Liver and biliary levels of glutathione and thiobarbituric acid reactants after acute lindane intoxication

The i.p. administration of 60 mg kg-1 body weight of lindane, the gamma-isomer of hexachlorocyclohexane, to fed rats led to an enhancement of hepatic lipid peroxidation after 24 h of treatment. This was evidenced by significant increases in the hepatic production and biliary release of thiobarbituric acid reactive substances, and in the biliary release of glutathione disulphide. Under these conditions, the content of cytochrome P450 was enhanced concomitantly with increases in the total microsomal oxygen uptake, superoxide radical generation and (+)-catechin (cyanid-3-ol) sensitive respiration. The glutathione status of hepatocytes was altered by lindane as the content and biliary release of glutathione disulphide was drastically augmented, leading to a decrease in the cellular and biliary GSH/GSSG ratios. It is suggested that lindane treatment leads to an induced oxidative capacity, which, in turn, alters the glutathione status of the liver tissue.     

Glucose and lactate kinetics in the neonate.

To evaluate the ontogeny of neonatal glucose homeostasis, glucose production and lactate production have been measured in nine prematurely born appropriate for gestational age neonates [birth weight 1985 +/- 100 g, (SEM) gestational age 33.6 +/- 0.7 weeks] and five full term appropriate for gestational age neonates [birth weight 3254 +/- 111 g, gestational age 40.8 +/- 0.4 wks] and compared to six non pregnant, nondiabetic adults [weight of 57.7 +/- 2.2 kg, age 32 +/- 2 years]. Ra glucose (preterm) averaged 27.7 +/- 2.8 mumol.kg-1 min-1 (5.0 +/- 0.5 mg.kg-1 min-1) and Ra glucose (term) averaged 28.9 +/- 3.9 mumol.kg-1 min-1 (5.2 +/- 0.7 mg.kg-1 min-1); both were higher than the Ra glucose of the adult controls (16.1 +/- 2.8 mumol.kg-1 min-1 (2.9 +/- 0.5 mg.kg-1 min-1) (P less than 0.05 vs preterm and P less than 0.05 vs. term). Ra lactate (preterm) averaged 100 +/- 11.9 mumol.kg-1 min-1 (9.1 +/- 1.1 mg.kg-1 min-1) and Ra lactate (term) average 77.2 +/- 13.0 mumol.kg-1 min-1 (7.1 +/- 1.2 mg.kg-1 min-1); both were higher than the Ra lactate of the adult controls 35.9 +/- 6.5 mumol.kg-1 min-1 (3.3 +/- 0.6 mg.kg-1 min-1) (P less than 0.01 vs preterm and P less than 0.05 vs. term). The potential for gluconeogenesis from lactate was estimated by determining the ratio of [Ra Lactate/Ra Glucose]. The [Ra Lactate/Ra Glucose] (preterm) (187 +/- 12 (x10(-2)) was similar to that of the [Ra Lactate/Ra Glucose] (term) (136 +/- 16) (x10(-2)).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of high temperature on the enzyme activity of the small intestine in thyroidectomized rats]

It was revealed in acute experiments that exposure to high temperature changed the invertase, dipeptidase, lipolytic and alkaline phosphatase activity of the small intestinal mucosa in rats. The direction of these changes and their degree differed in the thyroidectomized and sham-operated animals. It is suggested that the thyroid hormones took part in the reaction of the fermentative systems of the small intestine to the action of the thermal factor.     

