RESUMO
Many chemicals shown to be teratogenic in laboratory animals are not known to be teratogenic in humans. However, it remains to be determined if the unresponsiveness of humans is due to lessened sensitivity, to generally subteratogenic exposure levels, or to the lack of an appropriate means of identifying human teratogens. On the other hand, with the exception of the coumarin anticoagulant drugs, those agents well accepted as human teratogens have been shown to be teratogenic in one or more laboratory species. Yet, no single species has clearly distinguished itself as being more advantageous in the detection of human teratogens over any other. Among the species used for testing, the rat and mouse most successfully model the human reaction, but the rabbit is less likely than other species to give a false positive finding. Among species less commonly used for testing, primates offered a higher level of predicability than others. Regarding concordance of target malformations, the mouse and rat produced the greatest number of concordant defects, but they also were responsible for the most noncorcordant responses as well. Since no other species is clearly more predictive of the human response, it is concluded that safety decisions should be based on all reproductive and developmental toxicity data in light of the agent's known pharmacokinetic, metabolic and toxicologic parameters.
Assuntos
Teratogênicos , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Gatos , Modelos Animais de Doenças , Cães , Feminino , Humanos , Camundongos , Gravidez , Ratos , Especificidade da Espécie , SuínosRESUMO
The experience of anger and its expression are sources of difficulty in the lives of many religious women. This article examines the circumstances that engender anger at the interpersonal and institutional levels. Elements that have assisted religious in coming to a mature integration of anger at the interpersonal-religious community levels are noted; the advantages and limitations of support groups are examined; and several techniques for coping with anger are indicated. The ability to transcend anger through the achievement of forgiveness is explored.
RESUMO
A potentiation of CCl4-induced hepatotoxicity was observed in rats pretreated with ethanol 18 hr prior to CCl4 exposure. Hepatic microsomal aldehyde dehydrogenase (ALDH) was significantly inhibited in animals sacrificed 1 hr following the sequential exposure, however, no more so than in those animals receiving CCl4 alone. The animals receiving ethanol alone had ALDH activity similar to vehicle treated controls. Twenty-four hours following a potentiating dose of ethanol and CCl4 an 81 and 57% decline in NAD+-dependent microsomal and mitochondrial ALDH activity was observed, respectively. Similar results were observed for microsomal and mitochondrial NADP+-dependent ALDH activity. The decline in membrane-bound ALDH was greater in potentiated animals than in those receiving CCl4 alone. A relatively smaller decline in cytosolic ALDH activity was observed in CCl4 treated rats with or without ethanol pre-exposure. The data suggest that inhibition of membrane bound ALDH may be one of the major mechanisms of in vivo potentiation of CCl4-induced hepatotoxicity by ethanol.
Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas , Etanol/farmacologia , Animais , Citosol/enzimologia , Sinergismo Farmacológico , Hepatopatias/enzimologia , Masculino , Microssomos Hepáticos/enzimologia , Mitocôndrias Hepáticas/enzimologia , NAD/farmacologia , Ratos , Ratos EndogâmicosRESUMO
In vitro inhibition of rat liver mitochondrial and microsomal aldehyde dehydrogenase (ALDH) under conditions of active CCl4 metabolism was investigated. Incubation of microsomes or mitochondria in the presence of NADPH alone caused significant, time-dependent inhibition of mitochondrial and microsomal ALDH. EDTA partially protected ALDH from inhibition. Incubation of microsomes or microsomes plus mitochondria in the presence of NADPH and CCl4 resulted in marked inhibition of microsomal and mitochondrial ALDH activity. The inhibition was both dose- and time-dependent and was relatively less in the presence of EDTA. It is proposed that the inhibition of membrane-bound ALDH may be one of the early events responsible for the genesis of CCl4-hepatotoxicity.
Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Tetracloreto de Carbono/farmacologia , Fígado/enzimologia , Animais , Tetracloreto de Carbono/metabolismo , Ácido Edético/farmacologia , Técnicas In Vitro , Masculino , Microssomos Hepáticos/enzimologia , Mitocôndrias Hepáticas/enzimologia , NAD/metabolismo , NADP/metabolismo , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
1. The evidence presented in this paper indicates the existence of NADPH-supported lipid peroxidation in human placental microsomes. Thiobarbituric acid assay was used to estimate quantitatively lipid peroxidation. 2. Several biochemical characteristics of the reaction were examined. Maximal lipid peroxidation occurred at pH 7.4 and at a protein concentration of approx. 0.2 mg microsomal protein/ml. The presence of NADPH and chelated iron was required. The reaction was linear up to 5 min and did not exhibit an initial lag phase. 3. Under optimal assay conditions, the rate of lipid peroxidation ranged from 2 to 6 nmol malondialdehyde formed/min/mg protein in different preparations of placental microsomes. 4. Inconclusive results were obtained when assays were performed in the presence of scavengers of reactive oxygen species. 5. Marked inhibition in the malondialdehyde accumulation was observed when phosphate buffer was added to the incubation media. 6. This inhibitory effect appeared to be due to the removal of chelated iron from the system and not due to interference with the electron transport mechanism.
