Alpha-1-antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human.

BACKGROUND & AIMS: Homozygous individuals with alpha-1-antitrypsin deficiency (AATD) type PiZ have an increased risk of chronic liver disease and hepatocellular carcinoma (HCC). It is noteworthy that HCCs are composed by hepatocytes without accumulation of AAT, but the reason for this remains unclear. The aim of this study was to determine liver pathology in PiZ mice, focusing the attention on the distribution of AAT globules in normal liver, regenerative foci and neoplastic nodules. METHODS: Liver of 79 PiZ mice and 18 wild type (Wt) was histologically analysed for steatosis, clear cell foci, hyperplasia and neoplasia. The expression of human-AAT transgene and murine AAT, in non-neoplastic liver and in hyperplastic/neoplastic nodules was tested by qPCR and qRT-PCR. RT-PCR was used to study expression of hepatic markers: albumin, α-foetoprotein, transthyretin, AAT, glucose-6-phospate, tyrosine aminotransferase. RESULTS: Liver pathology was seen more frequently in PiZ (47/79) than in Wt (5/18) and its development was age related. In older PiZ mice (18-24 m), livers showed malignant tumours (HCC and angiosarcoma) (17/50), hyperplastic nodules (28/50), non-specific changes (33/50), whereas only 9/50 were normal. Both human-AATZ DNA and mRNA showed no differences between tumours/nodules and normal liver, while murine-AAT mRNA was reduced in tumours/nodules. CONCLUSION: Accumulation of AAT is associated with an increased risk of liver nodules. The presence of globule-devoid hepatocytes and the reduced expression of murine-AAT mRNA in hyperplastic and neoplastic nodules suggest that these hepatic lesions in AATD could originate from proliferating dedifferentiated cells, lacking AAT storage and becoming capable of AFP re-expression.

[The effect of acute alcohol intoxication on some parameters of nitrogenous metabolism in rats with alloxan diabetes].

Acute alcohol intoxication in rats with alloxan diabetes is accompanied by the increase of urea and uric acid and by the decrease in free fatty acids in serum. In the liver of experimental animals the increase of activity of glutamate dehydrogenase, AMP deaminase, and tyrosine transaminase was found.

Biochemical and behavioral effects of soman vapors in low concentrations.

Soman belongs to the most dangerous nerve agents because of the low effectiveness of the presently available antidotes. Soman acts by inhibiting acetylcholinesterase (AChE) both peripherally and centrally, with a subsequent accumulation of neuromediator acetylcholine and other metabolic changes. From the data published in literature it can be concluded that exposure to nerve agents leading to acute effects or chronic exposure to nerve agents may lead to delayed and persistent adverse effects. The aim of this study was to demonstrate changes in AChE and butyrylcholinesterase (BuChE) activities, stressogenic markers (i.e., tyrosine aminotransferase [TAT] activity, and plasma corticosterone level), and neuroexcitability and behavior 24 h and 4 wk following a single soman inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the dose of soman) 24 h and 4 wk after the exposure. A similar decrease in AChE activity in different brain parts was observed. One of the stressogenic parameters, TAT, was changed 24 h after exposure only. Behavior of experimental animals was changed 24 h after the exposure, and 4 behavioral parameters persisted 4 wk after the exposure. Neuroexcitability was increased at 24 h after the exposure and had become about normal 4 wk after the exposure. Summarizing, long-term effects (4 wk) were observed after inhalation exposure of guinea pigs to sublethal concentrations of soman.

Biochemical effects of low level exposure to soman vapour.

The aim of this study was to demonstrate changes in acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities, tyrosine aminotransferase activity (TAT) and plasma corticosterone level, neuroexcitability and behavior following 24 hours and 4 weeks of soman sublethal inhalation exposure at low level. AChE activity in erythrocytes and BuChE activity in plasma was decreased (dependent on the concentration of soman) 24 h and 4 weeks after the exposure. Similar decrease in AChE activity in different brain parts was observed. One of stressogenic parameters (TAT) was changed after 24 h exposure only. 4 weeks after the exposure, these parameters (corticosterone and TAT) were in the range of normal values. Behaviour of experimental animals was changed 24 h after the exposure persisting 4 weeks after the exposure as well as neuroexcitability.