阿特拉津和林丹对紫贻贝生长与繁殖净能的影响

本研究评估了亚致死浓度的林丹(1/2的60dLC50,0.935mg/L)和阿特拉津(1/2的60dLC50,3.585mg/L)对海洋性贝类影响的生理学反应。林丹和阿特拉津是已被公认的环境污染物质。56d的实验表明,这两种农药在贝类体内具有积累作用,而且在体内各器官的积累程度与其作用的靶器官相一致。林丹在体内的积累浓度(每克干重372μg)比阿特拉津(每克干重137μg)更高。该贝类在林丹中暴露56d,其氧的消耗比对照组降低10%,而在阿特拉津中则比对照组提高了29%。经林丹和阿特拉津暴露后,增加了氨排泄物。但是,两种农药均使贝类的取食率和吸收率下降。林丹会降低贝类的取食率、氧消耗、氨排泄、食物吸收率以及生长范围。在形式上,阿特拉津对贝类的影响与林丹的影响有不同之处,它会降低贝类的取食率和食物吸收率,但与林丹不同的是,它会提高贝类的氧消耗和氨排泄。总之,阿特拉津会明显地减小贝类繁殖净能。因此,阿特拉津暴露与林丹暴露的毒性症状是一致的。结合组织化学分析,贝类的生理学反应可作为一种理想的环境监测工具。研究结果表明,在二分之一的半致死浓度下暴露两个月,不仅能有效地证明林丹和阿特拉津在贝类组织内具有积累作用,而且对这些积累能产生生理反应。     

Ventilatory effects of substance P, vasoactive intestinal peptide, and nitroprusside in humans.

Animal studies suggest that the neuropeptides, substance P and vasoactive intestinal peptide (VIP), may influence carotid body chemoreceptor activity and that substance P may take part in the carotid body response to hypoxia. The effects of these peptides on resting ventilation and on ventilatory responses to hypoxia and to hypercapnia have been investigated in six normal humans. Infusions of substance P (1 pmol.kg-1.min-1) and of VIP (6 pmol.kg-1.min-1) were compared with placebo and with nitroprusside (5 micrograms.kg-1.min-1) as a control for the hypotensive action of the peptides. Both peptides caused significantly less hypotension than nitroprusside. Substance P and nitroprusside caused significantly greater increases in ventilation and in the hypoxic ventilatory response than VIP. No changes were seen in hypercapnic sensitivity. The stimulation of ventilation and the differential effects on ventilatory chemosensitivity that accompanied hypotension are consistent either with stimulation of carotid body chemoreceptor activity or with an interaction with peripheral chemoreceptor input to the respiratory center, as is seen in animals. The similar cardiovascular but different ventilatory effects of the peptides suggest that substance P may also stimulate the carotid body in a manner independent of the effect of hypotension. This is consistent with a role of substance P in the hypoxic ventilatory response in humans.     

Leucine metabolism during fasting and exercise

Whole body leucine kinetics were examined in seven healthy young men while in a 14-h postabsorptive state (PAS) and after a 3.5-day fast (FS). Subjects received a primed constant intravenous infusion of L-[1-13C]leucine while resting for 3 h and then while exercising on a cycle ergometer at 45% maximal O2 uptake to exhaustion. Blood samples drawn during isotopic steady state were analyzed for 13C enrichment of leucine and alpha-ketoisocaproic acid, and expired gas samples were analyzed for 13CO2. Resting leucine flux was higher in the FS, and there was a slight increase in leucine oxidation. During exercise, leucine flux did not differ between PAS and FS but leucine oxidation rose markedly. In the FS, leucine oxidation was 25 +/- 7 (SD) mumol.kg-1.h-1 at rest and rose to 75 +/- 21 mumol.kg-1.h-1 during exercise; in the PAS, oxidation was 20 +/- 5 mumol.kg-1.h-1 at rest and 52 +/- 17 mumol.kg-1.h-1 during exercise. These data indicate that the high rate of leucine oxidation previously found during exercise was increased further by a 3.5-day fast.     

