Malnutrition and sensitivity to toxic substances.
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Animals↗
Biomedical subjects
S Mitjavila
Publications and source records attributed to S Mitjavila.
The effect of dietary essential fatty acid deficiency on the composition and properties of the liver microsomal membrane of rats.
The effect of dietary essential fatty acid (EFA) deficiency on lipid composition, fluidity and important enzyme and transport activities of liver microsomal membrane was studied in weanling rats. After 133 d of EFA deficiency, no difference was noticed in membrane phospholipid, cholesterol and protein levels, but a significant change occurred in the fatty acid composition of bilayer phospholipids. In EFA-deficient rats, linoleic (18:2(n-6] and arachidonic (20:4(n-6] acids were both severely lower while oleic (18:1(n-9], palmitoleic (16:1(n-7] and particularly 5,8,11-eicosatrienoic (20:3(n-9] acids were significantly higher than in controls. The higher level of the latter tended to compensate for the lower level of 20:4(n-6). Membrane fluidity, as estimated by the reciprocal of the order parameter S, was lower in the deficient rats than in the controls, and all the measured microsomal enzyme activities were markedly affected. NADH-Cyt b5 electron transferring system, coupled with the fatty acid desaturation system, was higher than in controls. In contrast, the cytochrome P450 complex activity was lower and some of the important liver detoxifying enzyme activities were lower due to physical-chemical changes in the microsomal membrane. Calcium uptake and Ca2+-ATPase activity were also significantly lower in EFA-deficient rats than in controls. It was concluded that fatty acid composition may be the major factor contributing to membrane fluidity and function and that EFA might play a role in regulating the intrinsic membrane protein activities.
Animals↗
Intestinal absorption of ester and ether glycerophospholipids in guinea pig. Role of a phospholipase A2 from brush border membrane.
In vivo intestinal perfusion was used to follow the absorption of three different choline glycerophospholipids (CGP) in guinea pig. These included 1-[3H]palmitoyl-2-acyl-sn-glycero-3-phosphocholine (diacyl-GPC), 1-[3H]-O-hexadecyl-2-acyl-sn-glycero-3-phosphocholine (alkylacyl-GPC) and 1,2-di-O-hexadecyl-sn-glycero-3-phospho-[3H]-choline (dialkyl-GPC). About 80% of diacyl-GPC was absorbed within 4 hr, compared to 60% of alkylacyl-GPC and 30% of dialkyl-GPC. The radioactivity disappearing from the perfusion fluid was recovered in intestinal lipids, mostly triacylglycerol, free fatty acid and CGP from diacyl-GPC, CGP from alkylacyl-GPC and dialkyl-GPC. These results indicated that the nonhydrolyzable substrate dialkyl-GPC was much less absorbed, whereas diacyl-GPC, which released over 80% of [3H]palmitic acid in the perfusion fluid, displayed the highest absorption rate. The intermediate picture observed for alkylacyl-GPC suggested the possible involvement of a phospholipase A2, which was detected in the entire intestinal tract. This enzyme was further found to concentrate in villus cells, where it is localized in the brush border membrane, as shown using two different subcellular fractionation procedures. These data suggest a possible role of this new enzyme in the digestion of alimentary phospholipids.
Alkaline Phosphatase↗
Radical activation of carbon tetrachloride in foetal and maternal rat liver microsomes.
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Animals↗
Na+-coupled D-glucose uptake and membrane order of enterocyte brush border membrane vesicles, under the effect of a series of N-phenylcarbamates.
The importance of the hydrophobic effect of exogenous substances and of modifications of membrane order on D-glucose uptake are still poorly defined. Our results show that the concentrative Na+ -coupled D-glucose uptake of rat enterocyte brush border membrane vesicles is inhibited by N-phenylcarbamates increase the membrane order. However, since the concentrations required for membrane order increase are much greater than those active on D-glucose uptake, the effects on lipid order cannot be responsible for the inhibition of D-glucose uptake. Measurements of D-glucose uptake under conditions of Na+ equilibrium show that these carbamates do not act directly on the carrier but indirectly by favouring the dissipation of the Na+ gradient.
Animals↗
Studies on the mechanism of nabam- and zineb-induced inhibition of the hepatic microsomal monooxygenases of the male rat.
In vitro effects of the ethylene bis-dithiocarbamate fungicides, nabam and zineb, on the hepatic microsomal monooxygenases of male rats were examined. Incubation of nabam and zineb with hepatic microsomes, without NADPH, leads to an inhibition of the metabolism of aminopyrine and aniline and to a denaturation of cytochrome P-450 into cytochrome P-420; in addition nabam causes the destruction of cytochrome P-450. Addition of NADPH into the incubation medium increases the inhibition of the monooxygenases, principally the inhibition of the metabolism of aniline induced by nabam. We studied the in vitro effects of three of the chief breakdown products of these fungicides: ethylene bis-isothiocyanate sulfide (EBIS), ethylene thiourea (ETU), and carbon disulfide (CS2). EBIS appears to be the only metabolite affecting directly (without NADPH) the hepatic monooxygenases activity. EBIS accounted partly for nabam-induced inhibition of the hepatic microsomal monooxygenases. The data suggest that the decrease of monooxygenases activity seen on incubation of nabam with hepatic microsomes may be due to the denaturation and destruction of cytochrome P-450 resulting from covalent binding of the compounds with cysteine sulfhydryl groups in cytochrome P-450. Inhibition of monooxygenase activity induced by zineb seems to be due to the reaction with the sulfhydryl groups of cytochrome P-450 and to another mechanism, probably related to its lipophilic character.