Increased excretion of aromatic amino acid catabolites in animals infected with Trypanosoma brucei evansi.

Aromatic amino acid catabolism by Trypanosoma brucei evansi was investigated in vivo using C3HeB/FeJ mice. The major catabolites detected by gas chromatography in the urines of infected animals were phenylpyruvic acid, 4-hydroxyphenylpyruvic acid, and indole-3-pyruvic acid. Identity of each compound was confirmed by gas chromatography-mass spectrometry. Concentrations of catabolites in urine of infected mice were correlated with parasitemia and returned to normal following suramin treatment. Other aromatic amino acid metabolites, including indole-3-acetic acid, indole-3-lactic acid, and 4-hydroxyphenyllactic acid, were detected in urine from infected animals by gas chromatography mass spectrometry, although quantities were too low to be quantified reproducibly. Both phenylpyruvic acid and 4-hydroxyphenylpyruvic acid were also detected in urine of dogs and donkeys experimentally infected in Egypt with a recent field isolate of T. b. evansi. Tryptophan metabolites could not be assayed in dog and urine samples because formalin, which degraded the indole acids, had to be added before the samples could be imported into the U.S. Finally, concentrations of urinary catabolites during infection were correlated with the tyrosine aminotransferase activity in infected mouse sera.

Diagnosis of trypanosomiasis in experimental mice and field-infected camels by detection of antibody to trypanosome tyrosine aminotransferase.

Sera from animals with acute and chronic Trypansoma evansi infections were examined directly for trypanosome tyrosine aminotransferase activity and indirectly for their ability to inhibit tyrosine aminotransferase activity. It was shown that sera from acutely infected mice and camels with high parasitemias contained significant levels of trypanosome tyrosine aminotransferase activity. In contrast, the sera from chronically infected mice and camels did not contain significant tyrosine aminotransferase activity, but they were able to neutralize the enzyme activity in trypanosome homogenates. The sera from camels with other pathological conditions did not neutralize this enzyme activity. It is suggested that the inhibitory factor in the chronic sera is antibody. The potential use of the direct enzyme assay and the indirect neutralization assay as diagnostic tools are discussed. Finally, the use of these assays to distinguish between early (acute) and late (chronic) infections are also suggested.

[Enzyme adaptation and "vitauct" process]. / Enzymadaptation und "Vitauct"-Prozess.

The existence of a so-called "vitauct process" is discussed by means of the glucocorticoid-induced stimulation of tyrosine aminotransferase activity. Own experiments show that the highest possible stimulation of the enzyme by cortisol and stress in the liver of old Wistar rats is not lower than in young-adult animals. After stress and 4 h after cortisol injection of 0.75 mg/100 g b.w. even a higher sensitivity seems to exist. A main problem for the interpretation of the results is the treatment of the control animals. Stress-free animals and animals to which the hormone-free solvent only under light ether narcosis was injected i.p. (stressed controls) were used. With the lowest injected hormone dose (0.25 mg cortisol/100 g b.w.) the results lie below those of the stressed controls. As a result of the findings of this paper, of the role of the enzyme, and of different influencing factors (e.g., glucocorticoid receptors) we suggest that the used model does not allow a conclusive decision about the existence of a vitauct process.

Vitiligo, psoralen, and melanogenesis: some observations and understanding.

