RESUMO
The mixed-function oxidase which activates the carcinogen dimethylnitrosamine (DMN) was determined in the rat liver as a function of animal age. DMN-demethylase activity increased considerably at first to reach a maximum on day 29, and then substantially decreased to day 59; thereafter, enzyme activity remained essentially stable up to at least day 110. Pretreatment with 3-methylcholanthrene, which caused a pronounced decrease in this enzyme activity, did not affect the general shape of the age-dependence curve. The results suggest that rats between weaning and sexual maturity are more susceptible to the carcinogenic effects of pulse doses of DMN than are neonates or adult animals.
Assuntos
Envelhecimento , Dimetilnitrosamina/metabolismo , Fígado/enzimologia , Nitrosaminas/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Animais , Masculino , Metilcolantreno/farmacologia , Microssomos Hepáticos/enzimologia , RatosRESUMO
A comparative study of the effects of the polychlorinated biphenyl mixture Aroclor 1254, 3-methylcholanthrene, and starvation on hepatic dimethylnitrosamine (DMN) demethylase (a repressible enzyme) and azo dye N-demethylase (an inducible enzyme) has been carried out. As previously observed with polycyclic hydrocarbons and phenobarbital, Aroclor in rats is a potent inducer of liver tissue proliferation and of azo dye N-demethylase. However, in mice, although the inducing effect on liver tissue proliferation and azo dye N-demethylase activity is maintained, there is no change in DMN demethylase activity as a result of Aroclor administration. As in rats, 3-methylcholanthrene induces the azo dye N-demethylase in mice. This hydrocarbon, which is known to substantially repress the DMN demethylase in rats, has, however, no effect on this enzyme in mice. While starvation is known to have a substantial inducing effect on DMN demethylase in rats, in mice starvation brings about a moderate induction of DMN demethylase.
Assuntos
Arocloros/farmacologia , Microssomos Hepáticos/enzimologia , Oxirredutases N-Desmetilantes/metabolismo , Bifenilos Policlorados/farmacologia , Animais , Compostos Azo , Dimetilnitrosamina , Indução Enzimática , Repressão Enzimática , Masculino , Metilcolantreno/farmacologia , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Tamanho do Órgão , InaniçãoRESUMO
Glutamate is considered as the best candidate for the neurotransmission between the inner hair cell and the primary efferent neurons in the mammalian cochlea. In order to test its presence in the synapse, a degradative enzyme for glutamate, glutamate dehydrogenase (GDH) was perfused in the cochlea of guinea pigs. The intensity function of the VIIIth nerve compound action potential was recorded as a physiological test. The results show that the GDH induces a decrease in the auditory nerve responsiveness. The threshold elevation observed is dependent upon the enzyme concentration.
Assuntos
Cóclea/inervação , Glutamato Desidrogenase/farmacologia , Nervo Vestibulococlear/fisiologia , Potenciais de Ação/efeitos dos fármacos , Animais , Cóclea/fisiologia , Feminino , Cobaias , Masculino , Nervo Vestibulococlear/efeitos dos fármacosRESUMO
Adenosine has been implicated in neuromodulation in the central nervous system [(1985) Annu. Rev. Neurosci. 8, 103-124]. Its mechanism of action is thought to be a receptor-mediated inhibition of a transmitter release. To assess adenosine's role as a neuromodulator in the vestibular periphery, spontaneous activity of the afferent fibers in the ampullar nerve of the semicircular canal, in vitro, was used as the dependent variable. Afferent firing has been previously shown to depend on transmitter release by the hair cells [(1985) Brain Res. 330, 1-9]. Adenosine was shown to inhibit firing rate; the adenosine antagonist theophylline was shown to increase firing rate; the enzyme adenosine deaminase, which catabolizes adenosine to inosine, was shown to increase firing rate; the adenosine uptake inhibitor dipyridamole was shown to decrease firing rate; and adenosine was shown to be released from the isolated semicircular canal by electrical stimulation. All these findings are internally consistent and unreservedly support the hypothesis that adenosine has a neuromodulatory role in neurotransmission in the semicircular canal.
