DISTRIBUTION AND ACCUMULATION OF A MIXTURE OF ARSENIC,CADMIUM, CHROMIUM,NICKEL, AND VANADIUM IN MOUSE SMALL INTESTINE,KIDNEYS, PANCREAS,AND FEMUR FOLLOWING ORAL ADMINISTRATION IN WATER OR FEED

Manufactured gas plant (MGP) sites are contaminated with coal tar and may contain metals such as arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), and vanadium (V). These metals are known to cause cancer or other adverse health conditions in humans, and the extent and cost of remediating MGP sites may be influenced by the presence of these metals. Studies assessed the distribution of these metals in female B6C3F1 mice ingesting (1) a metal mixture in water or (2) an MGP mixture in NIH-31 feed. The highest metal levels were measured in the small intestine and kidneys of mice receiving the metal mixture in water. For mice receiving the metal mixture in water, levels of As, Cd, and Cr, in the small intestine, levels of As, Cd, Cr, and V in the kidneys, levels of As and Cd in the pancreas, and levels of Cr and V in the femur were significantly greater than controls at 4, 8, 12, 16, and 24 wk. Except for Ni levels in the small intestine and femur and Cr levels in the kidneys, levels of metals were much lower in mice administered the MGP mixture in feed. The highest concentrations of metals in mice ingesting the MGP mixture in feed were found in the small intestine and kidneys, but few were significantly greater than controls. Levels of As in the small intestine at 6 and 18 wk and levels of Cr in the kidneys at 12, 18, and 24 wk were significantly greater than in controls. The data suggest that tissue burdens in small intestine, kidneys, pancreas, and femur of arsenic, cadmium, chromium, and vanadium are less when metals are present as an MGP mixture in feed than as a mixture in water. The reduced distribution and accumulation of metals in the organs of mice ingesting the MGP mixture in feed compared to the levels in organs of mice ingesting the metal mixture in water suggests that metals may be less likely to accumulate in humans ingesting MGP mixtures, thereby presenting a lower overall human health risk. The data presented indicate that the matrix in which metals are present will affect the uptake of individual metals and the organ specificity.     

Distribution and accumulation of a mixture of arsenic,cadmium, chromium,nickel, and vanadium in mouse small intestine,kidneys, pancreas,and femur following oral administration in water or feed

Manufactured gas plant (MGP) sites are contaminated with coal tar and may contain metals such as arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni), and vanadium (V). These metals are known to cause cancer or other adverse health conditions in humans, and the extent and cost of remediating MGP sites may be influenced by the presence of these metals. Studies assessed the distribution of these metals in female B6C3F1 mice ingesting (1) a metal mixture in water or (2) an MGP mixture in NIH-31 feed. The highest metal levels were measured in the small intestine and kidneys of mice receiving the metal mixture in water. For mice receiving the metal mixture in water, levels of As, Cd, and Cr, in the small intestine, levels of As, Cd, Cr, and V in the kidneys, levels of As and Cd in the pancreas, and levels of Cr and V in the femur were significantly greater than controls at 4, 8, 12, 16, and 24 wk. Except for Ni levels in the small intestine and femur and Cr levels in the kidneys, levels of metals were much lower in mice administered the MGP mixture in feed. The highest concentrations of metals in mice ingesting the MGP mixture in feed were found in the small intestine and kidneys, but few were significantly greater than controls. Levels of As in the small intestine at 6 and 18 wk and levels of Cr in the kidneys at 12, 18, and 24 wk were significantly greater than in controls. The data suggest that tissue burdens in small intestine, kidneys, pancreas, and femur of arsenic, cadmium, chromium, and vanadium are less when metals are present as an MGP mixture in feed than as a mixture in water. The reduced distribution and accumulation of metals in the organs of mice ingesting the MGP mixture in feed compared to the levels in organs of mice ingesting the metal mixture in water suggests that metals may be less likely to accumulate in humans ingesting MGP mixtures, thereby presenting a lower overall human health risk. The data presented indicate that the matrix in which metals are present will affect the uptake of individual metals and the organ specificity.     

