Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs

Sodium ascorbate is preferentially toxic to tumor cells at high concentrations. It has not been established, however, whether sufficient intra-tumor ascorbate concentrations are safely achievable in vivo. We administered sodium ascorbate subcutaneously or orally for eighteen days to Sewall-Wright strain-2 guinea pigs bearing intradermal L-10 hepatocarcinoma tumors. Tumor masses and intra-tumor ascorbate concentrations were determined at necropsy. L-10 cells formed tumors that metastasized to the lymph nodes, with tumor burdens reaching nearly 50 grams in untreated animals. Subcutaneous injections of ascorbate (500 mg/kg/day) inhibited tumor growth by as much as sixty-five percent, with oral supplementation reducing it by roughly fifty percent. Tumor growth correlated inversely with intra-tumor ascorbate concentration, the latter exceeding 2 mM in some cases. Ascorbate concentrations sufficient to kill tumor cells can be safely achieved in solid tumors in vivo, suggesting a possible role for high dose intravenous ascorbate in treating cancer.     

Pharmacokinetics of all-trans retinoyl beta-glucuronide in rats following intraperitoneal and oral administration

The purpose of this study was to examine the pharmacokinetics of a single dose (6.3 mumol, 3 mg) of all-trans retinoyl beta-glucuronide (RAG), when given either orally in corn oil or by intraperitoneal (i.p.) injection in dimethylsulfoxide (DMSO) to adult Sprague-Dawley rats. Following dosing, serial blood samples were collected at various times up to 48 hours from each rat via saphenous vein puncture. Retinoids were extracted from plasma samples and analyzed by high-performance liquid chromatography. In the plasma of i.p.-dosed rats (n = 6), a derivative of RAG, tentatively identified as the lactone of RAG (RAGL), was the major product found. RAGL persisted in the plasma for up to 48 hours. Much smaller concentrations of RAG and of retinoic acid (RA) were also present in the plasma at two to four hours, but generally not thereafter. In orally dosed rats (n = 6), neither RAG nor its products, except for occasional traces of the lactone, were detected. Plasma retinol levels decreased in both i.p.-injected and orally treated rats, the decrease being significant in orally dosed rats.     

三氯乙烯致敏豚鼠皮肤及血清中IL-17的测定

目的比较三氯乙烯(TCE)致敏豚鼠和未致敏豚鼠皮肤和血清中IL-17表达水平,探讨TCE药疹样皮炎新的发病机制。方法将豚鼠随机分为空白对照组,溶剂(橄榄油)对照组,TCE处理组。根据豚鼠最大值试验方法(Guinea Pig Maximization Test,GPMT)处理豚鼠。按照《化学品毒性鉴定技术规范》的评分标准对动物的皮肤反应进行评分,评分≥1的判为致敏。在末次激发后24 h,72 h,1周和2周分四批采血和皮肤组织,用ELISA试剂盒测定血清中IL-17的含量;将皮肤组织制成蜡块,采用Elivison二步法免疫组织化学法检测其IL-17的表达情况。结果根据皮肤反应评分判断致敏阳性,TCE处理组致敏率为70%。TCE处理组血清中IL-17的水平及皮肤组织免疫组化评分明显高于溶剂对照组,且差异有统计学意义(P<0.05);TCE处理组的不同时间段相比,IL-17的表达差异有统计学意义(P<0.05);在TCE处理组72h和1周两个时点,TCE致敏鼠IL-17的表达比相应的未致敏鼠高,差异有统计学意义(P<0.05)。结论 TCE可以诱导豚鼠致敏,IL-17在豚鼠致敏的过程中有重要意义。     

In vivo vitamin C deficiency in guinea pigs increases ascorbate transporters in liver but not kidney and brain