Aminopyrine N-Demethylase↗
[Nutritional status of the rat in refeeding following massive mobilization of DDT by fasting].
Rats were subjected to fasting-induced mobilization of a quantity of DDT equivalent to 45% of the LD50. They were then fed for 1 week for a nutritional and toxicological study. Mobilization of DDT by starvation had no apparent effect on the activity of the various enzymes or the weight of the organs measured at the end of the refeeding period. The animals which had received DDT pretreatment showed higher protein efficiency than the control animals. Only the level of body lipids was lower in the animals pretreated with DDT, although the quantities of lipids stored during the study period were identical in both groups of animals. Overall, the results show that the nutritional state of the two groups of animals was very similar at the end of the refeeding period.
Animals↗
Inhibition of Ca2+ sequestration in foetal liver microsomes by carbon tetrachloride and bromotrichloromethane.
The purpose of the present work is to establish to what extent the calcium uptake of foetal liver microsomes can be modified, as in the adult, by classical hepatotoxins. The administration of liver toxins (BrCCl3, CCl4) to the pregnant rat or their addition to foetal and maternal liver microsome preparations causes a decrease in the level of cytochrome P-450 and a drop in the calcium storage capacity of microsomes. Lipid peroxidation of membrane phospholipids is observed in the mother but not in the foetus. On the 20th day of gestation, the foetal liver shows cytochrome P-450 dependent metabolic activity and constitutes a good model illustrating the hypothesis of calcium pump inhibition by .CCl3 radicals without lipoperoxidation.
Animals↗
Thermodynamic interpretation of effects of alcohols on membrane lipid fluidity.
The effect of a series of amphiphilic compounds, the first eight n-aliphatic alcohols, on the fluidity of rat enterocyte brush border was determined by ESR using 5-doxyl stearic acid as a lipid spin probe. Packing order variations are compared to the relative hydrophobic effect of the alcohols. The concentrations, [Ci]5 of each alcohol that decrease the membrane 2T' value by 5%, vary by a factor of 1500 from methanol to octanol. From [Ci]5, the membrane concentrations Cm and the variation of free energy delta F degree due to the incorporation of the alcohols in the lipids, were calculated. These calculations were performed taking into account the respective volumes of the aqueous phase and the membrane lipids. Cm is of the order of 0.18 mol/kg for the odd chain length alcohols and of 0.27 mol/kg for the even alcohols. The value of delta F degree in cal/mol -CH2- is -687 cal on average for the eight alcohols. This work shows that for all the alcohols, the concentrations at equilibrium in the membrane and in the aqueous phase are respectively in agreement with Meyer and Overton's theory and with the gradient of free energy which constitutes the most general index of interaction of lipophilic substances with membranes.
Alcohols↗
Inhibition of short-circuit current in rat ileum by aliphatic alcohols.
The importance of the hydrophobic nature of the membrane in certain functions of the intestinal epithelium was investigated by determining the variations in short-circuit current (Isc), potential difference (PD), and conductance (G) in rat ileum in the presence of the first eight alcohols in the n-aliphatic series. At the lowest alcohol concentrations and in the presence of Ringer-galactose, there was transitory stimulation of Isc and PD that did not occur in the presence of theophylline or in the absence of chloride. With or without theophylline all the alcohols tested inhibited Isc and PD and slightly increased G as a function of their concentration. The modifications in Isc were attributed to the inhibition of active sodium transport. These results demonstrate a linear relation between the logarithm of the concentrations causing 50% inhibition of Isc and the chain length of the alcohols. The variations in free energy required to transfer one -CH2- to the site at which the alcohols exert their activity were, respectively, -582 and -589 cal in the presence and absence of theophylline. These values show that the observed modifications in free energy are due to solubilization of the alcohols in a very hydrophobic zone of the tissue, confirming that the functional activities measured are dependent on the hydrophobicity of the membrane.
Alcohols↗
Hepatic microsomal calcium uptake during the perinatal period.
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Animals↗
Influence of experimental hepatic impairment on the toxicokinetics and the anticholinesterase activity of carbaryl in the rat.
The blood kinetics of carbaryl were followed over 24 h after oral administration of 14C-carbaryl at 20 mg kg (0.17 mu Ci mg-1) in control animals and in animals with an altered liver function (70% hepatectomy or tranylcypromine treatment). The variations in the primary toxicity of carbaryl were assessed by measuring the inhibition of the plasma and erythrocyte cholinesterases and by evaluation of the lethal doses. The 14C radioactivity in the blood and, in parallel, cholinesterase inhibition were maintained at a higher level in animals with an altered hepatic function. A study of acute toxicity also showed a decrease of the LD50 (91 mg kg-1 with tranylcypromine, 342 mg kg-1 in the hepatectomized group) in the treated animals, with respect to the controls (585 mg kg-1). In all cases, tranylcypromine had a greater effect on blood kinetics, cholinesterase inhibition and LD50 than did 70% hepatectomy.
