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Biomedical subjects

M Comporti

Publications and source records attributed to M Comporti.

At least 91 records · Page 5Linked to original sources
PubMed1981

[Cytotoxic effects of carbonyl compounds (4-hydroxyalkenals) derived from peroxidation of hepatic microsomal lipids on isolated hepatocytes].

Carbonyl compounds released during the NADPH-Fe dependent lipid peroxidation and identified as 4-hydroxyalkenals (almost entirely as 4-hydroxynonenal), when incubated with isolated hepatocytes, produce loss of viability in 95% of the cells, as measured by the trypan blue exclusion test. They also produce an almost complete permeabilization of the plasma-membrane, as measured by the test of the permeability to NADH. concomitantly with the permeabilization of the plasma-membrane, a marked release of enzymes (lactate dehydrogenase and glutamate-pyruvate transaminase) from the hepatocytes occurs. These and other activities of the above mentioned carbonyl compounds suggest the possibility that these products represent some of the effective mediators of the liver injury produced by those toxins, such as CCL4, which promote the peroxidation of membrane lipids.

Alanine Transaminase↗
PubMed1981

[Effect of reduced glutathione on carbon tetrachloride induced fatty liver: various considerations].

The hepatic triglyceride accumulation produced by CCL4 poisoning is decreased in rats pretreated with reduce glutathione (GSH) as compared to the non pretreated ones. Such as decrease, however, is not matched by an increase in the release of triglycerides in the blood compartment. In the pretreated animals the endogenous mRNA directed incorporation of aminoacids into the microsomal protein as measured in vitro, is maintained at nearly the normal level 30 min after CCL4 poisoning, but it is strongly depressed 60 min after poisoning. The effectiveness of GSH in decreasing the level of hepatic triglycerides in the intoxicated animals could be ascribed, at least in part, to non specific mechanisms. In fact, the administration of GSH results in the decrease of liver triglycerides even in the non intoxicated rats. In these rats heart triglycerides are decreased too.

Animals↗
PubMed1981

Inhibition of protein synthesis by carbonyl compounds (4-hydroxyalkenals) originating from the peroxidation of liver microsomal lipids.

Carbonyl compounds released during the NADPH-Fe dependent peroxidation of liver microsomal lipids and identified as 4-hydroxyalkenals (almost entirely as 4-hydroxynonenal) inhibit protein synthesis in a rabbit reticulocyte lysate. The ID50 was 0.48 mM. The inhibitory effect was reproduced by synthetic 4-hydroxynonenal. The inhibition was already evident at 1-2 min of incubation. The addition of -SH groups to the incubation medium afforded a marked protection against the inhibition of protein synthesis. The inhibitory effect seems to be due to an interaction of the carbonyl compound with -SH groups essential for the cellular protein synthetic machinery.

Aldehydes↗
PubMed1980

Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids.

During the NADPH-Fe induced peroxidation of liver microsomal lipids, products are formed which show various cytopathological effects including inhibition of microsomal glucose-6-phosphatase. The major cytotoxic substance has been isolated and identified as 4-hydroxy-2,3-trans-nonenal. The structure was ascertained by means of ultraviolet, infrared and mass spectrometry and high-pressure liquid chromatographic analysis. Moreover, 4-hydroxynonenal, prepared by chemical synthesis, was found to reproduce the biological effects brought about by the biogenic aldehyde. Preliminary investigations suggest that as compared to 4-hydroxynonenal very low amounts of other 4-hydroxyalkenals, namely 4-hydroxyoctenal, 4-hydroxydecenal and 4-hydroxyundecenal are also formed by actively peroxidizing liver microsomes. In the absence of NADPH-Fe liver microsomes produced only minute amounts of 4-hydroxyalkenals. The biochemical and biological effects of synthetic 4-hydroxyalkenals have been studied in great detail in the past. The results of these investigations together with the finding that 4-hydroxyalkenals, in particular 4-hydroxynonenal, are formed during NADPH-Fe stimulated peroxidation of liver microsomal lipids, may help to elucidate the mechanism by which lipid peroxidation causes deleterious effects on cells and cell constituents.

