CC BY
43
1 2 3 4
Tashkent 16,9 28,5 2,68
Fergana 41,1 50,0 2,94
Namangan 15,6 65,6 6,25
Samarkand 45,3 50,6 2,67
Navoi 63,1 31,5 5,26
Khorezm 6,0 30,0 8,0
Tashkent city 40,0 36,4 23,6
Uzbekistan 38,2 40,0 16,4
Thus, 2007 National Register data showed that 47.6% of children with type 1 diabetes had not achieved satisfactory levels of compensation and to change their treatment tactics, especially in Tashkent, Jizzakh, Andijan, Syrdarya, Khorezm and Kashkadarya regions.
Conclusions:
Thus, 2007 National Register data showed that 47.6% of children and 37.9% of adolescents with type 1 diabetes had not achieved satisfactory levels of compensation and to change their treatment tactics, especially in Tashkent, Jizzakh, Andijan, Syrdarya, Khorezm and Kashkadarya regions.
References:
1. Dedov I. I., Kuraeva T. L., Peterkova V. A. et al. Diabetes in children and adolescents. - 2002 - M. S. 91-136.
2. Dreval A. V., Remarchuk G. V., Losev V. A., Red'kin Yu. The prevalence of diabetes in children and adolescents in the Moscow re-gion.//Problems endokrinologii. - 1997. - № 2. - S. 3-5.
3. Dreval A. V., Red'kin Y. A., Misnikova I. V. Register diabetes as a medical and preventive care patient monitoring basis//Problems of Endocrinology. - 1999. - № 3. - S. 42-48.
4. Jalalova Sh. B., Rakhimova G. N., Akhmedova S. U., Alimova N. U., Zhalalova N. J. Analysis of the causes of inadequate compensation of carbohydrate metabolism in children and adolescents with diabetes 1tipa according to national register//Probl. Biology and meditsiny. - 2004. - № 2. - S. 8-11.
5. Suntsov Y. I., Santa I. I., Shestakova M. V. Screening for complications of diabetes as a method of evaluating the quality of medical care to patients// - Moskva, - 2008.
6. Shcherbachev L. N., Shireva T. Y., Suntsov Y. I., Kuraeva T. L. Type 1 diabetes in children of the Russian Federation: the prevalence, morbidity, mortality//Problems endokrinologii. - 2007. - № 2. - S. 24-29.
7. The Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus//New England journal of medicine. - 1993. -Vol.329. - P. 977-986.
8. Karvonen M., Viik-Kajander M., Molchanova E., et al. Incidence of chaeldhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group//Diabetes Care: - 2000:23:1516-1526.
9. Kyvik K. O. The epidemiology of Type 1 diabetes mellitus is not the same in young adults as in children//Diabetologia - 2004 -Vol . 47. - P. 377-384.
10. Saadine J. B., Engelgau M. M., Beckles G. L. Quality of Diabetes Care in the United States Between 1988and 1995//Clinical Diabetes -2003: 21:43-45.
DOI: http://dx.doi.org/10.20534/ESR-16-9.10-129-133
Sayfullaeva Saida Akromjanovna, Tashkent Medical Academy, Uzbekistan Associate of research laboratory Senior research E-mail: [email protected]
Influence modulators of nitric oxide synthesis on the activity of liver enzymes monooxygenase in animals with acute toxic hepatits
Abstract: A nonselective inhibitor L-NAME NOS (eNOS and nNOS) and selective inhibitor 7-NI (nNOS) inhibit, and selective inhibitor iNOS- S-MT, and the donor L-arginine NO- increase the activity of enzymes of the monooxygenase system of the liver. The inhibition of the activity of microsomal liver enzymes by the action of L-NAME statistically correlated with indicators of high activity in microsomesiNOS, content of ONO2-and low activity of eNOS. Under the action of the selective inhibitor iNOS- S-MT stimulation of functional activity of microsomal enzymes is correlated with the induction of eNOS, iNOS inhibition and the content ONO2-. The lack of correlation between the NO in the microsomes and microsomal enzymes in the liver give the reason to believe that an important factor modulating the activity of monooxygenases are isozymes NOS — eNOS, iNOS and the content of ONO2.
Keywords: pathophysiology, liver pathologies, NO- system with monooxygenase, cytochrome P-450, endothelial (eNOS), neuronal (nNOS), inducible (iNOS).
