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1.
The endocrine disruptor bisphenol A (BPA) is a frequently used chemical in the manufacture of consumer products. In humans, BPA is extensively metabolized to BPA glucuronide (BPAG) by different UDP-glucuronosyltransferase (UGT) isoforms. The study has been performed with the intention to improve the accuracy of published physiologically based pharmacokinetic models and to improve regulatory risk assessments of BPA. In order to gain insight into intestine, kidney, liver, and lung glucuronidation of BPA, human microsomes of all tested organs were used. BPAG formation followed Michaelis-Menten kinetics in the intestine and kidney, but followed substrate inhibition kinetics in the liver. Human lung microsomes did not show glucuronidation activity towards BPA. While the liver intrinsic clearance was very high (857 mL min(-1)kg body weight(-1)), the tissue intrinsic clearances for the kidney and intestine were less than 1% of liver intrinsic clearance. Since BPA is a UGT1A1 substrate, we postulated that the common UGT1A1*28 polymorphism influences BPA glucuronidation, and consequently, BPA detoxification. Hepatic tissue intrinsic clearances for UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28 microsomes were 1113, 1075, and 284 mL min(-1)kg body weight(-1), respectively. Prior to microsomal experiments, the bioproduction of BPAG and stable isotope-labeled BPAG (BPAG(d16)) was performed for the purpose of the reliable and accurate quantification of BPAG. In addition, a sensitive LC-MS/MS analytical method for the simultaneous determination of BPA and BPAG based on two stable isotope-labeled internal standards was developed and validated. In conclusion, our in vitro results show that the liver is the main site of BPA glucuronidation (K(m) 8.9 μM, V(max) 8.5 nmol min(-1) mg(-1)) and BPA metabolism may be significantly influenced by a person's genotype (K(m) 10.0-13.1 μM, V(max) 3.4-16.2 nmol min(-1) mg(-1)). This discovery may be an important fact for the currently on-going worldwide BPA risk assessments and for the improvement of physiologically based pharmacokinetic models.  相似文献   

2.
alpha-Adrenoceptors have been classified into alpha(1)- and alpha(2)-adrenoceptors. Recently, the alpha(1)-adrenoceptors were divided into two subtypes: alpha(1L) with low affinity and alpha(1H) with high affinity for prazosin. Little is known concerning the role of each subtype of alpha(1)-adrenoceptor in asthma. We investigated the effects of specific antagonists of alpha(1)- and alpha(2)-, alpha(1H)-, alpha(1L)-, and alpha(2)-adrenoceptors, namely moxisylyte, prazosin, 3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy) ethyl]-N-methylaminomethyl]-4-methoxy-2, 5, 6-trimethylphenol hemifumarate (JTH-601), and yohimbine, respectively, on antigen-induced airway reactions in guinea pigs. Fifteen minutes after intravenous administration of moxisylyte (0.01, 0.1 or 1 mg/kg), prazosin (0.01, 0.1, 1 or 10 mg/kg), JTH-601 (1, 3, 6 or 10 mg/kg) or yohimbine (0.1 or 1 mg/kg), passively sensitized and artificially ventilated animals received an aerosolized antigen challenge. Bronchial responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)) in non-sensitized animals. JTH-601 and moxisylyte, but not prazosin or yohimbine, dose dependently inhibited antigen-induced bronchoconstriction. None of the tested drugs altered PC(200). JTH-601 significantly reduced leukotriene C(4) levels in bronchoalveolar lavage fluid obtained 5 min after antigen challenge, but prazosin did not. These results indicate that prevention of antigen-induced bronchoconstriction by blockade of alpha-adrenoceptors is due to the inhibition of mediator release via alpha(1L)-adrenoceptor antagonism.  相似文献   

3.
BACKGROUND AND PURPOSE: Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. EXPERIMENTAL APPROACH: Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. KEY RESULTS: TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. CONCLUSIONS AND IMPLICATIONS: Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.  相似文献   