Three months energy restricted diet does not reduce peripheral insulin resistance in newly diagnosed non insulin dependent diabetics

Sixteen newly diagnosed non insulin dependent diabetic patients were treated for 3 months with an individual energy restricted diet. The effect on weight, hyperglycaemia and insulin response to oral glucose was measured in all subjects, and in 7, peripheral insulin resistance was estimated using a hyperinsulinaemic glucose clamp at two insulin infusion rates (40 and 400 mU m-2 X min-1). After diet, fasting plasma glucose fell from 12.0 +/- 0.7 mmol/l (mean +/- SEM) to 7.4 +/- 0.5 mmol/l (P less than 0.001) and weight fell from 92.9 +/- 4.2 kg to 85.0 +/- 3.1 kg (P less than 0.001). The plasma insulin response to oral glucose was unchanged after diet therapy. Insulin induced glucose disposal (M) was also unaffected by diet at insulin infusion rates of 40 mU m-2 X min-1 (12.5 +/- 1.5 mumol X kg-1 X min-1 vs 15.7 +/- 1.6 mumol X kg-1 X min-1) and 400 mU m-2 X min-1 (49.5 +/- 2.7 mumol X kg-1 X min-1 vs 55.1 +/- 2.5 mumol X kg-1 X min-1). These results show that 3 months reduction of energy consumption with weight loss in newly diagnosed non insulin dependent diabetics improves B-cell responsiveness to glucose but has no effect on liver glucose output or on peripheral insulin action.     

Reproductive and endocrine function in rams exposed to the organochlorine pesticides lindane and pentachlorophenol from conception.

There is controversy over the potential endocrine modulating influence of pesticides, particularly during sensitive phases of development. In this study, ram lambs were exposed to lindane and pentachlorophenol from conception to necropsy at 28 weeks of age. The rams (and their mothers) were given untreated feed (n = 7) or feed treated with 1 mg kg-1 body weight per day of lindane (n = 12) or pentachlorophenol (n = 5). Semen was collected from 19 weeks onwards and reproductive behaviour was tested at 26 weeks. Serum was collected every 2 weeks and at 27 weeks every 15 min for 6 h during both day and night, and for 1 h before and 5 h after stimulation with GnRH, adrenocorticotrophic hormone and thyroid-stimulating hormone. The pesticides did not affect body weight and ejaculate characteristics, or cause overt toxicity. In pentachlorophenol-treated rams, scrotal circumference was increased. However, seminiferous tubule atrophy was more severe and epididymal sperm density was reduced in comparison with untreated rams at necropsy (P < 0.05). Thyroxine concentrations were lower in pentachlorophenol-treated rams than in untreated rams (P < 0.05). However, after thyroid-stimulating hormone treatment, the thyroxine response was unaltered. Reproductive behaviour was reduced in lindane-treated rams compared with control rams (P < 0.05). Serum LH and oestradiol concentrations during reproductive development, LH pulse frequency at 27 weeks and testosterone secretion after GnRH treatment were lower in lindane-treated rams than in untreated rams (P < 0.05). In summary, the effects of pentachlorophenol on the testis may be linked to a decrease in thyroxine concentrations, and reduced reproductive behaviour in lindane-treated rams may be related to decreased LH, oestradiol and testosterone concentrations.     

Relationship between the phagocytic inhibition of the rat reticuloendothelial system and the anticholinesterasic effect of an insecticide, Carbaryl (author's transl)]

Phagocytic activity of the reticuloendothelial system (RES) and blood cholinesterase activity were determined in male rats after veinous administrations of carbaryl and 1-naphthol, a carbaryl metabolite. The various parameters were measured 1, 24, 48 and 72 hours after administration of the following four doses per 100 g body weight : 1.875, 3.75, 7.5 and 15 mumol. 1. Results showed an inhibition of the RES phagocytic activity (clearance of colloidal carbon) after carbaryl administration; although 1.875 mumol/100 g had no effect, the other doses inhibited RES activity, blockade time being a function of the dose given. The phagocytic function had returned to normal 72 hr after carbaryl administration. 2. Reductions in spleen weight and protein content were observed together with the RES blockade. 3. At all four doses, the anticholinesterase effect was already apparent one hour after carbaryl administration. 4. 1-naphthol, one of carbaryl's chief metabolites, had no effect either on the RES or on the different parameters studied. These results show a relationship between the phagocytic inhibition of the reticuloendothelial system and the anticholinesterasic effect by carbaryl. They suggest an inhibition of some esterases of macrophages interfering with the phagocytosis.     