One of the fundamental problems in modern pathophysiology is to identify the relationship NO- system with other inter-system cell compartment [2, 32]. At liver pathologies a particular interest performs interrelation NO- system with monooxygenase [19, 23]. NO-system aims at maintaining homeostasis NO in tissues, organs and systems involving the family of cytochrome P-450 — of similar enzyme using the amino acid L-arginine as a substrate [7, 22]. All isoforms NO- synthase — endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) use L-arginine, oxygen and NADPH as substrates for NO synthesis [8]. Cofactors of the catalytic activity of NOS isoforms are tetrahydrobiopterin (BH4), calmodulin, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMH) [9, 15]. It is noted that the reduction of L-arginine and BH4 initiates iNOS, nNOS and eNOS to aproduct of superoxide anion radical and formation of reactive oxygen species (ROS) [4. 34]. In this process overexpression of NO [5], holds an important place which is associated with inactivation of the enzymes of DNA damage acceleration of apoptosis [29, 30, 33]. At the same time monooxygenase system, which is mainly responsible for the homeostasis of the cell in complex with antioxidants for the detoxification of ROS and superoxide, also in its reaction it uses oxygen and the same NADPH cofactorsas of NOS [1, 35, 38]. Despite the importance of these systems in the maintenance ofphysical-chemical cell homeostasis, their functional relationship at the level of the liver microsomal oxidation remains absolutely not clear. In recent years, for detecting of functional activity of NO-system, for contributing to this process various isoforms of NO-synthase are used nonselective and selective inhibitors of NOS [6, 24]. For nonselective NOS inhibitors refers L-NAME (Nw-nitro-L-Arginine Methyl Egter), which blocks constitutive forms of NOS — eNOS and nNOS, a selective inhibitor of nNOS -7-nitro-indarole (7-NI) and a selective inhibitor of iNOS — S -Methylisothiourea (S-MT) [9, 13]. As an activator, of NO-synthase is used its predecessor amino acid L-arginine [21]. To estimate the functional activity of NO-synthase, along with determining level of NO, the activity of eNOS, iNOS the substance of peroxynitrite (ONO2-) is studied in tissues. Increasing ONO2-concentration is an effective measure of expressiveness iNOS, development of destructive processes in the tissues [18, 25].
In view of the above, the purpose of the research held in liver microsomes in experimental animals with acute toxic hepatitis (OTG) is to study the influence of nitric oxide synthase modulators for the activity of monooxygenase enzymes and the elucidation of their possible functional relationship with isoenzyme activity as a part of NOS.
Material and methods. The experiments were conducted on 48 white nondescript male rats weighing 180-250g. Animals were divided into 6 groups, 8 rats each. OTG was reproduced with classical method (NH Abdullaev, Karimov H. YA. 1986.). 1, 2, 3 and 4 groups consisted of animals injected with medications produced «Acrosorganies» US after reproduction OTG: nonselective inhibitor of NOS — Nw-nitro-L-Arginine MethylEgter (L-NAME) at a dose of 10 mg/kg, selective inhibitors NOS- 7-nitro-indarole (7-NI) and S-Methylisothiourea (S-MT) at doses of 10 and 3 mg/kg, as well as aqueous solutions intraperitoneally L-arginine («Merk») at a dose of 150 mg/kg, once in the morning for 6 days and nights at 0. 5 ml per 100 g body weight. Animals with intact rats and OTG of (5 and 6gr) were used as a control group. Investigations were carried out on the 7th day. The animals were kept under standard vivarium conditions and dietary feeding. Slaughtering of ani-
mals was under Rauschnarcosis conducted by the instant decapitation. The withdrawal and isolation of subcellular fractions was performed in a cold chamber at 0 ± 4° C. The selected by preparative ultracentrifugation apparatus 601 VAC (Germany) at 105000g microsomal liver tissues fractions was determined by a two-beam spectrophotometer UV-2100 (Ltd, China) cytochrome P-450, P-420 and b5 in classical methodby T. Omura, R. Sato [27]; the activity of microsomal enzymes: NADPH-cytochrome C-reductase (NADPH cit. C-red.) in C. H. Williams, H. Kamin [36]; benzo (a) pyrenehydroxylase (B (a) NG) -by C. H. Yang, L. P. Kicha [37]; N-amidopyrinedemethylase (N-UP) — by A. Bast, J. Nordhosck [16]; aniline hydroxylase (AG) — on AI Archakova et al. [3]; Glucose 6-phosphatase (G-6-Phase) to the NS Gnosh, N. C. Kar [17]; microsomal protein (mg/ml) — by O. H. Lowry et al. [28]. At the same time allocated microsomes determinedthe content of NO according to the basic stability of its metabolites — NO2-and NO3-by P. P. Golikov'sapproach andet al. [8]; the activity of eNOS- according to V. V. Sumbaev, I. M. Yasinskaya [12]; the activity of iNOS and the concentration of peroxynitrite (ONO2-) according to M. U. Ravaeva, E. N. Chuyan [10]. The obtained data were statistically processed using statistical analysis BioStat 2008 using parametric (Student's t-test) and nonparametric (Mann-Whitney) criteria. The data were presented as arithmetic average M ± m error of the mean. In order to study the statistical correlation calculation there was performed Spearman correlation coefficient (r). The data were considered statistically significant at P <0. 05.
