[Clinical and anamnestic analysis of multiple primary neoplasms with lesions of the endometrium in women of the Novosibirsk region].

Based on the study of 60 women who were treated at the gynecology department of the Novosibirsk Regional Oncology Dispensary from 2003 to 2013 with a diagnosis of primary multiple synchronous and metachronous neoplasia with endometrial lesion it was found that the most common risk factors for this disease could be considered: overweight and obesity; late age at onset of menarche; late age of menopause; concomitant cardiovascular diseases and disorders of the endocrine metabolism.

[Microrna, evolution and cancer].

MicroRNAs are known as a posttranscriptional negative regulators of gene expression by binding to the 3'UTP of target mRNAs in cytoplasm. More than 1600 microRNAs expressed in human cells, are involved in the regulation of embryogenesis, differentiation, cell cycle, apoptosis, senescence, thus determining cell fate. Up to 60 % of protein coding genes are under their control. Various sets of microRNAs found in different human tissues under normal and pathological conditions, including cancer, suggest that miRNAs are involved in most cellular pathways. To date, there is no doubt that regulatory potential of the genome is largely determined by miRNAs. In our study, we performed a comparative phylogenetic analysis of the origin and evolution of the total set of 1048 miRNAs in the human genome and investigated the role of certain miRNAs in carcinogenesis of thyroid and mammary glands, as potential diagnostic and prognostic biomarkers of malignancy. Analysis of phylogenetic distribution of miRNAs in the human genome has shown four peaks of appearance of new miRNA genes in the evolution from Methazoa to H. sapiens. The highest amount of new miRNA genes appeared after divergence of H. s. from common ancestor with P. t. Expansion of transposable elements in genome was accompanied by the origin of new miRNA genes on the basis of their sequences. More than 14 % from 1600 miRNAs of human genome originated from mobile elements and still remain. Profiles of expression of 5 miRNAs, pertaining to oncomicroRNAs - miR-21, -221, -222, -155 and -205 - allow distinguishing ductal invasive carcinoma of mammary gland and thyroid papillary carcinoma. The data obtained suggest different ways and roles of participation of the same miRNAs in carcinogenesis of thyroid and mammary glands. So, these miRNAs and profiles of their expression might be used in the diagnosis and prognosis of cancer.

[A study of the interaction of substrates with cytochrome P-450 by a method of UV- and 1H-NMR spectroscopy]. / Izuchenie vzaimodeistviia substratov s tsitokhromom P-450 metodom UF- i 1H-IaMR-spektroskopii.

Acceleration of substrate longitudinal relaxation (T1) was used to study cytochrome P-450-aminopyrine (1st type substrate) and P-450-4-methoxypyridine (2nd type substrate) complexes. Dissociation constant, T1 and/or residence time of substrate in the complex can be obtained from the dependence of T1 of substrate protons on substrate concentration. Basing on the relaxation times, distances between Fe3+ ion in the active site and protons of the substrate moiety were determined. For aminopyrine all the distances proved to be about 8 A. In the P-450-4-methoxypyridine complex the pyridine nitrogen is directed towards Fe3+ ion. Cytochrome P-450 is compared with its denatured form, cytochrome P-420, and metmyoglobin.

[Change in activity of microsomal cytochrome P-450-dependent monooxygenases from rat liver exposed to chronic low doses of radiation]. / Izmenenie aktivnosti mikrosomal'nykh tsitokhrom-P-450-zavisimykh monoksigenaz pecheni krys pod vliianiem khonicheskogo vozdeistviia malykh doz radiatsii.

The activity changes of cytochrome P-450-dependent monooxygenases of hepatic microsomal fraction were studied in, experimental animals after prolonged application (1 month) of low radiation doses (0.258 mkl/kg). The obtained results show the increase in catalytic activities of main forms of cytochrome P-450, participating in steroid hydroxylation, as well as the decrease in total content of cytochrome P-450 in hepatic microsomal fraction and the lowering of its demethylase activity.

[Activity of the liver monooxygenase system after induction with phenobarbital in the early neonatal period]. / Issledovanie aktivnosti monooksigenaznoi sistemy pecheni pri induktsii fenobarbitalom v rannem neonatal'nom periode.

