 61%, and 44% respectively.
Assuntos
Córnea/metabolismo , Substância Própria/metabolismo , Endotélio Corneano/metabolismo , Glucose/farmacocinética , Animais , Células Cultivadas , Epitélio/metabolismo , Coelhos , Fatores de TempoRESUMO
Soft contact lenses have been used as therapeutic bandages to aid epithelial healing following pentrating keratoplasty. Often the hydrogel lenses are used in conjunction with topical medications such as gentamicin. A reported complication is the persistence of infectious ulcers even though the eye is being treated with topical antibiotics. The purpose of this study was to measure the gentamicin diffusion coefficients for some hydrogel bandage lenses and to design a kinetic model to estimate the drug distribution on an eye covered with a hydrogel contact lens. The model includes the hydrogel diffusion coefficients and literature values for tear production, tear exchange per blink around the edge of a lens, fit, etc. From the computer generated data, it can be shown that the permeability of gentamicin sulfate through the Saulfon-80 hydrogel lens on a normal eye was only 0.002% of the amount of the drug under the contact lens after 10 minute intervals of topical drug application. The important drug distribution pathway was around the edge of the lens.
Assuntos
Lentes de Contato Hidrofílicas , Córnea/metabolismo , Gentamicinas/metabolismo , Modelos Biológicos , Disponibilidade Biológica , Transporte Biológico , Córnea/cirurgia , Difusão , Gentamicinas/administração & dosagem , Humanos , Cinética , Matemática , Soluções Oftálmicas , Cuidados Pós-Operatórios , Propriedades de Superfície , Lágrimas/fisiologia , Cicatrização/efeitos dos fármacosRESUMO
7-Dehydrocholesterol (7DHC), an intermediate of cholesterol, accumulates in animals after administration of BM 15.766 and can be measured in addition to cholesterol photometrically. The effect of compounds acting at different points in the cholesterol biosynthetic pathway on BM 15.766-induced 7DHC accumulation was investigated in rats to evaluate its usefulness as in vivo test system for cholesterol lowering agents. 7DHC in liver of rats proved to be an appropriate measure for cholesterol de novo synthesis. In contrast to previously described methods no radiolabelled precursors are necessary. The extraction of 7DHC and its photometric determination is, in comparison with separation and measurement of radioactive cholesterol, a simple analytical procedure.
Assuntos
Anticolesterolemiantes/farmacologia , Colestadienóis/metabolismo , Colesterol/biossíntese , Desidrocolesteróis/metabolismo , Piperazinas/farmacologia , Animais , Inibidores de Hidroximetilglutaril-CoA Redutases , Fígado/efeitos dos fármacos , Fígado/metabolismo , Lovastatina/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
Rats, due to their availability and ease of handling, are a frequently used animal model for studying the effects of drugs on lipid metabolism. Hypolipidemic effects showed great variations in different studies. We investigated the effect of bezafibrate on serum concentrations of cholesterol and triglycerides in different strains of rats from several breeders. Under these conditions Lewis rats seemed to be the most suitable strain to investigate drug effects on cholesterol in serum. A hypercholesterolemic male Lewis rat found in a screening program was mated with normolipidemic female Lewis rats. The hyperlipidemia was found in some of the male and female offspring. Cholesterol and triglycerides were dramatically elevated in older animals. Bezafibrate (75 mg/kg/d) produced a marked reduction of lipids in serum in normo- and hyperlipidemic male rats but only in hyperlipidemic female rats, which is in agreement with former findings. These spontaneously hyperlipidemic rats could be a useful tool for investigation of drug effects on disturbed lipid metabolism and its pathophysiology. Therefore, we tried to establish a hyperlipidemic strain of rats.