The distribution patterns of trace elements in the blood and organs in a rabbit experimental model of copper pollution and study of haematology and biochemistry parameters

In a rabbit model of five copper overfeeding, we investigated the distribution pattern of trace elements of copper [Cu], zinc [Zn], chromium [Cr], manganese [Mn], and selenium [Se] in blood serum, red cell, and whole blood and in the organs: brain, gallbladder, liver, intestines, heart, kidney, lung, and spleen. Furthermore, their haematology and biochemistry parameters as well as feed consumption and weight development were also performed in this study. Changes in trace element concentrations were determined by contrast and control group. Observably, the increased concentrations of Cr were observed in the heart; that of Cu, Zn, Cr, Mn in the liver; that of Cu, Cr, Mn in the intestines; that of Cu in the spleen; that of Cu in the blood serum; and that of Cu in the whole blood. But remarkably, the decreased concentrations of Mn were observed in heart; that of Zn and Se in the encephalon; that of Cr, Mn and Se in the spleen and that of Zn in the blood serum. In the gallbladder, the concentrations of Zn, Cr, Mn, and Se were also reduced. Excessive Cu was accumulated mainly in liver, intestines, and blood serum. In contrast group, only a few changes were detected in excretion of Mn, Zn, and Cr, but increased concentrations of Cu and Se compared with the control group. For the different biochemistry parameters measured, the contrast group showed changes, mainly owing to the altered activity of enzymes induced by trace element excess and imbalance. Increased concentrations of LDL were measured in contrast group, while a substantial decrease was seen in TG and VLDL as a result of excessive Cu. Regarding haematological parameters, increased concentrations of NEUT% and EO% were found in contrast group, but considerably decreased concentrations were detected in PLT, MONO%, BASO%, MONO#, BASO#, and P-LCR, but a minor decrease was also seen in EO#. The present paper shows the effect of copper pollution in the animals and analyzes the interplay among trace elements in their bodies at length. It is significant for environment protection and toxicology study.     

Distribution of 14C-pethidine in the blood of certain species

Binding of 14C-pethidine to erythrocytes of some species, particularly human, rat and rabbit, was examined in two different concentrations. This binding was investigated by direct measurement of the relative representation in erythrocytes, plasma proteins and the free fraction in blood. In the case of human erythrocytes the relative representation was 33%, in the rat ones 44%, and in the rabbit ones 54%. The fraction bound to plasma proteins was 45% in man, 29% in rats, and 27% in rabbits. The portion of the free fraction was 22% in man, 27% in rats, and 19% in rabbits. The ratio of the concentrations of the fraction bound to erythrocytes and the fraction free in the blood was 1.72 in man, 2.09 in rats, and 3.92 in rabbits. On the basis of these results it can be concluded that binding of pethidine to erythrocytes does not play an insignificant part in total pharmacokinetics of pethidine.     

Regional haemodynamic responses to infusion of lipopolysaccharide in conscious rats: effects of pre- or post-treatment with glibenclamide

1. To determine the putative contribution of K(ATP)-channels to the haemodynamic sequelae of endotoxaemia, three experiments were carried out in different groups of conscious, chronically-instrumented, unrestrained, male Long Evans rats. 2. In the first experiment, pretreatment with the K(ATP)-channel antagonist, glibenclamide, abolished the initial hypotension, but not the renal vasodilatation caused by LPS infusion. Subsequently, however, in the presence of glibenclamide and LPS there was a significant increase in mean arterial blood pressure, and a bradycardia, in contrast to the fall in mean arterial blood pressure and the tachycardia seen in the presence of vehicle and LPS. The pressor and bradycardic changes in the presence of glibenclamide and LPS were accompanied by significant reductions in hindquarters flow and vascular conductance, and these were significantly greater than those seen in the presence of vehicle and LPS, or glibenclamide and saline. 3. Administration of glibenclamide 6 h after the onset of saline and LPS infusion, or 6 h after the onset of saline and LPS infusion in the presence of the AT(1)-receptor antagonist, losartan, and the ET(A)-, ET(B)- receptor antagonist, SB 209670, in the absence or presence of dexamethasone, caused a significant increase in mean arterial blood pressure and reductions in renal, mesenteric and hindquarters conductances, although the latter was the only vascular bed in which there was a reduction in flow. 4. The results are consistent with a contribution from K(ATP)-channels to the vasodilatation caused by LPS, particularly in the hindquarters vascular bed.     