Assuntos
Adenosina/fisiologia , Percepção Auditiva/fisiologia , Células Ciliadas Auditivas/fisiologia , Transmissão Sináptica , Animais , Vias Auditivas/fisiologia , Inibição Neural , Rana pipiens , Canais Semicirculares/inervação , Sinapses/fisiologia , Nervo Vestibular/fisiologiaRESUMO
Aminooxyacetic acid (AOAA) has been shown to confer protection against noise-induced cochlear trauma [3]. We, therefore, decided to study the possible protective effect of AOAA against kanamycin (KM) ototoxicity and found, instead, that AOAA potentiated the toxicity. To produce ototoxicity in guinea pigs, KM is usually given in 10-14 daily doses of 400 mg/kg s.c. However, when combined with a single dose of AOAA (8, 11, 15, or 25 mg/kg) a single 400 mg/kg dose of KM is sufficient to cause cochlear damage. Such animals show a negative Preyer's reflex between 1 to 3 days post injection. 21 days later hearing thresholds as detected electrocochleographically at 2, 4, 8, 12 and 16 kHz have changed drastically sometimes to the point of being undetectable. The damage seen histologically at this time is destruction of both inner and outer hair cells. A pharmacokinetic analysis of this potentiation revealed a slight prolongation of KM's sojourn in the inner ear. The possible mechanisms of this unexpected, marked potentiation are discussed but remain unknown.
Assuntos
Acetatos/farmacologia , Ácido Amino-Oxiacético/farmacologia , Cóclea/efeitos dos fármacos , Canamicina/farmacologia , Animais , Potenciais Microfônicos da Cóclea/efeitos dos fármacos , Sinergismo Farmacológico , Cobaias , Células Ciliadas Auditivas/efeitos dos fármacos , Perda Auditiva/induzido quimicamente , Canamicina/metabolismo , Fatores de TempoAssuntos
Mitocôndrias/análise , Proteínas/análise , Trifosfato de Adenosina/farmacologia , Animais , Cálcio/farmacologia , Precipitação Química , Ácido Edético/farmacologia , Magnésio/farmacologia , Microscopia Eletrônica , Mitocôndrias Hepáticas/análise , Mitocôndrias Musculares/análise , Proteínas Musculares/análise , Cloreto de Potássio , Coelhos , UltracentrifugaçãoAssuntos
Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/metabolismo , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Oxirredutases/metabolismo , Animais , Dimetilnitrosamina , Indução Enzimática/efeitos dos fármacos , Repressão Enzimática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , RatosAssuntos
Dimetilnitrosamina/metabolismo , Fígado/enzimologia , Pulmão/enzimologia , Metilcolantreno/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/análise , Biotransformação , Citocromo P-450 CYP2E1 , Sinergismo Farmacológico , Inativação Metabólica , Masculino , Camundongos , Camundongos Endogâmicos , Oxirredutases N-Desmetilantes/análise , Compostos Policíclicos/metabolismo , Ratos , Ratos EndogâmicosRESUMO
The items in the Denver Developmental Screening Test (DDST) have been restandardised on a random sample of 1547 Cardiff children aged up to six years. Some differences were found between the ages at which the Cardiff and Denver children achieved certain test items. Cardiff children were consistently slightly slower on gross motor items throughout the age-range, with the exception of three items, but were slightly more advanced on early language items below the age of 18 months and on some personal and social items. The implications of the findings for the use of the DDST in Britain are discussed.