Aldehydes↗
PubMed1980

Effects of carbonyl compounds (4-hydroxyalkenals) originating from the peroxidation of liver microsomal lipids on various microsomal enzyme activities of the liver.

Carbonyl compounds released during the NADPH-Fe dependent peroxidation of liver microsomal lipids and identified as 4-hydroxyalkenals (almost entirely as 4-hydroxynonenal) while inhibiting microsomal enzymes (such as glucose 6-phosphatase and aminopyrine demethylase) which are affected by lipid peroxidation, have no effect on microsomal NADPH-cytochrome c reductase. The latter enzyme activity is unaffected (or even increased) when liver microsomes are allowed to peroxidize in the NADPH-Fe dependent system. NADPH-cytochrome c reductase, contrary to the other enzymes, is similarly unaffected after CCl4 poisoning, that is in a situation in which peroxidation of membrane lipids of liver endoplasmic reticulum has been unequivocally demonstrated. It appears therefore that the effects exherted by lipid peroxidation or by 4-hydroxyalkenals originating from lipid peroxidation parallel the effects of CCl4 intoxication in vivo.

Aldehydes↗
PubMed1979

Effects of diffusible products of peroxidation of rat liver microsomal lipids.

The effects on cellular structures of products of peroxidation of rat liver microsomal lipids were investigated. A system containing actively peroxidizing liver microsomal fraction was separated from a revealing or target system by a dialysis membrane. The target system, contained in the dialysis tube, consisted of either intact cells (erythrocytes) or subcellular fractions (liver microsomal fraction). When liver microsomal fractions were incubated with NADPH (or an NADPH-generating system), lipid peroxidation, as measured by the amount of malonaldehyde formed, occurred very rapidly. The malon-aldehyde concentration tended to equilibrate across the dialysis membrane. When the target system consisted of erythrocytes, haemolysis occurred abruptly after a lag phase. The lysis was greatly accelerated when erythrocytes from vitamin E-deficient rats were used, but no haemolysis was observed when erythrocytes from vitamin E-treated rats were used. When, in the same system, freshly prepared liver microsomal fractions were exposed to diffusible factors produced by lipid peroxidation, the glucose 6-phosphatase activity markedly decreased. A similar decrease in glucose 6-phosphatase activity, as well as a smaller but significant decrease in cytochrome P-450, was observed when the target microsomal fractions were exposed to diffusible factors derived from the peroxidation of liver microsomal lipids in a separate preincubation step. These and additional experiments indicated that the toxicological activity is relatively stable. Experiments in which the hepatic microsomal fractions destined for lipid peroxidation contained radioactively labelled arachidonic acid, previously incorporated into the membranes, showed that part of the radioactivity released from the microsomal fraction into the incubation medium entered the dialysis tube and was recovered bound to the constituents of the microsomal fractions of the target system. These results indicate that during the course of the peroxidation of liver microsomal lipids toxic products are formed that are able to induce pathological effects at distant loci.

Animals↗
PubMed1979

Binding of products originating from the peroxidation of liver microsomal lipids to the non-lipid constituents of the microsomal membrane.