Valproate-dependent changes in the spectrum of free amino acids in rats: l-carnitine effects

The effect of L-camitine (LC) in a dose of 100 mg/kg on the spectrum of free amino acids in the tissues and blood plasma was studied in rats pretreated for 8 days with valproic acid (VA) in a dose of 200 mg/kg. The VA treatment led to a decrease in the concentration of Ser, Gln, and Ala in the blood plasma and of Gln, Cys, Phe, and His in the liver, and to an increase in the level of Tau, Thr, Gly, alpha-Aba, Ile, and Tyr in the liver. In the rat brain, the concentration of PEA, urea, Ile, Val, Tyr, Phe, and alpha-Aba increased, while the Orn level decreased. The introduction of LC led to correction of the dysbalance of free amino acids, whereby the levels of Asp, Ctn, and Orn in the blood plasma and the levels of Cys and Tyr in the liver were increased, while the levels of Thr, Cly, alpha-Aba, and Ile in the liver and the levels of alpha-Aba, Val, and Phe in the brain were decreased. The character of variation of the spectrum of free amino acids and their derivatives in the tissues and blood plasma of rats confirms the toxicity of VA and shows the ability of LC to normalize (to a certain extent) the balance violated by the VA-induced LC insufficiency.     

中青年血清胆红素轻度增高者胆红素与血糖、血脂及血压的关系

目的观察中青年血清胆红素轻度增高者血糖、血脂及血压水平。方法中青年男女556人,高胆红素组296人,对照组260人。测定两组研究对象血清总胆红素、直接胆红素、空腹血糖、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇及血压并对数据进行分析。结果男性胆红素高于女性,差异有统计学意义（P〈0．01）。高胆红素组空腹血糖低于对照组,男性二组差异有统计学意义（P〈0．01）,女性二组差异无统计学意义（P〉0．05）。高胆红素组收缩压低于对照组,但差异无统计学意义（P〉0．05）,舒张压高于对照组,且差异有统计学意义（P〈0．05）。高胆红素组男性总胆固醇、甘油三酯高于对照组,高及低密度脂蛋白胆固醇低于对照组,其中高密度脂蛋白胆固醇与对照组差异有统计学意义（P〈0．05）。高胆红素组女性总胆固醇、甘油三酯、高与低密度脂蛋白胆固醇均高于对照组,但差异无统计学意义（P〉0．05）。空腹血糖与男性总胆红素、直及间接胆红素和女性直接胆红素负相关。舒张压与男性总胆红素及直接胆红素和女性总胆红素及间接胆红素正相关;收缩压与男性胆红素不相关,与女性直接胆红素负相关。男性低密度脂蛋白胆固醇、女性总胆固醇、腰围与直接胆红素负相关。男性腰围与总胆红素、间接胆红素正相关。结论胆红素不同形式对空腹血糖均有影响,中青年阶段空腹血糖随着胆红素的增高而降低。胆红素对中青年男女舒张压的维持有一定作用,对收缩压的影响有性别差异,女性胆红素较高者,舒张压较低。中青年男女在高胆红素水平时有较少的心脑血管危险因素。     

Tissue-specific regulation of insulin-like growth factors and insulin-like growth factor binding proteins in male diabetic rats in vivo and in vitro

1. Insulin-like growth factors (IGFs) are associated with the development of diabetes mellitus. The liver, kidney and heart have been implicated as important organs in the onset of diabetes mellitus. However, the effect of diabetes on the IGF system in these organs has not been fully described. Thus, we investigated changes in IGF-I, IGF-II and IGF binding proteins (IGFBPs) in male steptozotocin-induced diabetic rats, as well as in a high glucose-induced in vitro model. 2. Serum levels of IGF-I were decreased, but the levels of IGF-II were increased, in diabetic rats compared with controls. The expression of IGFBP-3 in the serum was markedly decreased; in contrast, the expression of IGFBP-1 and -2 was increased in diabetic rats. The expression of IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-4 in the liver of the diabetic group was similar to that in the serum of diabetic rats. 3. In heart tissue of the diabetic group, IGF-I levels were decreased, but IGF-II levels were increased. In addition, the expression of IGFBP-3, IGFBP-1 and IGFBP-2 was decreased in diabetic rats. 4. In the kidney of the diabetic group, IGF-I and IGF-II levels were increased. There was only slight expression of IGFBP-3 in the kidney and this was not altered in diabetic rats. Levels of IGFBP-1 and -2 were markedly increased in the kidney of diabetic rats. 5. Insulin treatment recovered the changes in expression of IGF-I, IGF-II and IGFBPs in the serum, liver, heart and kidney. In the liver, heart and kidney, the expression of the insulin receptor was increased in male diabetic rats. 6. In conclusion, diabetes tissue-specifically alters the IGF system in the liver, heart and kidney in rats; this effect can be recovered by insulin treatment.     