Assuntos
Desenvolvimento Infantil , Testes Psicológicos , Logro , Fatores Etários , Ordem de Nascimento , Criança , Pré-Escolar , Colorado , Inglaterra , Feminino , Humanos , Lactente , Desenvolvimento da Linguagem , Masculino , Destreza Motora , Fatores Sexuais , Classe SocialRESUMO
The educational needs of general practitioners and other doctors wishing to provide child health surveillance are unknown. This study determines the needs of doctors prior to attending a course in child health surveillance by testing their knowledge of childhood immunization, and by self assessment of their skills and knowledge in different aspects of surveillance. A child health surveillance course must cover a core content to enable participants to reach a required standard. Assessment of educational needs allows greater emphasis and time to be given to certain aspects, thus making the course of greater educational value and more relevant to the participant.
Assuntos
Educação Médica Continuada/normas , Medicina de Família e Comunidade/educação , Pediatria/educação , Medicina Preventiva/educação , Humanos , Imunização/normas , Inquéritos e Questionários , País de GalesRESUMO
The previously observed alterations in the energy transducing system of rat liver mitochondria during 3'-methyl-4-(dimethylamino)azobenzene (3'-Me-DAB) carcinogenesis were investigated using aliphatic dicarbonyl compounds as molecular probes and the effect of temperature on the membrane-linked NADH-indophenol reductase. The vicinal diketone, diacetyl, uncouples oxidative phosphorylation in normal rat liver mitochondria while the higher diketones, acetylacetone and acetonylacetone, are increasingly less effective in that order; diacetyl totally abolishes respiratory control with substrates the oxidation of which involves the NADH leads to CoQ segment, but only partially with succinate which bypasses this segment. Diacetyl, likewise, uncouples oxidative phosphorylation in liver mitochondria from rats fed 3'-Me-DAB, but the mitochondria are most resistant to this uncoupling (in terms of the P/O ratio) at the time period when the respiratory control index (determined in the absence of diacetyl) is at the dye-induced minmum. This time period is at 3 to 4 weeks of dye administration, representing the cumulative dose for tumorigenesis threshold. At this threshold period of feeding 3'-Me-DAB, discontinuities in the Arrhenius plot of the mitochondrial membrane-localized NADH-indophenol reductase appear, with a return toward the control state (no break) at 8 weeks, only to reappear in the plot of the enzyme from tumor mitochondria, suggesting sequential membrane phase transitions in the mitochondria during azo dye carcinogenesis.
Assuntos
Cetonas/farmacologia , Metildimetilaminoazobenzeno/farmacologia , Mitocôndrias Hepáticas/efeitos dos fármacos , NADH NADPH Oxirredutases/metabolismo , Fosforilação Oxidativa/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , p-Dimetilaminoazobenzeno/análogos & derivados , 2,6-Dicloroindofenol , Animais , Ditioeritritol/farmacologia , Glutamatos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Cinética , Masculino , Membranas/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Piruvatos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Succinatos/metabolismo , TermodinâmicaRESUMO
During diethylnitrosamine (DEN) administration, a distinctive difference was observed between rats and guinea-pigs in the sequence of ultrastructural changes in the hepatic endoplasmic reticulum (ER). In DEN-induced hepatic tumour cells in the guinea-pig there was extensive proliferation of the rough ER, while the smooth ER was quite sparse; in the premalignant liver the opposite was noted. This is in contrast to the rat, in which administration of either DEN or 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) brings about, in both premalignant and malignant hepatic tissue, proliferation of the smooth ER and sparsity of the rough ER. Yet, as in the rat, the number of ribosomes on the outer surface of the guinea-pig liver rough ER is greatly reduced and this is paralleled by a 49% decrease of the RNA/protein ratio as early as 4 weeks of nitrosamine administration. The decrease of RNA/protein ratio and ultrastructurally observed loss of ribosomes from the ER, following nitrosamine administration, correlate with a decrease of photometric response of microsomal suspensions to the sulphydryl probe, p-chloromercuribenzoate. While azo-dye-reductase activity is higher in untreated rats than in untreated guinea-pigs, feeding 3'-Me-DAB for 6 weeks brings about a 76% decrease in the rat, but no significant decrease in the guinea-pig, which is refractory to azo-dye carcinogenesis. Thus, the ability of the liver to inactivate the dye is greatly decreased in the rat, but not in the guinea-pig, as administration progresses toward the threshold dose for tumorigenesis. On the other hand, constitutive levels of nitrosamine dealkylase are identical in the 2 species and remain essentially unchanged following administration of DEN for 10 weeks. Inasmuch as nitrosamine dealkylation represents activating metabolism, this provides a rationale for the comparable susceptibility of the rat and guinea-pig to DEN carcinogenesis. Of the 2 enzymes in the 2 species, it is only azo-dye reductase in the guinea-pig which appears to be unregulated by glucose repression, since starvation brings about no change in this activity. Starvation-induced increase of azo-dye reductase in the rat is not influenced by administration of 3'-Me-DAB and only slightly by DEN. The starvation-induced increase of nitrosamine dealkylation is abolished, however, in both species by administration of DEN but only slightly decreased by 3'-Me-DAB.