The binding of products derived from the peroxidation of liver microsomal lipids to the non-lipid constituents of the microsomes was studied. To this end arachidonic acid labelled with tritium at the positions of the double bonds was given to rats and allowed to incorporate into the membrane lipids of the liver cell. When liver microsomes containing labelled arachidonic acid were incubated aerobically in the NADPH-dependent system, a marked production of malonic dialdehyde (MDA) occurred and, concomitantly, there was a consistent release of radioactivity from the microsomes into the incubation medium. The addition of EDTA to the incubation medium prevented, to a large extent, both the MDA formation and the release of radioactivity. Chromatographic studies showed that the bulk of the radioactivity released from the incubated microsomes is not MDA. In the incubated microsomes, the radioactivity decreased in total lipids, while it increased by about 15 times in the non-lipoidal residue. A similar increase in radioactivity was seen in microsomal protein, while no increase was observed in microsomal RNA (the radioactivity was negligible in both the incubated and the non-incubated samples). It seems therefore that products originating from lipoperoxidation of arachidonic acid covalently bind to the microsomal protein. In order to investigate whether alterations similar to those observed in the in vitro peroxidation of liver microsomes could be detected in the in vivo intoxication with carbon tetrachloride, rats given labelled arachidonic acid as above, were poisoned with CCl4. Sixty minutes after poisoning, the radioactivity present in the microsomal lipids was generally lower in the intoxicated rats than in the controls, while the labelling of the non-lipoidal residue and of the protein was higher in the CCl4-poisoned rats.

Animals↗
PubMed1978

Effect of cicloxilic acid on the liver damage produced by a choline-free, high-fat low-protein diet.

The effects of cis-2-hydroxy-2-phenylcyclohexanecarboxilic acid (cicloxilic acid) on the liver damage produced by a choline-free, high-fat low-protein diet (Handler's diet) were studied in rats. Treatment with cicloxilic acid significantly counteracted the increase in liver weight, hepatic lipids, serum transaminase and ornithine carbamoyl transferase activities, caused by the unbalanced and deficient diet. Histological examination of the liver showed a near-normal structure of the hepatic cells in the cicloxilic acid-treated animals. Other antihepatotoxic and choleretic drugs, with which cicloxilic acid was compared, showed either much less protective activity or none at all. Furthermore, while cicloxilic acid (which exhibits choleretic activity) did not alter the hepatic glycogen content, another choleretic drug, 1-phenyl-1-hydroxypentane (PC 1), caused marked depletion. It is concluded that the protective activity exerted by cicloxilic acid on the liver is separable from its choleretic activity.

Animals↗
PubMed1978

Effects of cicloxilic acid on CCl4-induced liver injury.

The effects of cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) on the liver injury produced by carbon tetrachloride poisoning were studied in rats. It was found that oral treatment counteracts the CCl4-induced increase in liver weight, rise of liver triglycerides, fall of plasma triglycerides and rise of serum transaminase and ornithine carbamoyl transferase activities. Further, cicloxilic acid, when administered alone, altered none of the parameters studied. Cicloxilic acid was found to be more effective at the lowest doses than any of the other antihepatotoxic and choleretic drugs used. When cicloxilic acid was administered at the highest doses, the plasma triglyceride level of the intoxicated animals was not significantly different from that of the controls. To find out whether cicloxilic acid was effective in maintaining a normal lipoprotein secretion after CCl4 poisoning, experiments were carried out with Triton WR-1339. The results indicate that cicloxilic acid maintains the output of triglycerides from the liver to the plasma compartment at near-normal level in CCl4 poisoned rats. Possible mechanisms for the effects of cicloxilic acid on the CCl4-induced liver damage are discussed.

Animals↗
PubMed1978

Hepatic microsomal mixed-function oxidase system in rats pretreated with cicloxilic acid.

In a study of the hepatic microsomal drug metabolising system in rats, pretreatment with cis-2-hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) did not prolong pentobarbital sleeping time or decrease the cytochrome P 450 content of the liver microsomes. The drug interacted with the liver microsomes to yield a type II spectral change. Cicloxilic acid did not affect the metabolism of CCl4 in vivo, as judged by the covalent binding of 14C from 14CCl r to microsomal lipids, or delay the gastrointestinal absorption of CCl4, as judged by the concentration of free CCl4 in the liver. The protection afforded by cicloxilic acid against CCl4 liver damage is therefore due neither to inhibition of the metabolism nor to delayed absorption of the toxin.

Animals↗