Subacute toxicity evaluation in rats exposed to concrete and hwangto building environments

This study examined the potential adverse effects of the subacute exposure of rats to concrete and hwangto building environments. Polycarbonate was used as a comparison. Groups of 10 male rats were exposed to polycarbonate, concrete, or hwangto cages for a 4-week period in summer or winter. During the study period, the clinical signs, mortality, skin temperature, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were examined. The concentration of total volatile organic compounds (VOCs), temperature, and relative humidity in the each cages were also measured. There were no exposure-related effects in any group of the study examined in the summer. The temperature, relative humidity, and the concentration of VOCs in the cages were similar in all groups. However, in the winter study, significant differences in several parameters were detected among the groups. In the concrete group, there was an increase in the clinical signs, a reduction in the body weight gain, food intake, and liver weight, an increase in the lung weight, and an increase in the histopathological alterations in the lung and thymus. Infrared thermal analysis showed that the skin temperature of the rats in the concrete group was lower than that in the polycarbonate group. However, in the hwangto group, there was a decrease in the clinical signs and an increase in the body weight, food intake, and the weights of the heart, lung, spleen, and epididymides. Overall, the 4-week exposure of the rats to the concrete building environment had adverse effects on the clinical signs, skin temperature, body weight, and some organs in the winter but not in the summer. On the other hand, the exposure of hwangto building environment did not have any exposure-related adverse effects on the general health parameters and skin temperature in rats.     

Preparation of Alendronate Liposomes for Enhanced Stability and Bioactivity: In Vitro and In Vivo Characterization

Liposomes containing bisphosphonates have been shown to deplete circulating monocytes and reduce experimental restenosis. However, acceptable shelf life was not achieved, and the disruption extent and rate of the vesicles in the circulation has not been examined. Designing an optimal liposomal formulation in general, and for an anti-inflammatory effect in particular, requires careful consideration of the factors that contribute to their in vitro stability and integrity in the blood after injection. An improved liposomal alendronate formulation was prepared by a modified thin lipid film hydration technique followed by extrusion, resulting in relatively smaller size vesicles, narrow size distribution, and low drug to lipid ratio in comparison to the reverse phase evaporation method. In order to rule out premature leakage of the drug, the integrity of the vesicles was examined by means of size-exclusion chromatography in vitro and in vivo, with subsequent analysis of size, drug (fractions of encapsulated and free) and lipid concentrations. Vesicles were found to be stable in serum, with 15 +/- 3% leakage of the drug after 10 min in rabbit's circulation, and intact liposomes were detected in the circulation 24 h following administration. It is concluded that the new formulation results in increased stability (2.5 years) as determined by the insignificant changes in vesicle size, drug leakage, lipid and drug stability, in vitro bioactivity (macrophages inhibition), as well as in vivo in depleting circulating monocytes and inhibition of restenosis in rabbits. Our in vitro stability results regarding dilution in serum paralleled in vivo data. Thus, in vitro assessment may provide a valuable tool in assessing in vivo integrity of liposomal formulations.     

EFFECT OF SECRETAGOCUES ON PANCREATIC EXOCRINE SECRETION IN THE MONKEY AND THE DOG

The effects of secretin, cholecystokinin, dopamine, histamine and acetylcholine on the secretion of pancreatic juice were investigated in the monkey and the dog. In the resting state, bicarbonate concentration and the volume of pancreatic juice in the monkey were greater than those in the dog. However, the protein concentration of pancreatic juice in the monkey was less than that in the dog. Intravenous administration of secretin, cholecystokinin, histamine and acetylcholine caused a dose dependent increase in pancreatic secretion in both species. The responses in the monkey were greater than those in the dog. Dopamine caused pancreatic secretion only in the dog. The increase in bicarbonate concentrations of pancreatic juice induced by secretin and histamine in the monkey were greater than that in the dog. Increase in protein concentrations of the juice induced by cholecystokinin and acetylcholine in the monkey were less than that in the dog. However, pancreatic juice pH in both species was the same and was not affected by the secretagogues in the resting state or during the stimulation by secretogogues. From these results, it is concluded that there is a species difference in the secretory actions of the secretagogues in the monkey and the dog.     