Moderate vitamin C (vitC) deficiency (plasma concentrations less than 23 μmol/L) affects as much as 10% of adults in the Western World and has been associated with an increased mortality in disease complexes such as cardiovascular disease and the metabolic syndrome. The distribution of vitC within the body is subjected to complex and nonlinear pharmacokinetics and largely depends on the sodium-dependent vitC-specific transporters, sodium-dependent vitamin C transporter 1 (SVCT1) and sodium-dependent vitamin C transporter 2 (SVCT2). Although currently not established, it is likely to expect that a state of deficiency may affect the expression of these transporters to preserve vitC concentrations in specific target tissues. We hypothesized that diet-induced states of vitC deficiency lead to alterations in the messenger RNA (mRNA) and/or protein expression of vitC transporters, thereby regulating vitC tissue distribution. Using guinea pigs as a validated model, this study investigated the effects of a diet-induced vitC deficiency (100 mg vitC/kg feed) or depletion (0 mg vitC/kg feed) on the expression of transporters SVCT1 and SVCT2 in selected tissues and the transport from plasma to cerebrospinal fluid (CSF). In deficient animals, SVCT1 was increased in the liver, whereas a decreased SVCT1 expression but increased SVCT2 mRNA in livers of depleted animals suggests a shift in transporter expression as response to the diet. In CSF, a constant plasma:CSF ratio shows unaltered vitC transport irrespective of dietary regime. The study adds novel information to the complex regulation maintaining vitC homeostasis in vivo during states of deficiency.     

Modification of serum proteins in guinea pigs immunized and challenged with toluene diisocyanate

OBJECTIVES: Guinea pigs were used to determine whether immunization and challenge by toluene diisocyanate (TDI) induce changes in the serum protein concentrations of the "acute-phase response" and whether TDI can form adducts with serum proteins. METHODS: Guinea pigs were immunized by weekly intradermal injections of TDI and challenged with TDI 7 days after the 3rd injection. The animals were killed 6 hours after the challenge, and serum was analyzed for protein characterization by gel electrophoresis and for specific antibodies to TDI by enzyme-linked immunosorbent assay (ELISA) and Western blotting. RESULTS: The total serum protein concentration of the immunized TDI-challenged guinea pigs increased in comparison with that of nonimmunized animals [75 (SE 0.7) versus 47.4 (SE 2.3) mg/ml; ]. Albumin and alpha, and alpha2 globulins increased significantly [respectively: 65.8 (SE 0.2)%, 2.1 (SE 0.1)% and 7.2 (SE 0.1)% versus 59 (SE 1.3)%, 1.3 (SE 0.1)% and 3.7 (SE 0.1)%], whereas beta1 and beta2 globulins decreased in the immunized TDI-challenged guinea pigs [7.8 (SE 0.2)% and 0.8 (SE 0.2)% versus 15.8 (SE 0.7)% and 4.8 (SE 0.2)%]. The gamma globulin concentrations did not change significantly. In the immunized TDI-challenged animals, albumin was modified by TDI and ran faster on agarose gel electrophoresis than did albumin from nonimmunized guinea pigs. In the ELISA, only immunized animals had high titers of TDI-specific antibodies (IgG and IgG1); by blotting, the antibodies reacted against TDI, the TDI-BSA-conjugate and several TDI-conjugated guinea pig serum proteins, but they did not react against any native or denaturated serum protein when unconjugated with TDI. CONCLUSIONS: These findings indicate that, in guinea pigs, immunization and challenge with TDI induces changes in serum proteins of the "acute phase response" and TDI is adducted to serum proteins with different molecular weights (eg, albumin).     

Provocation of respiratory allergy in guinea pigs following inhalation of free toluene diisocyanate

An animal exposure experiment which simulated a workplace exposure situation was made to compare toluene diisocyanate (TDI) concentrations which resulted in antibody production with those which elicited pulmonary responses. Groups of guinea pigs were exposed to inhaled TDI from 0.02 to 1.0 ppm (g/g) for 3 h/day on 5 consecutive days. Three weeks later the animals were challenged with 0.02 ppm of free TDI for 15 min. TDI specific antibodies and pulmonary responses were evaluated. Specific antibody production showed a linear correlation to TDI concentration at induction. Most of the animals exposed to TDI levels above 0.2 ppm displayed significant pulmonary responses, but no correlation was found between TDI concentration at induction and the intensity of pulmonary response upon challenge to free TDI. These results indicated that there was a threshold concentration of 0.02 ppm TDI for antibody production and for the development of pulmonary response. It was also found that exposure to TDI at a level lower than its threshold concentration for sensitization may elicit a response in previously sensitized individuals.     

Effect of glucocorticoids and calcium intake on bone density and bone, liver and plasma minerals in guinea pigs.