Assuntos
Dietilnitrosamina/toxicidade , Resistência a Medicamentos , Neoplasias Hepáticas/induzido quimicamente , Nitrosaminas/toxicidade , p-Dimetilaminoazobenzeno/toxicidade , Animais , Retículo Endoplasmático/ultraestrutura , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/ultraestrutura , Masculino , Camundongos , Microscopia Eletrônica , NADH NADPH Oxirredutases/metabolismo , Neoplasias Experimentais/induzido quimicamente , RatosRESUMO
The dealkylation of dimethyl-, diethyl- and dipropylnitrosamine by hepatic microsomes of Sprague-Dawley rats is repressed by pretreatment of the animals with 3-methylcholanthrene (MC), and this repression progressively decreases with the increase of alkyl chain length. In contrast to its effect on the demethylation of dimethylnitrosamine (DMN), in vivo phenobarbital induces rather than represses the deethylation of diethylnitrosamine. The rates of demethylation of the DMN analog substrates (dimethylformamide, dimethylacetamide, dimethylpropionamide, and dimethylbutyramide), although low as compared to DMN, increase with the acyl chain length. These analogs are potent in vitro inhibitors of Dmn demethylation when used in combination with DMN as substrates, and the inhibition decreases with the length of the acyl chain. Dimethylaminoacetone, which corresponds to the insertion of a CH2 group between the N atom and the carbonyl group in dimethylacetamide, is not an in vitro inhibitor of DMN demethylation; the demethylation rates are additive when theis compound is used as substrate in combination with DMN. The rate of demethylation of dimethylaminoacetone is substantially higher than the rates of the dimethylacylamides, and is significantly repressed by MC-pretreatment. The rate of demethylation of methylphenylnitrosamine is not influenced by MC-pretreatment; the compound is, however, a potent inhibitor of demethylation when used as substrate in combination with DMN. The demethylation rates of 1,1-dimethylhydrazine (the reduction product of DMN) and dimethylaniline are not influenced by MC-pretreatment; neither do they affect the overall rate of demethylation when used as substrate in combination with DMN.
Assuntos
Metilcolantreno/farmacologia , Nitrosaminas/metabolismo , Oxirredutases/metabolismo , Animais , Sítios de Ligação , Remoção de Radical Alquila , Dietilnitrosamina/metabolismo , Dimetilnitrosamina/análogos & derivados , Dimetilnitrosamina/metabolismo , Dimetilnitrosamina/farmacologia , Repressão Enzimática , Masculino , Microssomos Hepáticos/enzimologia , Conformação Molecular , Oxirredutases/antagonistas & inibidores , RatosRESUMO
Fifty-two surviving low-birth-weight infants who had low Thrombotest (Owren) results on the first day, together with the same number of matched controls with higher Thrombotest results, were examined for the integrity of their central nervous system. Gross abnormalities were found in 13.5% of the low Thrombotest group compared with 1.9% in the higher group. Minor brain damage syndromes were more common in the low Thrombotest group. The combined brain damage syndromes were 23.1% in the low Thrombotest group compared with 3.8% in the higher group.It is suggested that the causes of the brain damage in the low Thrombotest group are either non-fatal cerebral haemorrhage or intravascular fibrin deposition associated with disseminated intravascular coagulation.
