Free heme pool and activity of key enzyme of heme synthesis in the rat liver under action of agents affecting reduced glutathione level.

The decrease of GSH level in the rat liver was found to be accompanied by an increase of tryptophan 2,3-dioxygenase (TDO) heme saturation during first hours after HgCl2, phenylhydrazine (Ph) injection or rhabdomyolysis (the coefficient of correlation -0.978). The activity of the key enzyme of heme synthesis--5-aminolevulinate synthase (ALAS) was 2.5-fold increased in the first hours after Ph injection and rhabdomyolysis. Glutathione injection in vivo as well as CdCl2 caused the increase of GSH content and the inhibition of ALAS. The coefficient of correlation for GSH content and ALAS activity under the action of agents altering both these parameters (CdCl2, Ph, GSH injection and rhabdomyolysis) is 0.938. Taking into account the presence of heme regulatory motif with conserved cystein in many proteins, including ALAS and TDO (accession number in SwissProt database AAH61793 and P21643, respectively), the link between alterations of GSH content, ALAS activity and heme saturation of TDO in the rat liver could be proposed. The further experiments should be performed in order to elucidate the mechanisms of GSH level influence on free heme pool formation in the liver cells.

[Metabolism of heme and hemeproteins and some indices of the antioxidant system in rat erythrocytes and tissues under anemia caused by phenylhydrazine]. / Metabolizm hemu ta hemoproteïniv i deiaki pokaznyky antioksydantnoï sistemy v erytrotsytakh i tkanynakh shchuriv pry fenilhidrazynovii anemiï.

The decrease of activity of several antioxidant enzymes in erythrocytes in the first hours after injection of phenylhydrazine to rats (7 mg per 100 g body weight) was found to be accompanied by accumulation of heme-containing compounds in rat serum and appearance of free heme in liver and decrease of cytochrome P450 content. Tissue-specific features of dynamics of activity of enzymes studied and reduced glutathione content were revealed, that might be caused by differences in total and free heme content in these organs. The role of key enzymes of heme biosynthesis and degradation in adaptation of metabolism under phenylhydrazine action is discussed.

Regulation of delta-aminolevulinate synthase activity during the development of oxidative stress.

Activities of rat liver delta-aminolevulinate synthetase (delta-ALAS), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH), GSH content in the liver, and the absorption spectrum of blood serum were investigated after CoCl2, HgCl2, or beta-adrenoblocker (propranolol) injection and after CoCl2 and propranolol co-administration. Inhibition of the activity of the key heme biosynthesis enzyme delta-ALAS was most pronounced and prolonged during the first hours after CoCl2 and CoCl2 plus propranolol injections; this was associated with accumulation of Co2+--protoporphyrin-containing products of hemolysis. Inhibition of delta-ALAS after propranolol injection is not mediated by hemolysis. A decrease in GSH content precedes the induction of heme biosynthesis only in the case of HgCl2 administration, and this was associated with inhibition of GR and G6PDH. The decreased GSH content during the first hours after injection of propranolol and co-administration of CoCl2 and propranolol was not followed by increase in delta-ALAS activity 24 h after the injection. The mechanisms of the increase in the free heme content in the liver during the early stages of oxidative stress and the regulation of the key heme biosynthesis enzyme are discussed.

[Metabolism of heme and hemoproteins in rat liver upon administration of mercuric chloride]. / Metabolizm gema i gemoproteinov v pecheni krys pri vvedenii khlorida rtuti.

Rat liver delta-aminolevulinate synthase (delta-ALAS) activity in the early period after mercury chloride administration (0.7 mg per 100 g body weight) was found to be followed by free heme level increase, which was registered by the increase of heme saturation of the heme-binding protein tryptophan-2,3-dioxygenase (T-2,3-DO). delta-ALAS and heme oxygenase activity increase was observed 24 h after action. Microsomal cytochromes P450 and b5 levels decrease. Heme saturation of the T-2,3-DO returned to control level. Heme oxygenase and T-2,3-DO induction promoted hepatocytes free heme level normalization. Heme oxygenase and delta-ALAS induction role in the liver cells defense from the oxidative damage is discussed.

[Content and composition of lipoproteins of rat blood and liver and various parameters of oxidative stress during administration of cobalt chloride]. / Soderzhanie i sostav lipoproteinov krovi i pecheni krys i nekotorye pokazateli okislitel'nogo stressa pri vvedenii khlorida kobal'ta.

Cobalt chloride effect on rat liver and serum blood lipoproteins content and composition and on some characteristics of lipid peroxidation and oxidative stress was investigated. The activation of free-radical oxidation and oxidative stress development were judged from the dynamics of lipid peroxidation products accumulation, from cathepsin D unsedimental activity and from the alteration of microsomal cytochrome P-450 content and from activity of a number antioxidative enzymes. In order to evaluate the state of glutathione-defence system the activities of glutathione peroxidase, glutathione S-transferase, glutathione reductase and some NADPH-generating enzymes and reduced glutathione level alteration were studied in liver. The data obtained show that the cobalt chloride injection leads to the development of the oxidative stress and to activation of some antioxidant defence system, namely, glutathione-depending enzymes, and of microsomal cytochrome P-450 catabolism. The system blood lipoproteins (liver lipoproteins was found to participate in metabolism adaptation under oxidative stress and in maintenance of biological membranes structure and functioning.