Effect of enflurane on selected neuropeptides and marker enzymes in rabbit brain

The aim of this study was to evaluate the effect of 5-, 15-, and 60-min enflurane anesthesia on the levels of Met-enkephalin, Leu-enkephalin and neuropeptide Y in discrete areas of the rabbit brain. We also evaluated the effect of enflurane anesthesia on energetic, transport and catabolic processes by measuring the activities of succinate dehydrogenase, magnesium-dependent adenosine triphosphatase and acid phosphatase in the rabbit striatum and hypothalamus. Induction of anesthesia (5 min) decreased Met-enkephalin levels in the hypothalamus and striatum, and increased them in the hippocampus and mesencephalon. Induction of anesthesia increased Leu-enkephalin levels in all brain areas studied, except for the striatum, and increased neuropeptide Y content in the hippocampus. 15- and 60-min enflurane anesthesia increased Met-enkephalin content in the hypothalamus and hippocampus. After 15- and 60-min anesthesia, and after cessation of anesthesia, Leu-enkephalin levels were increased in the hypothalamus and mesencephalon, and were decreased in the striatum and hippocampus. In the striatum, neuropeptide Y content was significantly decreased during anesthesia and after cessation of anesthesia. Histochemical analysis revealed that enflurane enhanced ATP production, catabolic processes, and the rates of exchange and transport of energetic substrates in the striatum and hypothalamus. In conclusion, enflurane affects the levels of Met, Leu-enkephalins and NPY in a manner depending on the duration of anesthesia and the brain structure. Compared with isoflurane , which was studied in our previous study enflurane produces stronger alterations in the activities of enzymatic marker in the rabbit brain. This suggests that enflurane may be less safe than isoflurane.     

Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats

RATIONALE: Sex differences in the antinociceptive effects of opioids have been reported in a variety of nociceptive assays, and it has been postulated that these differences are mediated by gonadal hormones. OBJECTIVES: The present study examined the influence of gonadectomy on opioid antinociception in male and female rats. METHODS: In a warm-water, tail-withdrawal procedure, the antinociceptive effects of the high-efficacy micro opioids etorphine and morphine; the low-efficacy micro opioids buprenorphine and dezocine; and the low-efficacy, mixed-action opioids butorphanol and nalbuphine were examined in intact and gonadectomized rats of the F344 and Sprague Dawley (SD) strains. RESULTS: The opioids examined were generally more potent in producing an antinociceptive effect in intact males than intact females, with larger sex differences observed with the less-effective opioids. In F344 males, gonadectomy produced small decreases in the potency of etorphine and morphine, and large decreases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. Similar effects were obtained in SD males, with gonadectomy decreasing the potency of each of the opioids tested. In F344 females, gonadectomy produced small increases in the potency of etorphine and large increases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. A similar effect was obtained in SD females, as gonadectomy increased the potency of etorphine, morphine, and buprenorphine. In both sexes, gonadectomy had a greater effect in F344 than SD rats. CONCLUSIONS: These findings suggest that gonadectomy decreases opioid antinociception in male rats and increases opioid antinociception in female rats. Additionally, the influence of gonadectomy on opioid antinociception appears to be determined by the relative effectiveness of the opioid tested and the rodent strain used.     

Pharmacokinetic study of rifampicin in biliary surgery

Following the oral administration of 600 mg rifampicin, the concentration of antibiotic in serum, bile of the gallbladder and choledochus, cholecystic wall, and hepatic tissue was determined with the agar diffusion method in 23 patients undergoing surgery for cholelithiasis. After 80-340 minutes the average rifampicin concentration was 6.4 microgram/ml in serum, 78.4 microgram/ml in the bile of the gallbladder, 91.6 microgram/ml in the bile of the choledochus, 4.0 microgram/g in the cholecystic wall, and 23.3 microgram/g in the hepatic tissue. After 24 hours the level was significantly reduced in the serum and hepatic tissue. The rifampicin level in the bile of the gallbladder was twelvefold, in the bile of the choledochus fourteenfold, in the cholecystic wall 61.1% and in the hepatic tissue 364% of the serum level. In general, the rifampicin concentration obtainable in the bile and hepatic tissue is sufficient against bacterial strains causing infections of the biliary duct, and for this reason rifampicin will play in the future an important role in the treatment of infections of the biliary duct.     

