Effects of dietary oltipraz and ethoxyquin on aflatoxin B1 biotransformation in non-human primates.
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Following aflatoxin B1 (AFB) exposure, rats readily develop liver tumors. However, treatment of rats with a variety of compounds, including the synthetic dithiolthione oltipraz and the antioxidant ethoxyquin, protects these rodents from AFB-induced hepatocarcinogenesis. Several epidemiological studies strongly suggest that AFB is also a causative agent of liver cancer in humans. However, relatively little is known about the efficacy of cancer chemoprevention in human and non-human primates. To this end, we examined the effects of chemopreventive agents on AFB metabolism in non-human primates. Hepatic aflatoxin B1 metabolism profiles of macaque (Macaca nemestrina) and marmoset (Callithrix jacchus) monkeys were determined and compared to humans. Quantitatively, the oxidative metabolism of this mycotoxin was similar in the three primate species. In contrast to macaques, both humans and marmosets lacked AFB-glutathione conjugating activity. It was concluded that marmosets resembled human AFB metabolism more closely than the macaques, and therefore, marmoset monkeys were chosen for this study. Eleven adult male marmosets were randomly assigned to three groups. Animals received the synthetic dithiolthione oltipraz, the antioxidant ethoxyquin, or vehicle only. In addition, two single doses of AFB were also administered orally before and after animals were treated with aforementioned compounds. Both oltipraz and ethoxyquin induced aflatoxin B1-glutathione conjugating activity in the livers of some but not all marmosets. In addition, 10 microM oltipraz inhibited cytochrome P450-mediated activation of AFB to the ultimate carcinogenic metabolite, aflatoxin B1-8,9-epoxide, in vitro, up to 51%. Furthermore, animals treated in vivo with oltipraz, but not ethoxyquin, exhibited a significant reduction (53% average) in AFB-DNA adduct formation relative to the control animals (p < 0.05). Together, our data suggest that chemoprevention is also effective in primates; however, most likely to a lesser degree than in rodents. (+info)
Stability of hemoglobin and albumin adducts of benzene oxide and 1,4-benzoquinone after administration of benzene to F344 rats.
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The stability of cysteinyl adducts of benzene oxide (BO) and mono-S-substituted cysteinyl adducts of 1,4-benzoquinone (1,4-BQ) was investigated in both hemoglobin (Hb) and albumin (Alb) following administration of a single oral dose of 400 mg [U-14C/13C6]benzene/kg body weight to F344 rats. Total radiobound adducts to Hb were stable, as were adducts formed by the reaction of [13C6]BO with cysteinyl residues on Hb. In both cases adduct stability was indicated by zero-order kinetics with decay rates consistent with the lifetime of rat erythrocytes. Hb adducts of 1,4-BQ were not detected, possibly due to the production of multi-S-substituted adducts within the erythrocyte. Regarding Alb binding, total radiobound adducts decayed more rapidly than expected (half-life of 0.4 days), suggesting that uncharacterized benzene metabolites were noncovalently bound or formed unstable adducts with Alb. Although adducts from reactions of BO and 1,4-BQ with Alb both decayed with rates consistent with those of Alb turnover in the rat, the half-life for 1,4-BQ-Alb (2.5 days) was shorter than that for BO-Alb (3.1 days), suggesting some instability of 1,4-BQ-Alb. Assuming similar rates of adduct instability in humans and rats, the 1,4-BQ-Alb adducts would be eliminated with a half-life of approximately 8 days, compared with BO-Alb, which would be expected to turnover with Alb (half-life of approximately 21 days). (+info)
Organoid culture of cannulated rat resistance arteries: effect of serum factors on vasoactivity and remodeling.
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We developed an organoid culture technique to study the mechanisms involved in arterial remodeling. Resistance arteries were isolated from rat cremaster muscle and mounted in a pressure myograph at 75 mmHg. Vessels were studied during a 4-day culture period in DMEM with either 2% albumin, 10% heat-inactivated FCS (HI-FCS) or 10% dialyzed HI-FCS (12 kDa cut off) added to the perfusate. The albumin group showed a gradual loss of endothelial function and integrity, whereas smooth muscle agonist and myogenic responses were retained. No remodeling was observed. Vessels cultured in the presence of serum showed a progressive constriction. Smooth muscle responses and substance P-induced endothelium-dependent dilation were maintained. An inward remodeling of 17 +/- 4% in the HI-FCS group and 26 +/- 3% in the dialyzed HI-FCS group was found, while media cross-sectional areas were unchanged. These data show that pressurized resistance arteries can be maintained in culture for several days and undergo eutrophic remodeling in vitro in the presence of high molecular weight serum factors. (+info)
Surfactant function affected by airway inflammation and cooling: possible impact on exercise-induced asthma.
