摘要:

Aminoglycoside antibiotics are hydrophilic molecules consisting of an aminated cyclitol associated with amino sugar. They bind in vivo as well in vitro to negatively charged membranes. Their use as chemotherapeutic agents is unfortunately accompanied by oto‐and nephrotoxic reactions, and the purpose of this review is to examine the role of the molecular interactions between aminoglycosides and membranes in the development of nephrotoxicity.31P Nuclear magnetic resonance (NMR) and fluorescence depolarization have been used to characterize the effect of aminoglycosides on phosphate heads and fatty acyl chains of phospholipids.15N NMR has been used to obtain interesting information on regioselective interactions of amino groups of antibiotics with phospholipids. The binding of aminoglycosides with negatively charged membranes is associated with impairment of phospholipid catabolism, change in membrane permeability, and membrane aggregation. Biochemical analysis and2H NMR spectroscopy have brought information on the molecular mechanism involved in the impairment of phospholipid catabolism. Nephrotoxic aminoglycosides could induce sequestration of phosphatidylinositol and therefore reduce the amount of negative charge available for optimal lysosomal phospholipase activity toward phosphatidylcholine included in liposomes that also contain cholesterol and sphin‐gomyelin. Conformational analysis shows that aminoglycosides, which have a high potency to inhibit lysosomal phospholipase activity, adopt an orientation parallel to the lipid/water interface. This orientation of the aminoglycoside molecule at the interface is also critical to explain the marked increase of membrane permeability induced by less nephrotoxic aminoglycosides such as isepamicin and amikacin. This effect is indeed only observed with aminoglycosides oriented perpendicular to this interface, probably related to the creation of a local condition of disorder. The impairment of phospholipid catabolism, which is considered to be an early and significant step in the development of aminoglycoside tox‐icity, is therefore not related to the change in membrane permeability. However, the role of this latter phenomenon and of membrane aggregation for aminoglycoside nephrotoxicity could be further investigated.

ISSN:0098-4108    

DOI:10.1080/15287399509531960

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

The ability of a physiologically based pharmacokinetic (PBPK) model to predict the uptake and elimination of perchloroethylene (PCE) in venous blood was evaluated by comparison of model simulations with experimental data for two species, two routes of exposure, and three dosage levels. Unanesthetized male Sprague‐Dawley rats and beagle dogs were administered 1, 3, or 10 mg PCE/kg body weight in polyethylene glycol 400 as a single bolus, either by gavage or by intraarterial (ia) injection. Serial blood samples were obtained from a jugular vein cannula for up to 96 h following dosing. The PCE concentrations were analyzed by headspace gas chromatography. For each dose and route of administration, terminal elimination half‐lives in rats were shorter than in dogs, and areas under the blood concentration‐time curve were smaller in rats than in dogs. Over a 10‐fold range of doses, PCE blood levels in the rat were well predicted by the PBPK model following ia administration, and slightly underpredicted following oral administration. The PCE concentrations in dog blood were generally overpredicted, except for fairly precise predictions for the 3 mglkg oral dose. These studies provide experimental evidence of the utility of the PBPK model for PCE in interspecies, route‐to‐route, and dose extrapolations.

ISSN:0098-4108    

DOI:10.1080/15287399509531961

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Pretreatment of male Fischer 344 rats for 5 wk with coal tar creosote, a coal distillation product that is widely used as a wood preservative, potentiated the excretion of urinary mutagens in 2,6‐dinitrotoluene (DNT) treated rats. Creosote increased the bioactivation of DNT to significantly greater levels of urinary genotoxic metabolites and/or formed DNA adducts in the liver. A significant increase in the excretion of mutagenic DNT metabolites was observed after the first week of creosote treatment, peaked at wk 3, and then decreased by 33% after 5 wk of treatment. Nevertheless, there was a significant increase (66%,) in the formation of DNT‐derived DNA adducts in the livers of rats treated with DNT plus creosote at wk 5. Increased cecal β‐glucuronidase activity and reduced small intestinal nitroreductase activity may play roles in the bioactivation of DNT. The excretion of mutagenic DNT metabolites supplies useful information about the bioactivation of DNT; it does not provide a useful index of DNT‐derived hepatic DNA adduct formation. Such interactions could be important to predictive risk assessment because the overall cancer risk of such chemical mixtures may exceed the sum of the component risks.