Activity of enzymes participating iH metabolism of xenobiotics was studied after their induction by means of phenobarbital in rats of Wistar strain within first weeks of life. After administration of phenobarbital into the neonatal rats content of cytochrome P-450 and activity of NADPH-cytochrome c reductase were increased in liver microsomes. The rates of N-demethylation of benzphetamine and benz(alpha)pyrene hydroxylation were also increased after administration of the inducing agent. Immunochemical studies with antibodies towards some forms of cytochrome P-450 showed that enzymatic forms of cytochrome P-450 PB were induced; this enzymatic form is predominant in adult animals treated with phenobarbital. When the metabolism of benzphetamine and benz(alpha)pyrene was inhibited by antibodies, several forms of cytochrome P-450, involved in these metabolic reactions were found in neonatal rats, whereas in the adult animals only one form of the enzyme exhibited activity towards these substrates.

[Dynamics of accumulation of CYP2B mRNA in the liver of rats from various strains during induction with xenobiotics]. / Dinamika nakopleniia mRNK dlia CYP2B v pecheni krys razlichnykh linii vo vremia induktsii ksenobiotikami.

The transcription level of CYP2B1/2 gene in the liver of Sprague-Dawley (SD), Brattleboro (BL) and Wistar (W) rats treated with isosafrol (IS), Arochlor 1254 (AC), phenobarbital (PB) and triphenildioxane (TPD) was studied. The quantity of CYP2B1/2 mRNA was assessed by dot-blot analysis at 18, 48 and 72 hours after inducers administration. The mRNA level in SD and BL rats treated with PB reached its maximum by 18 hours followed by fast decline. For W strain the amount of mRNA reached maximum by 48 hours after treatment. After TPD treatment this parameter for SD, W rats reached maximum by 18 hours, while for BL-72 hours. No differences in the mRNA amount in rats treated with IS and AC were detected. We are not aware of any other data concerning the dynamics of CYP2B1/2 mRNA accumulation during IS-induction. We showed that in this case a maximum of mRNA was reached by 18 hours. Thus, we revealed inducer- and strain-dependent of differences in mRNA accumulation dynamics.

[Change in the rat liver microsomal monooxygenase system upon induction with phenobarbital in acute pancreatitis]. / Izmenenie mikrosomal'noi monooksigenaznoi sistemy pecheni krys pri induktsii fenobarbitalom na fone ostrogo pankreatita.

While injecting phenobarbital (PB) into the rats, on the second day of an experimental pancreatitis, cytochrome P450 2B1 and 2C6 activities were found, on the forth day of disease, as being considerably higher in comparison with data obtained in sham-operated control animals. On the tenth day of the acute pancreatitis (in three days upon having the induction canceled), activity of the cytochrome P450 isozymes was lower than that of control animals. Thus, the rats with acute pancreatitis, are characterized by an increased indycibility of liver monooxygenases. In addition, a release from induction (decrease of these activities upon having the induction canceled) proceeds faster than that in control animals.

[Interstrain differences in enzymatic activity of CYP2B1 and expression of its gene in the rat liver during induction with phenobarbital and triphenyldioxane]. / Mezhlineinye razlichiia v fermentativnoi aktivnosti CYP2B1 i ékspressii ego gena v pecheni krys pri induktsii fenobarbitalom i trifenildioksanom.

The interstrain differences in hepatic 7-pentoxyresorufin-O-dealkylase and 16 beta-androstendione hydroxylase activities specific for cytochrome P450 2B1 have been found in Sprague-Dawley, Brattleboro and Wistar rats treated with with phenobarbital, triphenyldioxane. Similar differences were found in the accumulation of corresponding mRNAs suggesting differences in expression of cytochrome P450 gene. Analysis of the enzymatic activity and mRNA level revealed positive correlation between these parameters. Thus, differences in transcriptional activity of CYP2B1 gene during induction by phenobarbital and triphenyldioxane may be one of reasons for interstrain differences between enzymatic activities of rat liver cytochrome P4502B1.

[Immunological study of the identity of cytochrome P-448 in the mouse and rat liver after induction with 3-methylcholanthrene]. / Immunokhimicheskoe issledovanie identichnosti tsitokhromov P-448 pecheni myshei i krys pri induktsii 3-metilkholantrenom.

As shown by means of Ouchterlony double immunodiffusion technique after induction with 3-methyl cholanthrene the antibodies towards cytochrome P-448 from rat liver tissue developed a clear-cut precipitation line with homologous antigen and interacted also with cytochrome P-448 from mice liver tissue although the precipitation was less distinct. Antibodies towards mice liver cytochrome P-448 reacted also with the rat liver cytochrome P-448 but less distinctly as compared with the mice cytochrome. At the same time, these antibodies inhibited similarly the benz(a)-pyrene-hydroxylase reaction, catalyzed by both mice and rat cytochromes P-448. Partial immunological identity appears to occur in the cytochromes studied. Role of total antigenic determinants in enzymatic reactions catalyzed by cytochrome P-448 is discussed.