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Pulmonary surfactant maintains patency of narrow conducting airways. An inflammation, with a leakage of plasma proteins into the airway lumen, causes surfactant to lose some of this ability. Will a lowering of temperature aggravate the deteriorating effect of an inflammation? Calf lung surfactant extract (CLSE) with proteins added was studied with a capillary surfactometer (CS) at temperatures of 25-42 degrees C. BALB/c mice were infected with respiratory syncytial virus (RSV). Six days later the lungs were lavaged and the surfactant in the lavage fluid was studied with the CS at temperatures of 25-42 degrees C. Lavage fluid from allergen challenged asthmatics was examined for its content of surfactant inhibitors at reduced temperatures. It was shown that CLSE with proteins gradually lost its ability to maintain patency as the temperature was lowered. Lavage fluid from the RSV infected mice showed a similar dysfunction at low temperatures. Lavage fluid from the airways of human asthmatics, when challenged with antigen but not with saline, contained agents inhibiting surface activity, particularly at reduced temperatures. Airway inflammation causes surfactant to lose its ability to maintain patency, particularly as the temperature is reduced. That might be a reason for the increased airway resistance observed in asthma patients hyperventilating in cold weather. (+info)
IgG2 immunodeficiency: association to pediatric patients with bacterial meningoencephalitis.
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An IgG subclass deficiency is often associated with bacterial infections. We studied four pediatric patients suffering from meningoencephalitis, two of them due to Streptococcus pneumoniae and two due to Haemophilus influenzae type b. Simultaneous diagnostic serum and cerebrospinal fluid samples were taken during income. The four subclasses of IgG and albumin were quantified in both biologic fluids by radial immunodiffusion. Very low levels of seric IgG2 with non detectable cerebrospinal fluid IgG2 were found in the patients. No intrathecal IgG subclass synthesis was found in two patients. One patient with S. pneumoniae had IgG3 intrathecal synthesis. Intrathecal IgG1, IgG3 and IgG4 synthesis was found in one patient suffering from H. influenzae according with reibergrams. Substitutive therapy with intravenous gammaglobulin was given to the patients as part of the treatment. (+info)
Standard peritoneal permeability analysis in children.
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Peritoneal transport characteristics in children on peritoneal dialysis (PD) has been reported to be different compared to adults. However, various test methods can influence this difference. Thirty-one standard peritoneal permeability analyses (SPA) were performed in 18 PD children with a median (range) age of 9.8 yr (2 to 19) and a median duration of PD of 2.6 yr (0.19 to 6.8). The median mass transfer area coefficient (MTAC) for creatinine was 9.6 ml/min per 1.73 m(2) (4.4 to 18.0), and for urea 17.3 ml/min per 1. 73 m(2) (12.2 to 22.8). The median dialysate to plasma creatinine ratio (D/P(Cr)) was 0.69 (0.44 to 0.92), the glucose absorption 59% (23 to 75), and the D/D(0) for glucose 0.38 (0.23 to 0.62). The median clearance of beta(2)-microglobulin was 923 microl/min per 1. 73 m(2) (366 to 1828), of albumin 103 microl/min per 1.73 m(2) (55 to 211), of IgG 48 microl/min per 1.73 m(2) (20 to 105), and of alpha(2)-macroglobulin 12 microl/min per 1.73 m(2) (5 to 49). No correlation was found between these results and age or PD time. The restriction coefficient for macromolecules indeed increased with duration of PD treatment (r = 0.38, P = 0.03). The median transcapillary ultrafiltration rate was 1.2 ml/min per 1.73 m(2) (-0. 01 to 2.8), the net ultrafiltration rate 0.2 ml/min per 1.73 m(2) (-1.97 to 1.82), and the effective lymphatic absorption rate 1.04 ml/min per 1.73 m(2) (-0.06 to 2.91). When corrected for body surface area, no differences were found in peritoneal fluid and solute transport characteristics between children and adults. No effect of time on PD on the transport parameters was found in a cross-sectional analysis, except for an increase of the restriction coefficient to macromolecules. This finding is similar to observations in adults. Therefore, the present study showed no evidence for the common belief that the peritoneal membrane in children is different from that in adult patients. (+info)
Variable pulmonary responses from exposure to concentrated ambient air particles in a rat model of bronchitis.