ISSN:0098-4108    

DOI:10.1080/15287399509531962

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Fluoride (F) and aluminum (Al), which are known to form a strong complex, are both present in finished drinking water. The effect of F and Al on one another's tissue accumulation was determined using adult male New Zealand white rabbits. Thirty‐six rabbits (three per group) were given Purina Rabbit Chow and drinking water containing no F or AI, F alone (1, A, or 50 ppm F as NaF), Al alone, (100 or 500 ppm Al as AICI3), or a combination of F and Al, ad libitum for 10 wk. None of these treatments altered food intake or weight gain in these rabbits. However, rabbits treated with 1 ppm F and 500 ppm Al consumed significantly less water than control rabbits. The F accumulation in plasma, urine, incisors, and tibia was increased as the F addition to the drinking water increased within groups receiving a single concentration of Al. In contrast, F accumulation in plasma, urine, incisors, and tibia decreased as the Al concentration increased within groups receiving a single F concentration, indicative of decreased intestinal absorption. Importantly, Al levels in tibia were significantly increased by the addition of F to the drinking water, even in animals receiving no Al in their drinking water. The effect of F on Al accumulation in bone was confirmed by our evaluating Al levels in sterna harvested from rats treated with 0 or 79 ppm F (as NaF in the drinking water) in a study conducted by the National Toxicology Program (Bucher et al., 1991). Therefore, some of the osteotoxicity seemingly associated with high F levels in bone may be due to the accumulation of Al or an Al‐F complex.

ISSN:0098-4108    

DOI:10.1080/15287399509531963

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

Erythrocyte δ‐aminolevulinic acid dehydratase (ALAD) activity, erythrocyte zinc protopor‐phyrin (ZPP)lheme ratio, and urinary coproporphyrin (UC) concentration have been employed as biological indicators of moderate‐ to high‐level lead exposure, corresponding to blood levels in excess of 50 μg/dl, in human subjects. The comparative efficacy of these measures as indicators of lead exposure consistent with sustained lower blood lead levels has not been systematically evaluated. In the present studies, we examined the relative sensitivity and magnitude of response of these three bioindicators in rats during chronic exposure to 0, 100, or 1000 ppm lead as lead acetate in drinking water for up to 10 wk, followed by a 10‐wk postexposure period, with weekly assessments, or during subchronic exposure to 0 or 1000 ppm lead as lead acetate in drinking water for 6 d, with daily assessments. Analysis of variance (ANOVA) was used to determine if the lead‐treated rats differed from controls and to distinguish between dose groups with respect to the three biochemical indices of lead exposure. The data were normalized by conversion to Z scores in order to compare indicators with regard to magnitude of change in response to lead treatment. The order of sensitivity of each indicator was determined by considering the magnitude of the correlation coefficient (r) between the indicator and the blood lead concentration in each study. The indicators in order of decreasing sensitivity to lead in the chronic study were UC > ZPP/heme > AMD. The indicators in order of decreasing magnitude of change in response to change in blood lead level were also UC > ZPP/heme > ALAD. None of the heme pathway parameters was judged a satisfactory substitute for direct blood lead measurement as an indicator of low‐level lead exposure. However, urinary coproporphyrin appears most useful in this respect owing to highest sensitivity and magnitude of change relative to blood lead content and relatively low variation of mean coproporphyrin levels.

ISSN:0098-4108    

DOI:10.1080/15287399509531964

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

摘要:

The effect of thiram, a fungicide that increases the incidence of tibial dyschondroplasia (TD) in poultry, was studied in vitro using growth plate chondrocyte culture. Thiram caused a significant reduction in alkaline phosphatase, acid phosphatase, and lactate dehydrogenase (LDH) activities at concentrations of 5 μMand above. It was highly cyto‐toxic to chondrocytes at and above this concentration as determined by their ability to reduce 3(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (triazolyl blue, MTT), a marker of cellular viability. An increase in the leakage of LDH into culture media was evident at concentration as low as 1 μM. Very few differences were noticed in the electro‐phoretic migration profiles of cell‐extract proteins at any treatment level relative to control. The cytotoxic effect of thiram is possibly due to its damaging effect on the cell membrane, which may be responsible for chondrocyte death.

ISSN:0098-4108    

DOI:10.1080/15287399509531965

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399509531966

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor

ISSN:0098-4108    

DOI:10.1080/15287399509531959

出版商:Taylor & Francis Group    

年代:1995

数据来源: Taylor