4.
Recently melamine was found to have contaminated the feed of multiple food production species leading to concern over the ability to establish an appropriate withdrawal interval and protect the safety of the food supply. To establish an appropriate withdrawal interval, a physiologically based pharmacokinetic (PBPK) model for melamine was developed for rats and extrapolated to pigs. The rat model underpredicted plasma concentrations, but better predicted tissue residues. Correlation values for plasma, kidney, and liver were 0.59, 0.76, and 0.73, respectively. The pig model underpredicted early plasma time points but had greater accuracy at later time points which is relevant to withdrawal times. Correlation (R(2)) between predicted and observed plasma values was 0.89 with a negative intercept of -0.76. The pig model estimated a withdrawal interval (based on kidney tissue residues) of 19.2 and 20.9h for single oral exposures of 3.0 and 5.12 mg/kg of melamine, respectively. Chronic oral dosing (3.0 and 5.12 mg/kg twice daily for 7 days) yielded withdrawal intervals of 20 and 21.3h, respectively. PBPK models, such as this one, provide evidence of the usefulness in species extrapolation over a range of dosing scenarios and can be used to protect the food supply after accidental exposure in the face of little in the target species.  相似文献   

5.
Chloroform causes hepatic and renal toxicity in a number of species. In vitro studies have indicated that chloroform can be metabolized by P450 enzymes in the kidney to nephrotoxic intermediate, although direct in vivo evidence for the role of renal P450 in the nephrotoxicity has not been reported. This study was to determine whether chloroform renal toxicity persists in a mouse model with a liver-specific deletion of the P450 reductase (Cpr) gene (liver-Cpr-null). Chloroform-induced renal toxicity and chloroform tissue levels were compared between the liver-Cpr-null and wild-type mice at 24 h following differing doses of chloroform. At a chloroform dose of 150 mg/kg, the levels of blood urea nitrogen (BUN) were five times higher in the exposed group than in the vehicle-treated one for the liver-Cpr-null mice, but they were only slightly higher in the exposed group than in the vehicle-treated group for the wild-type mice. Severe lesions were found in the kidney of the liver-Cpr-null mice, while only mild lesions were found in the wild-type mice. At a chloroform dose of 300 mg/kg, severe kidney lesions were observed in both strains, yet the BUN levels were still higher in the liver-Cpr-null than in the wild-type mice. Higher chloroform levels were found in the tissues of the liver-Cpr-null mice. These findings indicated that loss of hepatic P450-dependent chloroform metabolism does not protect against chloroform-induced renal toxicity, suggesting that renal P450 enzymes play an essential role in chloroform renal toxicity.  相似文献   

6.
The key to establishing a standardized melamine-induced animal bladder stone (cystolith) model is to determine the most appropriate daily dose of dietary melamine, which is unknown. Based on golden section theory that is a well-known preferred proportion (0.618), and the 50% lethal dose (LD50) of mouse oral melamine [4550 mg/kg body weight (bw)], we proposed that the daily dose may be close to the LD50’s golden section (i.e., 0.618 × 4550 mg melamine/kg bw). The latter as an average daily dose corresponds to 9373 ppm melamine diet in mice. In repeated experiments, a 100% incidence of cystoliths was observed on modeling day 14 in Balb/c and C57BL/6 mice fed the diet but not in mice fed similar diets containing 9842 (i.e., 9373 × 105%) or 8904 (i.e., 9373 × 95%) ppm melamine; the stones were relatively uniform and the difference in stone incidences between sexes or ages was not found in each 9373 ppm melamine group. In conclusion, 9373 ppm melamine diet is at least near the optimal dose diet or ideal for the rapid and stable establishment of a standardized cystolith model in the mice, and dietary melamine dose neither sex nor age is critical for stone formation.  相似文献   