Assuntos
Peróxidos Lipídicos/metabolismo , NADP/fisiologia , Placenta/metabolismo , Ácido Edético/farmacologia , Ácido Egtázico/farmacologia , Feminino , Humanos , Técnicas In Vitro , Ferro/fisiologia , Malondialdeído/metabolismo , Microssomos/metabolismo , Oxirredutases/farmacologia , Placenta/efeitos dos fármacos , GravidezRESUMO
Paraquat, a widely used herbicide, was found to cause a marked stimulation of lipid peroxidation in the human placental microsomes in vitro. Both NADPH and chelated iron were necessary to observe paraquat-stimulated lipid peroxidation. The malondialdehyde accumulation in the incubation medium increased with increase in time, protein and paraquat concentration. The reaction did not exhibit the initial lag phase suggesting that endogenous membrane-bound antioxidants in human placental microsomes are either absent or present in extremely small quantities.
Assuntos
Ferro/farmacologia , Peróxidos Lipídicos/metabolismo , NADP/farmacologia , Paraquat/farmacologia , Placenta/metabolismo , Humanos , Técnicas In Vitro , Microssomos/metabolismo , Superóxidos/metabolismoRESUMO
The mechanisms by which methanol potentiates CCl4 hepatotoxicity was studied in rats. Chloramphenicol, an inhibitor of cytochrome P-450, blocked the increase of serum glutamate-oxaloacetate transaminase activity enhanced by methanol pretreatment of rats exposed to CCl4. Chloramphenicol also decreased microsomal lipid peroxidation in both CCl4 and methanol-pretreated, CCl4-intoxicated animals when measured 30 minutes after exposure. Chloramphenicol prevented the loss of glucose 6-phosphatase activity after CCl4 and methanol. Sodium salicylate, which lowers the level of NADPH in the hepatocyte, blocked methanol potentiation of CCl4 damage as measured by the elevation of serum GOT activity. Therefore, methanol may potentiate CCl4 hepatotoxicity by stimulation of CCl4 bioactivation by cytochrome P-450 via an increase in the level of reduced NAD(P)H in the liver.
Assuntos
Intoxicação por Tetracloreto de Carbono/prevenção & controle , Cloranfenicol/farmacologia , Metanol/toxicidade , Salicilato de Sódio/farmacologia , Animais , Aspartato Aminotransferases/sangue , Intoxicação por Tetracloreto de Carbono/metabolismo , Sinergismo Farmacológico , Peróxidos Lipídicos/metabolismo , Masculino , Metanol/antagonistas & inibidores , Microssomos Hepáticos/enzimologia , Mitocôndrias Hepáticas/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Methyl palmoxirate, an inhibitor of long-chain fatty acid oxidation, was administered by gavage (0, 1, 5, or 20 mg/kg/day) to female rats over the last third of gestation and throughout lactation. Weight gain (mid- and high-dosage group) and survivability (high-dosage group) were significantly (p less than or equal to 0.05) reduced in offspring of methyl palmoxirate-treated dams as compared to control offspring. Mid- and high-dosage male offspring found dead after Day 4 of lactation exhibited grossly distended bladders and renal pelves. A dosage-related increased incidence of dilated renal pelves was observed in both sexes at necropsy of 21-day-old mid- and high-dosage group pups. Microscopic examination of the urinary tracts of a number of affected pups revealed renal parenchymal atrophy and urethral obstruction. Drug disposition studies indicated lactating pups were exposed to significant amounts of methyl palmoxirate via mammary secretions. Cross-fostering experimentation suggested that some of the adverse effects observed in offspring were due to lactational, rather than in utero, exposure.
Assuntos
Compostos de Epóxi/toxicidade , Éteres Cíclicos/toxicidade , Ácidos Graxos/metabolismo , Hidronefrose/induzido quimicamente , Propionatos/toxicidade , Animais , Nitrogênio da Ureia Sanguínea , Relação Dose-Resposta a Droga , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Lactação , Leite/metabolismo , Oxirredução , Gravidez , Proteínas/metabolismo , Ratos , Ratos Endogâmicos , Uretra/efeitos dos fármacosRESUMO
N-(4-hydroxyphenyl)-all-trans-retinamide (HPR) has potential efficacy in the treatment of dermatologic, arthritic, and neoplastic disorders. The teratogenicity of such a compound is of special concern in light of the known adverse effects of retinoids, in general, on the developing conceptus. In these studies, Sprague-Dawley rats and New Zealand White rabbits were treated orally from gestation days 6 to 15 and 6 to 18, respectively, with 0, 20, 125, or 800 mg/kg/day of HPR. In rat fetuses, low incidences of hydrocephaly (mid- and high-dosage groups) were observed. Fetal tissue (ng/g) and maternal plasma (ng/ml) concentrations of HPR, its major metabolite (N-[4-methoxyphenyl] retinamide [MPR]) and retinol were determined in separate groups of similarly-treated rats 3 h following the last dose on gestation day 15. Fetal tissue concentrations of HPR and MPR were approximately one-half maternal plasma concentrations. A dose related reduction in maternal plasma and fetal tissue concentrations of retinol were also observed. In mid- and high-dosage rabbit fetuses, a dose-related increase in the incidence of dome-shaped head was observed. Subsequent skeletal evaluation revealed delays in skull bone ossification and a widening of the frontal and frontoparietal sutures. Microphthalmia was also observed in two high-dosage fetuses. A dose-dependent and statistically significant reduction in maternal plasma retinol levels was observed across all dosage groups.