Assuntos
Peso ao Nascer , Encefalopatias/etiologia , Hipoprotrombinemias/complicações , Doenças do Recém-Nascido/complicações , Hemorragia Cerebral/complicações , Desenvolvimento Infantil , Pré-Escolar , Fibrina/metabolismo , Humanos , Hipoprotrombinemias/diagnóstico , Lactente , Recém-Nascido , Testes de Inteligência , Embolia e Trombose Intracraniana/complicações , Exame Neurológico , PrognósticoRESUMO
Studies with 58 polynuclear aromatic hydrocarbons have shown that to repress demethylation of dimethylnitrosamine (DMN) in rat liver, the hydrocarbons must satisfy specific requirements of molecular geometry regarding size, shape, and coplanarity. Expressing the molecular size of these planar compounds by the two-dimensional area occupied, the size for maximal repressor activity ranges between about 85 and 150 A2. In addition to being within the correct molecular size range the hydrocarbons must have an elongated-rather than compact-molecular shape; circularly shaped and/or highly symmetrical hydrocarbons, such as coronene, triphenylene, ovalene, and tetrabenzonaphthalene, have very low activity or are inactive, in spite of being in the optimum size range. Coplanarity of the molecule is a critical requirement; thus, the potent carcinogen, 9,10-dimethyl-1,2-benzanthracene, is inactive as repressor of DMN-demethylase synthesis. Two exceptions, fluoranthene and benzol[ghi] fluoranthene, showed significant induction of DMN-demethylase. The molecular size distribution of hydrocarbons that repress the DMN-demethylase shows a mirror-image relationship with respect to the earlier reported molecular size requirement for indcution of azo dye N-demethylase. Compounds other than hydrocarbons also show the mirror-image relationship in the sense that pregnenolene-16alpha-carbonitrile, alpha- and beta-naphthoflavone, and Aroclor 1254 (known to be inducers of various mixed-function oxidases) are strong repressors of DMN-demethylase. Aminoacetonitrile, a strong inhibitor of carcinogenesis by DMN, is also a potent repressor of DMN-demethylase. The enzyme is inhibited by pretreatment of the animals with cobaltous chloride, an inhibitor of the synthesis of cytochrome P-450. Pregnenolone-16alpha-carbonitrile and 3-methylcholanthrene, despite their similarity of action on DMN-demethylase, have different effects on azo reductase, which is repressed by the former and induced by the latter compound.
Assuntos
Oxirredutases N-Desmetilantes/antagonistas & inibidores , Compostos Policíclicos/farmacologia , Animais , Dimetilnitrosamina , Repressão Enzimática/efeitos dos fármacos , Masculino , Metilcolantreno/farmacologia , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/metabolismo , Peso Molecular , Oxirredutases N-Desmetilantes/metabolismo , Fenobarbital/farmacologia , Carbonitrila de Pregnenolona/farmacologia , RatosRESUMO
The clinical utility of the aminoglycoside antibiotics is hampered by their well-known capacity to cause labyrinthine and renal damage. The mechanism by which these damages are produced is unknown. Attention was focused on the aminosugar moiety of these antibiotics by the finding of Owada (1962) which demonstrated that 3-aminoglucose is as ototoxic as its parent antibiotic, kanamycin. It is known that aminosugars compete with glucose for transport and that the sensory cells of the cochlea depend on glucose as a primary energy source. The hypothesis that grew out of these considerations was that kanamycin might be causing its ototoxicity by inhibiting glucose transport at one of several sites in the inner ear. To test this hypothesis the ototoxicity of kanamycin was determined in hyperglycemic animals. Hyperglycemia clearly and dramatically protects animals against ototoxicity as evidenced both by electrocochleographical and histological examination.