Results and discussion. It was found that the OTG caused by CCl4, is observed inhibition in hepatocytes all studied enzymes MOS. The content of cytochrome P-450 and b5 — decreased — 1. 8 and 2 (P <0. 001) times, reduced form P-450 — cytochrome P-420 increased — 2 (P <0. 001) times; the activity of NADPH cit. c-red., B (a) NG AH, N-AP, G-6-phase decreased by 3. 0; 3. 8; 3. 3; 2. 6 and 3. 9 (P <0. 001) times, respectively. It was established that the non-selective inhibitor of NOS (eNOS and nNOS) L-NAME, and the nNOS selective inhibitor -7-NI at 6 days and nights administered to animals lead to a substantial reduction of detoxifying liver function. When administered L-NAME functional activity of liver detoxification suppressed more pronounced than the introduction of 7-NI. After 6 days of administration of L-NAME cytochrome P450 and b5 decreased by 22. 3 and 21. 6% (P <0. 01 and P <0. 05), respectively, the reduced form of cytochrome P-450 and P 420 increased by 31. 6% (P <0. 001); activity NADPH cytochrome s-eds., B (a) NG AH, N-AP, G-6-phase decreased by 31. 1 (P <0. 05); 34. 6 (p <0. 01); 28. 7 (P <0. 01); 22. 4 (P <0. 05) and 26. 5 (P <0. 01)%, respectively, compared with the group with OTG (table 1). However, after the introduction of 7-NI cytochrome P450 and b5 — has been reduced by 17. 1 and
19. 2 (P <0. 05), reduced form cytochrome P-450, P-420 increased by
20. 8% (P <0. 001), the activity of NADPH cit. c-red. decreased — by 14. 9% (p <0. 05), B (a) NG — by 19. 1% (P <0. 05), AG (hypertension), N-AP-6 and T-phase, respectively, — 18, 5; 16. 5 and 18. 4% (P <0. 05). At intraperitoneal 6 daily administration selective inhibitor iNOS- S-MT we detected a Table 1.
Significant increase in enzyme activity of the monooxygenase system of the liver compared to animals with OTG.
Similar results were obtained when we administered the substrate L-arginine NOS-. The content of cytochrome P-450 increased in both groups compared to the group with OTG 29. 6 and 34. 8% (P <0, 05), b5-23. 5 and 27. 3 (P <0. 05, and P <0. 01)%,
the reduced form of the P-450 cytochrome P-420 decreased — by 13. 2 and 26. 1% (P <0. 001); activity NADPH cit. c-red. increased by 20. 8 and 25. 7 (P <0. 001)% B (a) NG — 21. 2 and 27. 5 (P <0. 05 and 0. 001)%, hypertension — by 23. 3 and 36 1 (P <0, 05 and 0, 01)%, N-An- 21. 6 and 32. 3 (P<0. 01 and 0. 002)%, G-6-Phase-22. 2 and 30 7 (P <0. 01 and P <0. 001)%. Consequently, NOS modulators have the ability to alter the activity of microsomal liver enzymes. Their pharmacological effect, aimed at changing the functional activity of microsomal liver enzymes, depends on the ability to block isoformsin the active site of NOS [23]. Competitive inhibition of esters of L-arginine and specific braking of the activity of individual isoforms L-NAME blocks constitutive eNOS and nNOS, 7-NI — nNOS, S-MT — iNOS, they thereby interfere with the
To carry out this version, we studied the activity of NO-system in liver microsomes after a 6-day administration of drugs L-NAME, 7-NI, S-MT and L-arginine. It was found that the inhibitor L-NAME instead of the expected decrease in NO, as a consequence of inhibiting the activity of eNOS and nNOS led to its substantial increase over the OTG by 33. 3% (P <0. 001). The activity of eNOS was reduced by 26. 5% (P <0. 01). Reduced activity of eNOS at the same time was characterized by hyperexpression of of the enzyme iNOS by 24. 2% (P <0. 001) and the number of ONO2-29, 5% (P <0. 001) (table 2). When analyzing the actions of the selective nNOS inhibitor — 7NI established that its pharmacological effect in almost same direction as the action of L-NAME on the activity of NO-system in liver micro-somes, but to a lesser extent.