[The characteristics of the effect of centimeter-range microwaves on drug pharmacokinetics in the body of experimental animals]. / Osobennosti vliianiia mikrovoln santimetrovogo diapazona na farmakokinetiku medikamentov v organizme éksperimental'nykh zhivotnykh.

The experiments on 130 rat males have shown that the exposure of the animals' liver to centimeter microwaves enhances catalytic activity of P-450p cytochrome, an enzyme of drug microsomal metabolism. However, changes in pharmacokinetic parameters of elimination from the blood of the drugs based on microsomal substrates of hepatic enzymatic system are more dependent on the microwaves' impact on physiological factors modifying drug pharmacokinetics. This implies the necessity of pharmacokinetic investigations in each individual case of combining drugs with microwaves.

[The effect of low-intensity physical therapeutic factors on the microsomal oxidative systems of the liver in an experiment]. / Vliianie nizkointensivnykh fizicheskikh lechebnykh faktorov na mikrosomal'nye okislitel'nye sistemy pecheni v éksperimente.

The authors' rat experiments have shown that inhibition of pro-oxidant reactions in hepatocyte microsomal fraction in response to hepatic exposure to low-intensive IR-laser radiation and low-intensity ultrasound combines with multidirectional action of these factors on the basic enzymes of the other oxidant system of hepatocyte microsomes--cytochrome P-450-dependent monooxigenase system.

[Tissue-specific expression of hormonal carcinogenesis target genes in rats treated with polycyclic aromatic hydrocarbons].

We have investigated the effect of polycyclic aromatic hydrocarbons (PAHs) on estrogen-metabolizing genes CYP1A1, CYP1B1, CYP19 and ERalpha and cyclin D1 genes, which control of cell division in estrogen-depended tissues. Treatment of rats with benzo(a)pyren (BP) or 3-methylcholantrene (MC) significantly up-regulated CYP1A1, CYP1B1 gene expression in liver, uterus and ovary, whereas alfa-naphthoflavone (alpha-NF) did not have any effect. The high level of aromatase gene (CYP19) expression was detected in ovary only. Treatment of rats with BP or MC significantly down-regulated expression of this gene (15- and 5,5-fold, respectively), whereas alpha-NF did not have any effect. BP produced an increase in ERalpha and cyclin D1 gene expression in rat liver. This effect was not seen with MC and alpha-NF. ERalpha and cyclin D1 mRNA levels were unchanged in uterus of rats after PAHs treatment. On the other hand, BP treatment caused an increase of the ERalpha and cyclin D1 mRNA levels (3,5- and 2,5-fold, respectively) in ovary, whereas MC and alpha-NF did not have any effects. Thus, our results give evidence for tissue-specific effects of PAHs on expression of genes, which participate in hormonal carcinogenesis. Moreover, the fact that BP and MC treatment affects the expression of estrogen-metabolizing genes and genes, which control of cell division, supports the view that PAHs may be one of the causes of endocrine disorder and consequent hormonal carcinogenesis.

[Isolation and characterization of multiple forms of cytochrome P-450 from liver microsomes of 3-methylcholanthrene-induced Wistar rats]. / Poluchenie i kharaktteristika mnozhestvennykh form tsitokhroma P-450 iz mikrosom pecheni krys linii wistar, indutsirovannykh 3-metilkholantrenom.

Chromatography on 1.8-diaminooctyl-Sepharose and DEAE-Sephacel resulted in 4 fractions of cytochrome P-450 from liver microsomes of 3-methylcholanthrene-induced Wistar rats. All the four fractions differed in terms of their absorption maxima in the CO-reduced state, Mr and catalytic activity. Only one cytochrome fraction (cytochrome P-450 C) possessed a high activity upon benz(a)pyrene hydroxylation. All cytochrome P-450 forms were characterized by a low rate of aminopyrine N-demethylation. Antibodies against cytochrome P-450 C (P-448) (anti-P-448) were raised. Cytochromes of fractions A, B1 and B2 in the Ouchterlony reaction of double immunodiffusion did not give precipitation bands with anti-P-448. Neither of the four cytochrome P-450 forms interacted with the antibodies raised against cytochrome P-450 isolated from liver microsomes of rats induced with phenobarbital. The procedure developed is applicable to the isolation of multiple forms of cytochrome P-450 from liver microsomes of 3-methylcholanthrene-induced rats. Using rocket immunoelectrophoresis, cytochrome P-450 C possessing a high (as compared to benz(a)pyrene metabolism) activity (18 nmol/min/nmol cytochrome) and a high (60-70%) content in 3-methylcholanthrene-induced rat liver microsomes was shown to give a relatively high yield.