Effects of in vivo and in vitro lindane treatment on rat ventral prostate lipids

The rat ventral prostate accumulated lindane (gamma-hexachlorocyclohexane) (0.59 +/- 0.07 ppm) when this liposoluble toxicant was injected subcutaneously at a concentration of 1 mg of 100 g body weight for 12 days. Total lipids and phospholipids (especially phosphatidylcholine) amounts were augmented in treated rats. Lindane had no significant influence upon cholesterol mass content in the ventral prostate. Using [1-14C]acetate as radioactive precursor, it was possible to conclude that the mass lipid variations caused by lindane treatment were due, at least in part, to a modification of the endogenous biosynthesis of these lipids. No changes were found in the acetate oxidation to CO2 when control rats and lindane-treated rats were compared.     

Effect of hyperammonaemia on blood glucose and plasma insulin levels in sheep.

The effects of continuous intravenous infusions (6 h) of ammonium chloride (5.6; 11.2; and 16.8 mumol.kg-1.min) on plasma glucose and immunoreactive insulin (I.R.I.) levels were studied in three adult sheep. Infusions of 5.6 and 11.2 mumol.kg-1.min elevated ammonia levels in circulating blood from 100 to 150 and 300 microgram.100 ml-1, respectively, but showed no appreciable effect on plasma glucose and I.R.I. concentrations. Infusion of 16.8 mumol.kg-1.min-1 resulted in a blood ammonia concentration of about 400 microgram.100 ml-1 after six hours of infusion. Blood ammonia returned to normal 1 to 2 hours after the end of infusion. Plasma glucose concentration tended to increase slightly from 65 to 75 mg . 100 ml-1 when 16.8 mumol of NH4Cl were infused kg-1.min-1 and remained at the elevated level at least for two additional hours when ammonia infusions were stopped. Plasma I.R.I. tended to decrease from 48 to 38 microunits . ml-1 during the time of the NH4Cl infusion and increased continually to 82 microunits . ml-1 when NH4Cl infusions were stopped. It is concluded from the time courses of plasma glucose and plasma I.R.I. that the effect of ammonia infusion of these parameters cannot entirely be explained by a regulatory release of adrenaline.     

Alleviation of lindane induced toxicity in testis of Swiss mice (Mus musculus) by combined treatment with vitamin C, vitamin E and alpha-lipoic acid

Mitigation of lindane induced toxicity in testis of Swiss mice by combined treatment with vitamin C, vitamin E and alpha-lipoic acid has been evaluated. Male healthy mice (40), 8-10 weeks old were randomly selected and divided into 4 groups, control (C); lindane (L); antioxidant (A) and antioxidant plus lindane (A+L). Group C animals were administered only the vehicle (olive oil); in group L lindane was administered orally at a dose of 40 mg/kg body wt.; in group A combination of antioxidants at a dose of 125 mg/kg body wt.(vitamin C: 50 mg/kg body wt., vitamin E: 50 mg/kg body wt. and alpha-lipoic acid: 25 mg/kg body wt.) was administered orally; in group A+L both antioxidants (125 mg/kg body wt.) and lindane (40 mg/kg body wt.) were administered at their respective doses. In group A+L antioxidants were administered 1 h prior to lindane administration. All treatments were continuously given for 60 days. Histopathological changes due to lindane intoxication indicated shrunken and distorted seminiferous tubules, sparse Leydig cells and blood vessels and atrophy in the tissue. The testis weight also decreased significantly. Lindane treated group showed increased lipid peroxidation, whereas glutathione, glutathione peroxidase, superoxide dismutase, catalase and protein were significantly decreased compared to control. Lindane induced damage was minimized by administration of antioxidants. Results suggest that combined pretreatment with antioxidants can alleviate the damage caused to testis by lindane.     