7.
More and more fungal polysaccharides have been reported to exhibit a variety of biological activities, including antitumor, antioxidant and immunostimulant activity. The non-starch polysaccharides have emerged as an important class of bioactive natural products. In this study, the immune activities of a novel polysaccharide (LDG-A) isolated from Lactarius deliciosus (L. ex Fr.) Gray were investigated at 20, 40 and 80 mg/kg dose levels. The inhibitory rate in mice treated with 80 mg/kg LDG-A can reach 68.422%, being the highest in the three doses, which may be comparable to mannatide. Histology of immune organs showed that the tissues were arranged in more regular and firm pattern, but the tumor tissue arranged looser in LDG-A group than those in control group. Meanwhile, there was no obvious damage to other organs, such as heart, lung, and kidney. The antitumor activity of the LDG-A was usually believed to be a consequence of the stimulation of the cell-mediated immune response because it can significantly promote the lymphocyte and macrophage cells in the dose range of 50-200 μg/ml and 100-400 μg/ml in vitro, respectively. The level of cytokines (IL-6, TNF-α, and NO) of macrophage cells induced by LDG-A treatment was similar to lipopolysaccharides at different concentrations. The expression of all these genes studied (TNF-α, IL-6, and iNOS mRNA) in the untreated macrophage was little, but increased dramatically in a dose-dependent manner in the LDG-A-treated cells. The results obtained in the present study indicated that the purified polysaccharide of L. deliciosus (L. ex Fr.) Gray is a potential source of natural immune-stimulating substances.  相似文献   

8.
Melamine and its triazine analogs, such as cyanuric acid, have been used to artificially inflate protein content both in animal feed ingredients, as well as in milk products produced for human consumption. We report here a LC–MS/MS method to quantify and confirm melamine and cyanuric acid in serum from channel catfish and rainbow trout with a limit of quantification of 0.8 μg/mL. The method was applied to serum samples from a residue depletion study in which fish were given a single oral dose of 20 mg/kg body weight melamine, cyanuric acid, or both compounds together. Samples were taken at 1, 3, 7, 14, and 28 days (an additional 42 day was added for trout). When given alone or in combination with cyanuric acid, melamine residues were highest on day 1 in both catfish and trout. Cyanuric acid was only quantifiable at day 1 in trout when given alone, and not at all in catfish. The serum half life of melamine in catfish was 1.50–1.62 days and 3.09–3.67 days in trout. This work highlights the differences of depletion kinetics in fish, which can be measured in days, as compared to the depletion in mammals, measured in hours.  相似文献   

9.
The objective of this study was to evaluate the occurrence and levels of deoxynivalenol (DON), fumonisins B1 and B2 (FBs), and zearalenone (ZEN) contaminants in animal feeds used in Korea in 2012. Contamination with DON was observed in 91.33% and 53.33% in compound feeds and feed ingredients, respectively. Among compound feeds, poultry layer feed (laying) exhibited the highest contaminant level of 1.492 mg/kg. FBs contaminants were present in compound feeds and feed ingredients at 93.33% and 83.33%, respectively. Most poultry broiler (early) feeds were highly contaminated with FBs, and one of these feeds detected the level as 12.823 mg/kg as the highest level. The levels of ZEN in compound feeds and feed ingredients were 71.33% and 47%, respectively. Ninety-eight percent of compound feeds for cattle were contaminated with ZEN, and the highest contamination level of 0.405 mg/kg was observed in cattle fatting feeds.  相似文献   

10.

Aim:

To investigate the changes of expression and function of P-glycoprotein (P-GP) in cerebral cortex, hippocampus, liver, intestinal mucosa and kidney of streptozocin-induced diabetic rats.

Methods:

Diabetic rats were prepared via a single dose of streptozocin (65 mg/kg, ip). Abcb1/P-GP mRNA and protein expression levels in tissues were evaluated using quantitative real time polymerase chain reaction (QRT-PCR) analysis and Western blot, respectively. P-GP function was investigated via measuring tissue-to-plasma concentration ratios and body fluid excretion percentages of rhodamine 123.

Results:

In 5- and 8-week diabetic rats, Abcb1a mRNA levels were significantly decreased in cerebral cortices and intestinal mucosa, but dramatically increased in hippocampus and kidney. In liver, the level was increased in 5-week diabetic rats, and decreased in 8-week diabetic rats. Abcb1b mRNA levels were increased in cerebral cortex, hippocampus and kidney, but reduced in liver and intestinal mucosa in the diabetic rats. Western blot results were in accordance with the alterations of Abcb1a mRNA levels in most tissues examined. P-GP activity was markedly decreased in most tissues of diabetic rats, except kidney tissues.

Conclusion:

Alterations in the expression and function of Abcb1/P-GP under diabetic conditions are tissue specific, Abcb1 specific and diabetic duration-dependent.  相似文献   

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