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Experiments on the Wistar rats showed that neonatal daily injections of phenobarbital (35 mg/kg) during first 3 days of life resulted in the enzyme imprinting of liver microsomal monooxygenases. Rise in the activities of liver microsomal oxidation enzymes is constantly maintained during all the life leading to increase in average lifespan of rats. Analysis of the survival curves in Gompertz equation co-ordinates showed that enzyme imprinting by phenobarbital caused changes in mortality patterns at different stages of ontogenesis. The phenomenon of enzyme imprinting by phenobarbital and lifespan prolongation was registered only in females but not in males. An inverse correlation was found between the duration of phenobarbital sleeping time and lifespan of rats.

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Effect of the enzyme imprinting by phenobarbital upon alterations of hepatic microsomal monooxygenase activities and lifespan of Wistar rats has been studied. Phenobarbital-sodium (3.5 mg/100 g body weight per day, i.p.) was injected during 1-3 days after birth. This resulted in the enzyme imprinting of the liver microsomal monooxygenases, however, this effect being observed in female but not male rats. In the phenobarbital treated female rats of different age the duration of sleeping time was significantly lower than that in control animals, whereas it did not differ substantially in male rats. The cytochrome P-450 content increased by 34.5% in phenobarbital treated female rats in the age of 12 months in comparison with control animals. A mean lifespan of experimental female rats increased by 17.5% compared to the level of control animals and did not change in male rats. The analysis of survival of animals in Gompertz equation coordinates showed that enzyme imprinting by phenobarbital caused changes in the mortality patterns at different stages of ontogenesis in experimental female but not male rats. An inverse correlation was found between the duration of pentobarbital sleeping time and lifespan of female and male rats.

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The results obtained show the essential changes in functional state of hepatocyte's plasmatic membrane due to the implantation of human ApoA1 gene to the rat liver. The changes in phospholipid composition, hyperpolarization, increase in activity of membrane bound enzymes, cytochrome P-450 and biosynthesis of liver total proteins have been found. The essential changes characterizing cell effect were more marked in the adult rats, and membrane effect in the old ones.

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As a result of experiments carried out on adult (6-8 months) and old (24-26 months) male rats of the Wistar line it is established that emotional-pain stress results (in one day) in essential increase in the activity of spontaneous, NADPH--and ascorbate-dependent peroxidation of lipids in the liver microsomes, which is expressed in the old animals rather than in the adult ones. The induced peroxidation of lipid six days after the stress effect remains activated in the adult rats and decreases to the control level in the old ones. Accumulation of lipoperoxidation products in the membrane structure of hepatocytes is accompanied by the changes of physico-chemical parameters of microsomal membranes, microviscosity and surface potential in particular. Availability of conformational shifts of membrane proteins of microsomes under the conditions of lipoperoxidation activation evoked by the stress is accompanied by changes of physico-chemical parameters of microsomal membranes. Changes in the membrane structure are expressed to the less extent in the microsomes of old rats liver as well, that evidences for the age-dependent differences of adaptational capacities of the organism.

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The experiments on adult (6-8 months) and old (24-26 months) male Wistar rats have shown that treatment of animals with phenobarbital results in a significant increase in hepatic microsomal enzyme content, plasmatic membrane Na+, K(+)-ATPase activities and the elevation of hepatocyte membrane potential value. It is presumed that the changes in plasmatic membrane characteristics during microsomal monooxygenase induction are related to the synthesis of specific intracellular factors (invertors). This assumption was verified by the experiments with 'cellular hybrid' system (cytosol--plasmatic membranes). Using this cross-systems, it was shown that the hepatocyte cytosol of rats treated with phenobarbital produced Na+, K(+)-ATPase activity. The extent of Na+, K(+)-ATPase activation was essentially lower when cytosol derived from old rat hepatocytes was used. The presence of specific factors that activated Na+, K(+)-ATPase in hepatocyte plasmatic membrane was also discovered in blood serum of induced adult and old rats.

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A study was made concerning the role of adrenergic and cholinergic neural regulation in the functional activity of enzymes of microsomal oxidation in the liver. Experiments were performed on adult and old rats using surgical denervation of liver (vagotomy and sympathotomy). The results obtained showed changes that occurred in the monooxygenase activity (aminopyrine demethylase and aniline hydroxylase), as well as in the isoform composition and inductive synthesis of cytochrome P-450. The neural control over liver detoxication function was found to weaken in old age.

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Lipid peroxidation (LPO), physico-chemical properties of the membranes and isoformic composition of microsomal cytochrome P-450 from the rat liver were studied under conditions of antioxidant insufficiency (AOI) which was modelled by exclusion of alpha-tocopherol from the animals' ration. An insignificant accumulation of microsomal diene conjugates and schiff bases against a sharp increase of the ability to the prooxidant stimulated LPO in vitro took place. A significant decrease of membrane lipid microviscosity and a change in surface properties of microsomal membranes of rats with AOI was determined. Absence of alpha-tocopherol in the ration was accompanied by a significant change in the content of separate isoforms of cytochrome P-450 exhibited in growth of a polypeptide with m. w. 54 kDa and the lowering of proteins with m. w. 48 and 50 kDa. Less intensive quenching of tryptophan fluorescence by acrylamide was also revealed, which testified to a lower accessibility of the quencher to membrane proteins or their fluorophore sites. Modification of lipid composition and of physicochemical properties of the rat liver membrane microsomes which was observed at AOI was significantly correlated by pretreatment with the antioxidant 4-methyl-2,6-ditretbutylphenol (ionol).