Species differences in vacuolation of the choroid plexus induced by the piperidine-ring drug disobutamide in the rat, dog, and monkey

A subchronic oral toxicity study of disobutamide, a piperidine ring compound with antiarrhythmic activity, was conducted at doses of 30, 100, and 250 mg/kg in rats, 45 mg/kg in dogs, and 90 mg/kg in monkeys. Numerous vacuoles were observed in various organs such as the liver, kidneys, heart, lungs, spleen, thymus, stomach, and choroid plexus in these animals. The epithelium of the choroid plexus (CP), however, showed severe vacuolation in rats and monkeys but not in dogs. The vacuoles corresponded to enlarged and myelin-figured lysosomes observed by electron microscopy, revealing morphological characteristics which have been reported as drug-induced phospholipidosis. In a further study, the drug penetration to cerebrospinal fluid (CSF) and the drug concentration in CP were examined in these animals. Daily po doses of 250, 45, and 90 mg/kg were, respectively, administered to rats, dogs, and monkeys to maintain approximate equivalency in peak blood concentrations across species, over a course of 35 days. The concentration of the drug in the CP was higher in rats and monkeys than in dogs, and the CSF/serum ratio of the drug concentration was extremely high in rats. The uptake of the drug by the CP in vitro was high in rats, monkeys, and dogs, in this order. In dogs, both direct contact of the drug with the CP during incubation and intraventricular administration induced vacuolation in the epithelium. From these results it was concluded that differences of the drug's penetration into the CSF and its uptake by the choroid plexus epithelium are responsible for the species differences of CP vacuolation in the animals.     

Dimethylarsinic acid: results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice

Dimethylarsinic acid (DMA(V), cacodylic acid), a foliar herbicide, was administered in the diet to B6C3F1 mice (at dose levels of 0, 8, 40, 200, and 500 ppm) and to F344 rats (at dose levels of 0, 2, 10, 40, and 100 ppm) for 2 years, according to US EPA guidelines. In mice, there were no treatment-related tumors observed at any site. Treatment-related progressive glomerulonephropathy and nephrocalcinosis were observed in the kidneys in both sexes. The incidence of vacuolation of the epithelium in the urinary bladder was increased in both sexes, but was not associated with cytotoxicity, necrosis or hyperplasia. Based on non-neoplastic lesions found in the urinary bladder, the NOEL for mice was assessed to be 40 ppm in males and 8 ppm in females. In rats, treatment-related mortality occurred early in the study in five males in the 100 ppm group and in one male in the 40 ppm group. Papillomas and carcinomas with degeneration of the urothelium, necrosis and urothelial cell hyperplasia, were found in the urinary bladders of both sexes. In male rats, one papilloma was found in each of the 10 and 40 ppm groups; one urothelial cell carcinoma was found in the 2 ppm group and two in the 100 ppm group. Four papillomas and six urothelial cell carcinomas were found in the female 100 ppm group. Non-neoplastic treatment-related kidney lesions were confined to the 40 and 100 ppm levels and included necrosis, pyelonephritis, medullary nephrocalcinosis and tubular cystic dilation, hyperplasia of the epithelial lining of the papilla, and pelvic urothelial cell hyperplasia. All of these kidney changes appear to be related to an increase in the aging nephropathy of the rat. Dose-related increases in the height of the thyroid follicular epithelium were also noted in males and females, however, such changes reflect an adaptive response of the thyroid to decreased levels of circulating thyroid hormone, rather than an adverse effect. Based on the kidney and bladder lesions, the NOEL for non-neoplastic and neoplastic lesions was considered to be 10 ppm in males and females. Based on these studies, DMA(V) is carcinogenic only in rats and only at relatively high doses, with the urinary bladder as the target organ. Female rats appear to be more sensitive to the effects of DMA(V) than male rats. DMA(V) is not carcinogenic in mice.     