Animals↗
[Deperoxidation of hydroperoxylinoleic acid by the intestinal mucosa].
In the presence of glutathione, a homogenate of rat intestinal mucosa transforms linoleic acid hydroperoxide (LOOH) into the corresponding alcohol (LOH). The Km of the enzyme involved (a glutathione peroxidase) is 5.7 x 10(-6) M. The specific activity, measured as generated LOH, was found to be 0.058 mumol/mg protein/min, six times lower than that of the liver. A mitochondrial supernatant of the mucosal homogenate had 1.5 times the activity of the initial homogenate. The reduction of 1 mol LOOH requires 2 mol glutathione. Besides this enzymatic deperoxidation, 5% of the LOOH was decomposed in both the intestinal mucosa and liver by a non-enzymatic pathway, probably involving the Fe3+ of the haemoproteins.
Animals↗
[Effects of oxythioquinox on urinary nitrogen excretion in rats].
The amount of nitrogen excreted in urines is higher in pair-fed Rats subjected to a diet containing 400 mg/kg of oxythioquinox. This is a consequence of specific effect of oxythioquinox on protein catabolism and not to a renal failure as is shown by the increase in the urinary excretion of urea. The administration of vitamin B6, B12 and folic acid improves the growth but these vitamins have no effect on the nature of urinary nitrogen excretion.
Animals↗
Effects of polychlorinated biphenyls on liver regeneration in the rat: influence of position and degree of chlorination.
The effects of PCBs, administered intragastrically, were studied on partially hepatectomized (70%) rats. Seven days after hepatectomy, a relationship was noted between the increase in the degree of chlorination of the biphenyl molecule and the hypertrophy and lipid accumulation in the liver. When the 3' and 4' positions are chlorinated, the relationship still holds but, for a constant number of chlorine atoms, the intensity of the effects are decreased. Fourteen days after hepatectomy, there was only a significant difference in the case of decachlorobiphenyl and Phenoclor DP5, for which the hypertrophy is accompanied by hyperplasia. The relationships are discussed between the chemical structure of the PCBs, their metabolization, their toxicity, and the reversibility of their effects.
Animals↗
Carbaryl tricompartmental toxicokinetics and anticholinesterase activity.
The blood kinetics of carbaryl and the inhibition of plasma acetylcholinesterases were followed for 24 h after administration of 20 mg/kg [14C]carbaryl (0.17 microCi/mg). The kinetics of the radioactivity attributed to unaltered carbaryl is bi-exponential whereas that of the total 14C activity is tri-exponential. The kinetics were treated with open 2- and 3-compartment models respectively. The exchange rate constants between the various compartments as well as the elimination constant (expressed in h-1) were found to be: k12 = 1.93, k21 = 1.18 and k10 = 2.46 (2-compartment model) and k'12 = 18.65, k'21 = 13.90, k'13 = 1.14 k'31 = 0.125 and k'10 = 0.672 (3-compartment model). The 3-compartment model demonstrates the persistence in the blood of 14C activity which correlated with plasma acetylcholinesterase inhibition.
Acetylcholinesterase↗
Evaluation of the toxic risk of DDT in the rat: during accumulation.
An investigation was undertaken on the accumulation of DDT and its metabolites in the rat. Rats received 14.5 mg DDT/kg b.w. every day for 52 days. Growth, food intake, body composition, and the activities of various enzymes were little affected. However, the level of total lipids fell 30% and the weight of the liver rose 20% due to cellular hypertrophy induced by the DDT. The quantity of DDT and its metabolites found in the carcass was 24 mg/rat i.e. three times that found in rats dead after a single dose of 200 mg/kg. Liver and brain contained 130 micrograms/rat and 10 micrograms/rat, respectively i.e. five times lower than those found in the rats which died from an acute dose of DDT. In the carcass, p,p' DDT accumulates more than p,p' DDE or p,p' DDD; the latter is preponderant in the liver.
Analysis of Variance↗
Evaluation of the toxic risk of accumulated DDT in the rat: during fat mobilization.
The effects of greatly reduced food intake were investigated in rats which had accumulated three times as much DDT as rats killed with a single dose approaching LD50. DDT and its metabolites mobilized more quickly than the fat deposits. The hypertrophy of the liver due to DDT decreased during food restriction and demonstrated the existence of a large detoxication capacity shown through the high metabolism of the pesticide. The disappearance of p,p' DDE was most rapid, followed by p,p' DDD then p,p' DDT; they did not accumulate in the fat reserves. The half-life of the pesticide, which is normally three months in the rat, was reduced to five days under the experimental conditions. In spite of rapid mobilization, no major toxic signs were detected from either nutritional, physiopathological, or biochemical examinations.
Animals↗