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Transfer of human ApoA1 gene within the molecular construction which provides its expression, to the liver of the adult and aged rats resulted in the appearance of human protein in their blood, and was accompanied by changes in the content of high-density lipoproteins and of their subclasses HDL(3) and HDL(2), as well as by the shifts in their protein and lipid composition. Synthesis of human ApoA1 was more marked in the organism of adult rats, and gene-regulatory shifts in aged rats.

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The role of adrenergic and cholinergic neural regulation in the functional activity of the liver microsomal oxidation enzymes has been studied. The experiments on adult and old rats using surgical denervation of the liver (vagotomy and sympathectomy++) have revealed changes in the monooxygenase activity (aminopyrine demethylase and aniline hydroxylase), in isoform composition and inductive synthesis of cytochrome P-450. The neural control over detoxication function of the liver is found to weaken in old age.

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Experiments, carried out on adult and old animals with different specific lifespan (rat, guinea pig, rabbit, and dog), revealed age-related changes in content and activity of liver microsomal oxidation enzymes (cytochrome P-450, b5, aminopyrine demethylase, aniline hydroxylase). The changes become more pronounced with age. This allows to classify these species as chronobiological ones. A negative correlation between the specific lifespan and the level of decrease in activity of aminopyridine demethylase, an integral index of electron transport rate in microsomal chain, in aged animals was established.

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Positive correlation between the activity of enzymes of microsomal oxidation of the liver and individual lifespan was shown in experiments on Wistar female rats. The use of test of duration of pentobarbital hypnosis provides for the distinction between the animals with low and high life expectancy.

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Plasmic membrane hyperpolarization resulted in a significant activation of the cell genome and a stimulation of the synthesis of total RNA and protein of hepatocytes. Changes in the level of membrane potential are thought to be one of the mechanisms of regulation of cell's genetic apparatus. In old age the stimulating effect of hyperpolarization is weakened that may be a cause of a change in protein biosynthesis.

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Experiments were performed on Wistar male rats, starting from the 28th month of age. The effect of dietary sorbent (non coated nitrogen-containing carbon administered as 10 day courses at 1 month intervals in dosage of 10 ml/kg) on lifespan and a number of biological indices were studied. Enterosorption resulted in the increase of mean and maximal lifespan by 43 and 34% respectively. Analysis of the effect of enterosorption on activity of microsomal enzymes, intensity of total RNA and protein biosynthesis, lipid metabolism, formation of free radicals etc. showed that it produced a positive influence on the functional state of the studied systems and increased the organism's adaptive capacities. Enterosorption was found to delay the rate of onset of age-related structural changes in the organs and tissues.

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Distinct activation of both nonenzymatic and enzymatic forms of lipid peroxidation, with prevalence of the nonenzymatic reactions was detected in liver microsomes of rats kept on vitamin E-deficient diet. Content of main microsomal oxygenase cytochrome P-450 was unaltered, while activity of oxidative hydroxylation of the substrate of the type I (aminopyrine) was slightly decreased. After administration of the inhibitors of free radical reactions alpha-tocopherol and ionol into the animals reactions of lipid peroxidation and metabolism of xenobiotics were corrected to some degree in liver microsomes. At the same time, aminotransferase activities were normalized in liver subcellular fractions.

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Liver EPR signals were studied in adult (8 months) and old (24 months) Wistar male rats after the 30 days course of enterosorption carried out daily. The signals were analyzed at the values of g = 1.94, 2.00, 2.25, 2.035, 2.16, 2.10 and 1.97. Age-dependent differences were found in liver EPR signals of intact animals, i. e. the intensity of signals of g = 1.97, 2.00, 1.97 and 2.25 was decreased in old animals. In adult animals enterosorption caused a decrease of signals of g = 2.25, 1.94, 2.00, 2.16 and 2.10. In old animals the treatment led to a dissimilar effect: the intensity of signals was decreased at the ranges of g = 2.25, distinctly increased at g = 1.97 and unaltered at the other EPR signal values studied. Geroprotective action of enterosorption is discussed considering the decrease in enzymatic activity of electron transport systems due to the treatment studied.

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The effect of repeated courses of enterosorption upon the mean and maximal lifespan and some functional and metabolic indices was determined in 28-month-old Wistar rats. Significant increase of mean and maximal lifespan of old rats was noted at certain regimens of enterosorption. The experimental animals demonstrated less marked age-related structural and ultrastructural changes in the liver, kidneys, myocardium, intestines, pancreas, as compared with control animals. Enterosorption leads to a reduction of pentobarbital-induced sleep, decrease of content of cytochrome P-450, blood cholesterol and triglycerides, cardiac and cerebral tissue cholesterol, total lipids, liver cholesterol and triglycerides. Enterosorption was found to increase the RNA and protein biosynthesis in the liver, kidneys and adrenals of old animals.

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