Species differences in the metabolism of suprofen in laboratory animals and man

The metabolism of the oral anti-inflammatory agent suprofen (S), 2-4-(2-thienylcarbonyl)phenyl)propionic acid, has been studied in mice, rats, guinea pigs, dogs, monkeys, and human volunteers. The major metabolites of S in the serum, urine, and feces of these species were determined by GC/MS and HPLC techniques. The metabolic pathways of S in these species involved reduction of the ketone group to an alcohol (S-OH), hydroxylation of the thiophene ring (T-OH), elimination of the thiophene ring to a dicarboxylic acid (S-COOH), and conjugation with glucuronic acid or taurine. In 72-hr urine and feces of these species after po dosing of 1.6 to 2 mg/kg of S, S and these metabolites accounted for 46 to 92% of the dose and were mainly excreted in the urine. S was present as a major product (excreted mainly in conjugated form) in all species. S-OH was a major component in guinea pig and dog but a minor one in other species. T-OH was identified as a major metabolite in monkey, rat, mouse, and man, but a minor one in guinea pig, and it was absent in the dog. S-COOH was present as the minor metabolite in mouse and rat, and present at trace levels in dog, monkey, and man. Conjugation of the propionic acid functionality with taurine was observed only in the dog; in the other species, conjugation with glucuronic acid was extensive. Absorption parameters of S in the rat and monkey were similar to those in man; however, other species were very different from man.     

Immunocytochemical localization of cytochrome P-450 in hepatic and extra-hepatic tissues of the rat with a monoclonal antibody against cytochrome P-450 c

The cellular distribution of cytochrome P-450 has been studied in the liver and a number of extrahepatic tissues in the rat by immunocytochemistry, using an antibody raised against cytochrome P-450 form c. Immunoreactive cytochrome P-450, most probably form c, was found in the proximal tubules of the kidney, in the Clara cells of the lung, and in the olfactory epithelium and Bowman's glands of the olfactory tissue, in addition to its location in the liver. Immunoreactive cytochrome P-450 was not found in the small intestine, the testes or the adrenal gland, although these organs are known to contain isoenzymes of cytochrome P-450. The use of antibody titration enabled the effects of phenobarbitone, beta-naphthoflavone and clofibrate on the content and distribution of immunoreactive cytochrome P-450 to be studied in both the liver and in the other organs discussed. Phenobarbitone induces epitope-specific cytochrome P-450 in the centrilobular cells of the liver but has no effect in any of the other tissues studied. Clofibrate is without effect on the levels of immunoreactive cytochrome P-450 in any of the tissues studied. In contrast, beta-naphthoflavone induces immunoreactive cytochrome P-450 in the periportal region of the liver, and also in the Clara cells of the lung, in the enterocytes of the small intestine and in the proximal tubules of the kidney. Of all of the tissues studied, in which immunoreactive cytochrome P-450 could be detected, only the olfactory epithelium failed to undergo enzyme induction following treatment with beta-naphthoflavone.     

腺苷和虫草素在北虫草子实体各部位中的分布及含量

目的研究腺苷和虫草素在北虫草子实体各部位中的分布和总含量。方法用RP-HPLC法分别测定北虫草子实体头部、中部、底部及全部子实体中腺苷和虫草素含量。结果①1号样腺苷和虫草素的含量顺序为头部>底部>中部;总量顺序为中部>头部>底部。2号样腺苷分布规律没有明显变化,但各部位虫草素含量均有所改变,顺序为底部>中部>头部,总量顺序仍为中部>头部>底部。②两种样品的腺苷总含量没有明显差异,但2号样虫草素含量几乎是1号样的2倍。结论北虫草子实体各部位中腺苷和虫草素的分布以及总含量均有明显不同。     

Temporal variations in microsomal lipid peroxidation and in glutathione concentration of rat liver.

The temporal variation in the NADPH-dependent lipid peroxidation and glutathione-S-transferase activity and in the concentration of cytosolic and microsomal proteins and in reduced glutathione of rat liver were investigated at 0100, 0500, 0900, 1300, 1700, and 2100 in male Sprague-Dawley rats synchronized to a 12-hr light-dark cycle. Highly significant time-dependent variations were obtained in the microsomal rate of lipid peroxidation, and in the concentration of reduced glutathione and cytosolic and microsomal protein. The maximal mean values for the lipid peroxidation, for the concentration of reduced glutathione, and of cytosolic and microsomal proteins were obtained at 1300, 0900, 0100 and 2100, respectively, whereas the corresponding minimal values were determined at 0100, 1700, 0900, and 1700. There was no temporal variation in the glutathione-S-transferase activity of rat liver. The temporal variation in microsomal peroxidation and in the concentration of reduced glutathione exhibited a characteristic circadian rhythm. There was no reverse relationship between the daily variation in the rate of microsomal lipid peroxidation and the hepatic concentration of reduced glutathione.