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Chronic bronchitis may be considered a risk factor in particulate matter (PM)-induced morbidity. We hypothesized that a rat model of human bronchitis would be more susceptible to the pulmonary effects of concentrated ambient particles (CAPs) from Research Triangle Park, NC. Bronchitis was induced in male Sprague-Dawley rats (90-100 days of age) by exposure to 200 ppm sulfur dioxide (SO2), 6 h/day x 5 days/week x 6 weeks. One day following the last SO2 exposure, both healthy (air-exposed) and bronchitic (SO2-exposed) rats were exposed to filtered air (three healthy; four bronchitic) or CAPs (five healthy; four bronchitic) by whole-body inhalation, 6 h/day x 2 or 3 days. Pulmonary injury was determined either immediately (0h) or 18 h following final CAPs exposure. The study protocol involving 0 h time point was repeated four times (study #A, November, 1997; #B, February, 1998; #C and #D, May, 1998), whereas the study protocol involving 18 h time point was done only once (#F). In an additional study (#E), rats were exposed to residual oil fly ash (ROFA), approximately 1 mg/ m(3)x6 h/day x 3 days to mimic the CAPs protocol (February, 1998). The rats allowed 18 h recovery following CAPs exposure (#F) did not depict any CAPs-related differences in bronchoalveolar lavage fluid (BALF) injury markers. Of the four CAPs studies conducted (0 h time point), the first (#A) study (approximately 650 microg/m3 CAPs) revealed significant changes in the lungs of CAPs-exposed bronchitic rats compared to the clean air controls. These rats had increased BALF protein, albumin, N-acetyl glutaminidase (NAG) activity and neutrophils. The second (#B) study (approximately 475 microg/m3 CAPs) did not reveal any significant effects of CAPs on BALF parameters. Study protocols #C (approximately 869 microg/m3 CAPs) and #D (approximately 907 microg/m3 CAPs) revealed only moderate increases in the above mentioned BALF parameters in bronchitic rats exposed to CAPs. Pulmonary histologic evaluation of studies #A, #C, #D, and #F revealed marginally higher congestion and perivascular cellularity in CAPs-exposed bronchitic rats. Healthy and bronchitic rats exposed to ROFA (approximately 1 mg/m3) did not show significant pulmonary injury (#E). Analysis of leachable elemental components of CAPs revealed the presence of sulfur, zinc, manganese, and iron. There was an apparent lack of association between pulmonary injury and CAPs concentration, or its leachable sulfate or elemental content. In summary, real-time atmospheric PM may result in pulmonary injury, particularly in susceptible models. However, the variability observed in pulmonary responses to CAPs emphasizes the need to conduct repeated studies, perhaps in relation to the season, as composition of CAPs may vary. Additionally, potential variability in pathology of induced bronchitis or other lung disease may decrease the ability to distinguish toxic injury due to PM. (+info)
Alpha-1-antitrypsin content in the serum, alveolar macrophages, and alveolar lavage fluid of smoking and nonsmoking normal subjects.
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The content of alpha-1-antitrypsin in the serum, alveolar lavage fluid, and alveolar macrophages of smokers and nonsmokers was studied. Bronchoalveolar lavage was used to obtain alveolar fluid and macrophages from normal volunteers, and alpha-1-antitrypsin and albumin were measured using the electroimmunodiffusion technique. The serum level of inhibitor was not different between the two groups, while the total lavage fliud content of alpha-1-antitrypsin was increased in the smokers. The level of alpha-1-antitrypsin was also significantly greater (P less than 0.001) in the alveolar macrophages of the smokers suggesting the possibility of chronically increased alveolar levels in the cigarette smoker as a possible protective mechanism against proteolysis. (+info)