The purpose of this study was to see what effect glucocorticoids would have on bone density and mineral distribution in guinea pigs. Adult female guinea pigs were given prednisolone, a synthetic analogue of cortisol, for up to 24 weeks. Bone density and bone, liver and plasma levels of zinc, copper, iron, manganese, chromium, magnesium and calcium were studied in these animals. In one study, the effect of menopause was simulated by using ovariectomy. In another study, dietary calcium was varied to investigate its effect with glucocorticoids. Animals treated with 1 mg prednisolone/kg body weight showed increased femur density compared with controls, but no changes in tissue mineral concentrations. Animals fed 100 mg prednisolone/kg body weight experienced decreased femur density. Differences in effects were not observed between ovariectomized and intact animals. Bone loss was greatest in animals fed the cereal-based closed-formula diet and least in animals fed the low-calcium diet. Changes in mineral content of femurs observed in animals which lost bone mass were increased iron concentration and decreased magnesium concentration. Total liver stores of zinc and magnesium increased. Liver copper increased in concentration per gram as well as in total content. Liver concentration of manganese decreased. Plasma changes in animals fed the high level of drug were decreased iron and calcium, and increased copper. Hemoglobin and hematocrit increased with increasing drug levels. It is suggested that glucocorticoids have marked effects on mineral metabolism which may be related to the bone loss and that these effects may be modified by dietary changes.     

Effect of dietary ascorbic acid on levels of serum mineral nutrients in guinea pigs

The effect of dietary ascorbic acid on the serum mineral nutrients, Ca, Cu, Fe, K, Mg, Mn, Na and Zn in guinea pigs has been studied. Large amounts of ascorbic acid were administered to experimental animals in their drinking water. The daily ascorbic acid intake from the diet for the control animals was 10 mg/kg body weight. The mean ascorbic acid intakes for the two groups of experimental animals were 366 (37 times control) and 722 (72 times control) mg/kg body weight/day. In the ascorbic acid-treated animals, there was a significant increase in serum ascorbic acid levels in comparison with the controls. No substantial differences were observed in the body weights. The large quantities of dietary ascorbic acid did not influence serum levels of all eight minerals studied when the experimental and control values were compared using the two-tailed Student's t-test. However, serum level of copper in the guinea pigs ingesting a daily dose of 722 mg of ascorbic acid per kg body weight was slightly below control value when one-tailed Student's t-test was used.     

Toxicity and tissue levels in the rat and guinea pig following acute hexachlorobenzene administration

Summary DDT injected intraperitoneally into black surfperch caused substantial increases in plasma osmotic concentration only at doses much larger than are likely to be encountered in nature. Increased plasma concentrations were below those tolerated by fish adapted to high salinities. Death of marine teleosts from DDT poisoning probably involves factors other than simply osmoregulatory failure.     

IL-6和IL-8在三氯乙烯致敏豚鼠血清中的变化

目的通过豚鼠致敏最大值试验(guinea pig maximization test,GPMT)方法建立豚鼠致敏模型,检测并比较TCE致敏豚鼠与未致敏豚鼠血清中IL-6和IL-8的水平,探讨IL-6和IL-8在三氯乙烯(TCE)过敏性皮炎中的作用。方法将豚鼠随机分为空白对照组,溶剂(橄榄油)对照组,DNCB阳性对照组和TCE处理组。采用GPMT法建立豚鼠致敏模型。根据致敏结果及末次激发后采血的不同时点将TCE处理组分为TCE未致敏24h组,TCE致敏24h组,TCE未致敏72h组,TCE致敏72h组。用ELISA试剂盒测定血清中IL-6和IL-8的含量。结果DNCB组致敏率为100%,TCE组致敏率为62.1%。溶剂对照组与空白对照组差异均无统计学意义。与溶剂对照组相比,TCE未致敏24h组IL-6水平降低,差异有统计学意义(P<0.05),TCE未致敏72h组与TCE未致敏24h组相比,IL-6水平明显升高,差异有统计学意义(P<0.05)。与溶剂对照组相比,TCE未致敏72组IL-8水平明显降低,差异有统计学意义(P<0.05)。结论血清中细胞因子IL-6和IL-8水平在TCE诱导的致敏组和未致敏组豚鼠间...