[Induction of cytochrome P-450 forms in liver microsomes of rats in the early neonatal period after administration of phenobarbital and 3-methylcholanthrene]. / Issledovanie induktsii tsitokhroma P-450 mikrosom pecheni krys rannego neonatal'nogo perioda pri vvedenii fenobarbitala i 3-metilkholantrena.

The activity of cytochrome P-450 dependent monooxygenase system from rat liver microsomes after induction by phenobarbital and 3-methylcholantrene in early neonatal period (3-16 days after birth) was studied. It was found that the total amount of cytochrome P-450 increases after injection of these inducers in neonatal rats of all age groups. In parallel, in the case of 3-methylcholantrene induction the benz(a)pyrene hydroxylase and 7-ethoxyresorufin deethylase activities increase; phenobarbital induction causes a rise in the benzphetamine-N-demethylase and benz(a)pyrene hydroxylase activities. Immunochemical analysis involving the use of antibodies specifically directed against cytochrome P-450 of adult rats revealed that the level of cytochrome P-450 in the case of 3-methylcholantrene induction increases from 5 to 50%, whereas that of cytochrome P-450 upon phenobarbital induction increases from 5 to 40% in liver microsomes of 3- and 16-day-old rats. The mode of inhibition of various substrates metabolism by antibodies in neonatal rat microsomes suggests that the 3-methylcholantrene-induced cytochrome P-448, like in adult rats, participates in the hydroxylation of benz(a)pyrene and O-deethylation of 7-etoxyresorufin. The participation of phenobarbital-induced cytochrome P-450 in the metabolism of benzphetamine and aldrin in neonatal rats is much lower than in the adult ones. The metabolism of benz(a)pyrene in phenobarbital-induced neonatal rat microsomes in all age groups is not inhibited by antibodies. The age-dependent differences in inhibition of metabolism and the increase in the benz(a)pyrene hydroxylase activity in phenobarbital-induced rats suggest that the spectrum of inducible forms of cytochrome P-450 in neonatal rats differ from that in adult animals.

[Induction of cytochromes P-4501A and 2B in various rat organs, subjected to hexachlorobenzene and aroclor 1254]. / Induktsiia tsitokhormov P-4501A i 2B v raznykh organakh krys, poluchavshikh geksakhlorbenzol i arokhlor 1254.

The activity and content of CYP1A1, CYP1A2, CYP2B1 and CYP2B in the liver, lung and kidney of Wistar rats treated with hexachlorobenzene (HCB), Aroclor 1254 (AR), methylcholanthrene (MC) and phenobarbital (PB) were studied. Administration of MC and AR caused an increase in the ethoxyresorufin (ER) and methoxyresorufin (MR)-O-dealkylase activities in all organs. The effect of HCB on lung and kidney monooxygenases was considerably lower. The penthoxyresorufin (PR)-O-dealkylase activity in extrahepatic organs was at the same level for all treatments used in this study. Western blot analysis using monoclonal antibodies against CYP1A and CYP2B also revealed a tissue-specific expression of these proteins during different inductions. Whereas in the liver during MC, AR and HCB inductions one revealed immunologically identical CYP1A1 and CYP1A2, in MC lung only CYP1A1 was observed. In the lung of AR and HCB microsomes both CYP1A1 and CYP1A2 were found. In the kidney after treatment with AR or HCB only CYP1A1 was induced. These findings suggest that inducers of mixed type cause coordinated synthesis of CYP1A1 and CYP1A2 in the lung unobserved during MC induction. After treatment of rats with PB both CYP2B1 and CYP2B2 were observed in the liver, while only the former was found in the lung and kidney. HCB treatment did not significantly affect the induction picture. In the liver and lung of AR-treated rats, besides CYP2B1 and CYP2B2, one more P-450 was revealed whose nature is under discussion now. The data obtained thus suggest that induction of different P-450s is not only tissue-specific but also depends on the inducer type.