In assessing the pharmacological activity of S-MT and L-ar-ginine is tracedthepicture reducing NO, compared with the group with OTG — 13. 8 and 16. 2% (P <0. 05) in liver microsomes, accompanied by increased eNOS activity — 14. 8 and 13. 6 (P <0. 05 and P <0. 02)%, respectively, in the liver. At the same time there is a decrease level of iNOS and ONO2-in liver microsomes 21. 2-24. 8 (P <0. 001) and 18. 7% — 27. 5 (P <0. 02 and P <0. 01)%, respectively the investigated preparationin groups.
Consequently, all study drugs have an influence on the activity of eNOS, iNOS, ONO2-content in liver microsomes. Thereforeit can be assumed that the increase in activity eNOS in liver microsomes in our studies with S-MT effect connected with selective blockade of iNOS, and the increase of NO as a result of the high activity of eNOS. Simultaneously, the need for increased substrate
process of biotransformation NO — the level ofwhich is controlled by not only the NOS, but enzymes and microsomal oxidation [13, 15]. However, the change of NO level in microsomes under the influence of modulators NOS appears to be the important factor in the regulation of enzyme activity of the monooxygenase system of the liver of experimental animals. However, changes in the level of NO in microsomes under the influence of modulators NOS appears to be the important factor in the regulation of enzyme activity of the monooxygenase system of the liver of experimental animals. According to these experimental studies, in animals with OTG is observed increase in NO level of1. 8 (P <0. 001) times, depression enzyme eNOS 2. 1 (P <0. 001) times, iNOS expression by 2. 1 (P <0. 001) times, ONO2-2. 3 (P <0. 001) times.
oxidation and NO donor — L-arginine, which in a high activity of eNOS, is synthesized from residual nitrogen and creatinine function owing to increase L-ornithine cycle [20]. This is fully confirmed by experiments in animals when administered L-arginine. Decrease iNOS activity is associated with intensification of the microcirculation in the tissues, supplying tissues with oxygen, reducing the phenomena of hypoxia, the main mechanism for the formation of free radicals, reactive oxygen species (ROS) [6, 18].
On this basis, it can be assumed that the level is reduced in the liver microsomes ONO2-, the level of which is determined by the excess of NO and ROS [11, 15]. When administered to animals anonselective inhibitor L-NAME and selective inhibitor 7-NI overexpression of NO in liver microsomes and blood serum provides increased iNOS activity.
According to the literature blockade of eNOS and nNOS enzyme entails initiation iNOS [5, 11]. High levels of iNOS causes depletion stocks of L-arginine as well as adequately to areduction of L-arginine in the body of animals, the mechanism of the maintaining tone of the vascular bed with involvement of the ET-1 protein. Its increase promotes hypoxia in the tissues and a significant increase ONO2-, having a high cytotoxic and cytolytic properties [9]. In this regard, it is believed that among the causes of a modulating effect enzymatic detoxification system of the liver by the activity of nonselective and selective NOS inhibitors and L-arginine are the processes, not only the changes in the activity of enzymes NOS, and the level of L-arginine, but also ONO2-content vibrations. To substantiate this version we carried out studies on correlation dependence between the indicators of enzyme system and the
Table 1. - Indicators of activity of microsomal liver enzymes in the studied groups of animals, M ± m
Index intact (control) ОТG L-NAME 1 gr. 7-NI 2 gr. S-MT 3 gr. L-arginine 4 gr.