Lindane-induced liver oxidative stress: respiratory alterations and the effect of desferrioxamine in the isolated perfused rat liver

The effects of lindane administration (25-60 mg kg-1 for 24 h) on hepatic oxygen consumption were studied in the isolated perfused rat liver, in the absence and presence of the iron-chelator free-radical scavenger desferrioxamine. Lindane elicits a dose-dependent enhancement of total oxygen uptake by the liver, which is largely inhibited by 0.55 mM desferrioxamine. Total desferrioxamine- sensitive oxygen consumption exhibits a maximal increase (213 per cent) at 60 mg of lindane kg-1 over control values and represents 21 per cent of the total oxygen consumption. At the different doses of lindane used, it was calculated that about 60 per cent of the total increase in oxygen uptake by the liver is accounted for by oxygen related to oxidative stress, probably utilized at different stages of the induced lipid peroxidative process.     

Soluble calcium-binding proteins: parvalbumins and calmodulin from eel skeletal muscle

1. Eel skeletal muscle contains three parvalbumin isoforms. The overall parvalbumin concentration in the muscle is 0.5 mmol kg-1 wet weight. 2. Calmodulin (0.1 mumol kg-1 wet weight) was purified by extraction with ethylenediamine tetraacetate-containing buffer, fractionation with trichloroacetic acid and separation by ion exchange chromatography on DEAE-cellulose and by molecular sieving on Ultrogel AcA 54. 3. Troponin-C-free calmodulin was obtained by fast protein liquid chromatography on a Mono Q column.     

Plasma glutathione turnover in the rat: effect of fasting and buthionine sulfoximine

Hepatic glutathione (GSH) plays an important role in the detoxification of reactive molecular intermediates. Because of evidence that the intrahepatic turnover of glutathione in the rat may be largely accounted for by efflux from hepatocytes into the general circulation, the quantitation of plasma GSH turnover in vivo could provide a noninvasive index of hepatic glutathione metabolism. We developed a method to estimate plasma glutathione turnover and clearance in the intact, anesthetized rat using a 30-min unprimed, continuous infusion of 35S-labelled GSH. A steady state of free plasma glutathione specific radioactivity was achieved within 10 min, as determined by high-pressure liquid chromatography with fluorometric detection after precolumn derivatization of the plasma samples with monobromobimane. The method was tested after two treatments known to alter hepatic GSH metabolism: 90 min after intraperitoneal injection of 4 mmol/kg buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, and after a 48-h fast. Liver glutathione concentration (mean +/- SEM) was 5.00 +/- 0.53 mumol/g wet weight in control rats. It decreased to 3.10 +/- 0.35 mumol/g wet weight after BSO injection and to 3.36 +/- 0.14 mumol/g wet weight after fasting (both p less than 0.05). Plasma glutathione turnover was 63.0 +/- 7.46 nmol.min-1.100 g-1 body weight in control rats, 35.0 +/- 2.92 nmol.min-1.g-1 body weight in BSO-treated rats, and 41.7 +/- 2.28 nmol.min-1.g-1 body weight after fasting (both p less than 0.05), thus reflecting the hepatic alterations. This approach might prove useful in the noninvasive assessment of liver glutathione status.     

Determination of glucose turnover in sea bass Dicentrarchus labrax. Comparative aspects of glucose utilization

1. Parameters of in vivo glucose utilization by sea bass (132 +/- 6 g, mean +/- SEM) acclimated at 15 degrees C in sea-water were measured after single injection of labelled glucose. 2. Glucose turnover rate (RG; mumol . min-1 . kg-1) was found to be 0.55-065 (2-3H glucose) and 0.34 +/- 0.42 (U14C glucose). 3. Glucose transit time was 443-449 min, glucose mass 233-261 mumol . kg-1, and glucose recycling 37%. 4. Oxygen consumption (MO2) amounted to 94 +/- 6.2 mumol . min-1 . kg-1. 5. The comparison with other fish species, mammals and birds, taking into account body size, temperature, diet, exercise, in poikilotherms and homeotherms leads to the calculation of a glucose turnover index (RGI = RG x 6 x 100 x MO2(-1)). 6. Value of this, generally lower in ectotherm teleosts (2-9), than in endotherms: mammals, birds and thunidae (22-60), confirms the minor quantitative importance of glucose in the metabolism of most fish.     