Since the etiology of vitiligo is still unknown, we searched for some abnormal biochemical parameters, if any, in subjects with vitiligo. Higher urinary excretion of indole metabolites in vitiliginous patients have been noted, in association with higher dioxygenase, superoxide dismutase, and tyrosine aminotransferase activity in their serum. Similar results have also been found in an animal model, Bufo melanostictus, during induced tyrosinase inhibition. Treatment with psoralen can reverse the parameters, except tyrosine aminotransferase, to a normal level. Although psoralens are not the magic bullet for the therapy of vitiligo, they are still being used as a chemotherapeutic agent against vitiligo on a major scale to date. Tryptophan was found to participate in the pathway of melanogenesis, as a precursor as well as a positive regulator of tyrosinase. Its behavior in this regard is much more similar to the conventional substrates tyrosine and dopa (dihydroxyphenylalanine). In consideration of combined participation of tyrosine and tryptophan in the synthesis of melanin and its breakdown, the possible influence of different enzymatic reactions, like mono-oxygenase, dioxygenase, and deamination, has been suggested.

[The safety problem and a physiological strategy for using glucocorticoid hormones]. / Problema bezopasnosti i fiziologicheskaia strategiia primeneniia gliukokortikoidnykh gormonov.

Principal problems of glucocorticoid hormone application in non-endocrine diseases are discussed proceeding from the mechanism of their action and the role in organism's life. It appeared that the hazard of glucocorticoid therapy is mainly due to the absence of a test for sufficiency and real needs in these hormones. It was shown that the test has to be introduced reflecting on the whole body level the glucocorticoid activity in the cell, that is similar to blood glucose in relation to insulin. The introduction of free blood tyrosine as such test appears to allow the development of safe individual strategy for the usage of glucocorticoids.

Short time action of antirheumatic substances on the liver of rat. Protective effect of tryptophan + methionine.

1. A large number of drugs, including some antirheumatic substances, cause liver damage. 2. Only a little information is available, so far, on the causes of such damage and their prevention. 3. From studies on a number of antirheumatic drugs as to their effect upon the liver, three categories could be differentiated: (a) large effect (b) low effect (c) no effect. 4. Judging from our results, the liver damage is induced via a disturbance of the NAD-adenoribosylation metabolism.

Tyrosine transaminase activity in normal and cirrhotic liver.

Most cirrhotics have tyrosinemia and subnormal tyrosine tolerance; in some the ability to metabolize p-hydroxyphenylpyruvic and homogentisic acids is impaired. In previous studies, the initial transamination appeared to be the rate-limiting step. In this study, hepatic tyrosine transaminase activity was compared in liver biopsies from eight noncirrhotic and ten cirrhotic subjects to determine whether the subnormal tyrosine tolerance was related to decreased maximal activity of this enzyme. Fasting plasma tyrosine in the cirrhotics (133 +/- 43 micromol/liter) was significantly higher (P less than 0.005) than in the noncirrhotic subjects (64 +/- 25 micromol/liter). Tyrosine transaminase activity in the cirrhotic livers (42 +/- 11 micromol PHPA/g liver/hr, or 0.47 +/- 0.1 micromol PHPA/mg protein/hr) was not significantly different from the enzyme activity in the noncirrhotic liver (43 +/- 7 micromol PHPA/g liver/hr, or 0.39 +/- .12 micromol PHPA/mg protein/hr.) Thus elevated tyrosine levels in cirrhotics cannot be explained by decreased tyrosine transaminase activity in the liver, and other explanations must be sought.

[Change in the activity of tyrosine aminotransferase in the tissues of rabbits with various levels of corticosteroids in the body]. / Izmenenie aktivnosti tirozinaminotransferazy v tkaniakh krolikov pri razlichnom urovne kortikosteroido v v organizme

Experiments were conducted on rabbits. As revealed, hypocoriticism was accompanied by a reduction of the tyrosineaminotranspherase in the liver, muscles and blood plasma; the enzyme activity was unchanged in the brain and the spleen. An increase of the corticosteroid level in the organism after the administration of hydrocortisone to the intact and adrenalectomized animals led to increase of the enzyme activity in the tissues under study; the effect of hydrocortisone action depended on the initial hormonal background in the organism and the duration of the hormone administration. A single ACTH administration to the intact rabbits was accompanied by increase in the enzyme activity in the liver and the spleen, whereas to the adrenalectomized animals--in the brain, muscles and the blood plasma. A repeated administration of both hormones decreased the enzyme activity in the brain and the liver.