P-450, nmol/mg 0,96±0,031 0,53±0,012* 0,41±0,010*A 0,44±0,011*A 0,69±0,016*A 0,71±0,024*A
P-420, nmol/mg 0,05±0,001 0,10±0,001* 0,13±0,003*A 0,12±0,003*A 0,09±0,001*A 0,07±0,001*A
B5, nmol/mg 0,61±0,017 0,28±0,09* 0,22±0,007*A 0,33±0,008*A 0,35±0,011*A 0,36±0,012*A
HAA№-cit. c-red., nmol/min/mg 127,9±5,24 42,8±1,77* 29,5±1,19*A 36,4±1,52*A 51,7±2,23*A 53,8±2,67*A
Benz (a), nmol/min/mg 2,68±0,072 0,71±0,026* 0,46±0,015A* 0,57±0,19*A 0,86±0,031*A 0,91±0,038*A
Ar, nmola mino-phen/min/mg 0,72±0,025 0,22±0,006* 0,16±0,003*A 0,18±0,004*A 0,27±0,008*A 0,30±0,009*A
N-AP, nmol HC HO/min/mg 4,69±0,187 1,83±0,068* 1,42±0,049*A 1,53±0,052*A 2,22±0,075*A 2,42±0,086*A
r-6-Phase, nmol-Rneopg/min/mg 77,34±1,940 19,57±0,861* 14,38±0,525*A 15,97±0,631*A 23,91±0,992*A 25,58±1,102*A
* - P <0.05 compared with control A - P <0.05 compared with OTG
* - P <0.05 compared with control A - P <0.05 compared with OTG
parameters NOS detoxifying liver microsomes in groups of animals administered with L-NAME and S-MT. It was found that the administration of L-NAME was characterized by the presence of credible direct correlation link (r = 0. 88-0. 94, P <0, 001) between the increase in cytochrome P-420 activity and iNOS, content of ONO2-and reverse correlation (r = 0. 88-0. 93, P <0, 001) between the reduction of cytochrome P-450, b5, enzyme NADPHcit. c-red, B (a) NG AH, N-AP and with G-6-Phase. At the same time, also found a clear direct dependence with depression indicators eNOS reduction investigated indicators of detoxification enzymes of liver microsomes. With the preparation S-MT inhibition of iNOS, declining ONO2-parametres accompanied by a strong inverse relationship, the correlation index increases with an increase in the cytochrome P-450, b5, the activity of enzymes of microsomal oxidation — NADPHcit. c-red, B (a) NG AG, N-AP and F-6-Phase. There was revealed a strong direct correlation (r = 0. 89-0. 94, P <0, 001) indicators eNOS with all parameters of liver detoxification (except with cytochrome P-420, with which they had a strong in-
found no correlation dependence with the introduction of animal and L-NAME S-MT between the change in a parameter of NO in liver microsomes with indicators of activity of the studied enzymes of microsomal oxidation in the body. Hence, an important cause of directed changes catalytic activity of enzymes ofmicrosomal oxidation in the liver under the influence of NOS modulators based on processes of associated with the activity of enzyme eNOS, iNOS and level ONO2-. Thus, studies have shown that the enzyme activity at the level of the monooxygenase system of the liver microsomes functionally linked to the NOS, through modulation mechanism family of isoforms of cytochrome P-450 such enzymes using as substrate oxidation amino acid L-arginine. The orientation of the activity of enzymes MOS of the liver is determined by the intensity eNOS and iNOS, as well as the expression of ONO2-. The differences in the change of enzyme activity MOS liver depending on the modulating effects of NOS isoenzymes indicates the possibility of their participation in the specific functional and structural changes of the liver tissue when exposed to the body of pathogenic environmental factors.
verse correlation r = 0. 90-0. 95, P <0, 001). At the same time we
Table 2. - Indicators of NO-system in microsomes in animal studying groups, M ± m
Index Intact (control) ОТG L-NAME 1 gr. 7-NI 2 gr. S-MT 3 gr. L-arginine 4 gr.
NO, mkmol/mg 5, 52±0, 164 9, 95±0, 378* 13, 26±0, 584*A 11, 8±0,458*A 8, 58±0,284*A 8, 34±0,262*A
eNOS, mk-mol/min/mg 17, 42±0, 627 8, 48±0, 291* 6, 23±0,209*A 7, 25±0, 253*A 9, 73±0, 310*A 9, 63±0, 317*A
iNOS, mk-mol/min/mg 0, 10±0, 002 0, 21±0, 09* 0, 26±0, 011*A 0, 24±0, 009*A 0, 17±0, 005*A 0, 16±0, 004*A
ONO2-, mkmol/mg 0, 08±0, 002 0, 18±0, 007* 0, 23±0, 008*A 0, 21±0, 007*A 0, 15±0, 004*A 0, 13±0, 003*A
Conclusions:
1. A nonselective inhibitor L-NAME NOS (eNOS and nNOS) and selective inhibitor 7-NI (nNOS) inhibit, and selective inhibitor iNOS- S-MT, and the donor L-arginine NO- increase the activity of enzymes of the monooxygenase system of the liver.
2. The inhibition of the activity of microsomal liver enzymes by the action of L-NAME statistically correlated with indicators of high activity in microsomesiNOS, content of ONO2-and low ac-
tivity of eNOS. Under the action of the selective inhibitor iNOS-S-MT stimulation of functional activity of microsomal enzymes is correlated with the induction of eNOS, iNOS inhibition and the content ONO2.
3. The lack of correlation between the NO in the microsomes and microsomal enzymes in the liver give the reason to believe that an important factor modulating the activity of monooxygenases are isozymes NOS — eNOS, iNOS and the content of ONO2.
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