Effect of bile salts on the biliary excretion of glycodihydrofusidate in the rat

The biliary elimination of glycodihydrofusidate (GDHF), a structural analogue of bile salts, was studied in bile fistula rats. GDHF was excreted in bile with a maximal excretory rate (Tm = 0.80 mumol min-1 kg-1) which is much lower than bile salts Tm. The effects of dehydrocholate and taurocholate on GDHF biliary secretion suggest a stimulatory effect of bile salts on canalicular excretion of the drug. (a) When a bolus intravenous injection of 3 mumol of GDHF was followed after 2 min by a continuous dehydrocholate perfusion (10 mumol min-1 kg-1), biliary excretion of GDHF was increased in comparison with control rats. (b) Upon attaining the biliary Tm by continuous perfusion of GDHF at a rate of 1.35 mumol min-1 kg-1, infusion with either taurocholate or dehydrocholate increased its Tm to a similar degree. These results are similar to those previously obtained with the effects of bile salt infusions on the Tm of bromosulfophthalein. They suggest therefore that hepatic transport of GDHF and bile salts occurs by routes which are distinct for canalicular transport in spite of the striking structural similarities between GDHF and bile salts.     

A new class of potent gastrin antagonists

The hexapeptide Z-Tyr(SO-3)-Met-Gly-Trp-Met-Asp-NH2, from the natural sequence of C-terminal cholecystokinin was found to be a competitive antagonist of cholecystokinin receptors, in vitro. In the present study, we report that this peptide inhibits gastrin-induced acid secretion in vivo, (ED50 = 1.5 mumol . kg-1), without agonist activity. Desulfation of the tyrosine residue slightly altered this effect. The tripeptide Boc-Trp-Met-Asp-NH2 showed similar effects, but had lower potency (ED50 = 12 mumol . kg-1). From these preliminary results, it can be concluded that removal of the phenylalanine residue from the C-terminal sequence of CCK or gastrin, leads to an antagonist of the natural hormones and that C-terminal phenylalanine residue is important for agonist activity. As compared with proglumide, a well known gastrin receptor antagonist, these peptides were 20-200 times more potent as inhibitors on the same model.     

Biodegradation of lindane (gamma-hexachlorocyclohexane) by the white-rot fungus Trametes hirsutus

The ability of the white-rot fungus Trametes hirsutus to degrade an insecticide, lindane, in liquid culture was investigated and compared with that of Phanerochaete chrysosporium. Trametes hirsutus degraded lindane faster than P. chrysosporium but the mechanism of degradation appears to be the same in both. Two metabolites identified in both fungi were tetrachlorocyclohexane and tetrachlorocyclohexanol. The presence of lindane alone inside the mycelium ruled out the involvement of any intracellular enzyme(s) during the initial step of lindane degradation. Lindane at a concentration of 0.27 mumol l-1 exhibited no adverse effect on fungal growth.     

Possible antiestrogenic activity of lindane in female rats

During chronic peroral (PO) treatment of weanling, female Fischer 344 rats with daily injections (0.069 mmol/kg) of either 1,1′-(2,2,2-trichloroethylidene) bis [4-chlorobenzene] (p,p′-DDT), 2,4-dichlorophenoxy acetic acid (2,4-D), or γ-hexachlorocyclohexane (lindane), the lindane treatment induced a significant 20% increase in body weight after 110 days. Further investigation with 0,5,10,20, and 40 mg/kg lindane confirmed a significant increase in average body weight gain at the two highest doses after ten weeks of treatment. Significantly greater food consumption was observed, and the Lee index indicated that lindane treatment induced obesity. In addition to obesity, lindane caused a delay in vaginal opening, disrupted estrous cycling, reduced pituitary and uterine weight, and elevated food consumption during proestrus (when appetite is normally suppressed by estradiol). These responses suggest that, by inducing alterations in the reproductive function of the female rat and by interfering with hormonal regulation of energy balance, lindane may be antiestrogenic rather than estrogenic as previously proposed.