Effects of 1,2,3,4-tetrahydroimidazo[4,5-c]-pyridine derivatives on ethanol oxidation by alcohol dehydrogenase isoforms from human liver.

We studied in vitro effects of four 1,2,3,4-tetrahydroimidazo[4,5-c]-pyridine derivatives formed in the reaction of the corresponding aldehydes with histidine on the rate of ethanol oxidation by alcohol dehydrogenase isoforms from human liver. None of test compounds inhibited ethanol oxidation by these enzymes. Some of them increased alcohol dehydrogenase activity to 220-240% of the initial level. Only one test compound accelerated ethanol oxidation by b1b2-alcohol dehydrogenase (150% of the control). The molecular mechanism underlying these effects of 1,2,3,4-tetrahydroimidazo[4,5-c]-pyridine derivatives on ethanol oxidation by alcohol dehydrogenase isoforms from human liver is discussed.

[Synthesis of 1-hydroxyalkyl-3-substituted ureas and thioureas as a substrates for alcohol dehydrogenase]. / Sintez 1-gidroksialkil-3-zameshchennykh mochevin i tiomochevin kak substratov alkogol'degidrogenazy.

A series of 1-(2-hydroxyethyl)- and 1-(3-hydroxyethyl)-3-substituted ureas and thioureas were synthesized. 1-(3-Hydroxyethyl)-3-acylthioureas were shown to be specific substrates for alcohol dehydrogenase in vitro.

[Synthesis and antiproliferative activity of a novel N-acyl derivative of doxorubicin]. / Sintez i antiproliferativnaia aktivnost' novogo N-atsil'nogo proizvodnogo doksorubitsina.

Doxorubicin was acylated with estrone 3-hemisuccinate. The modified derivative exhibited high antiproliferative activity in vitro toward cell cultures of the MCF-7 human mammary adenocarcinoma and HepG2 human hepatoma.

[Comparative study of the effectiveness of the classical and modified Cooper protocol for breast cancer chemotherapy]. / Sravnitel'noe issledovanie éffektivnosti klassicheskoi i modifitsirovannoi skhem Kupera pri khimioterapii raka molochnoi zhelezy.

Efficiency of routine and modified Cuper procedures was studied after evaluation in saliva and urine of women with mammary gland tumor of the following parametres: alterations in dynamics of acrolein excretion with saliva, dynamics of alterations in calculated therapeutic doses of cyclophosphane administered using these procedures, dynamics of the ratio between non-metabolized cyclophosphane and its initial level in urine of the patients. Analysis of the data obtained suggest that the liver tissue enzymatic systems, involving in biotransformation of cyclophosphane, were distinctly less impaired during the modified Cuper procedure as compared with the routine course, thus corroborating advantages of the modified procedure used in chemotherapy of patients with mammary gland tumor.

NADPH-dependent reduction of amaranch in liver microsomes characterized the quantity of low spin forms of cytochrome P-450.

We confirmed that NADPH-dependent anaerobic amaranch reduction in rat liver microsomes is compatible with the interaction of the dye with Fe(III) heme of cytochrome P-450 as the type II substrate. This process is rate-limiting in the whole reaction. High positive correlation (r = 0.949) between the values of Vmax for reaction of NADPH-dependent anaerobic amaranch reduction and the relative content low spin forms of cytochrome P-450 determined by ESR in microsomes from liver of control and induced by PB, BP, IS and 4-MP rats was observed. Relative content of low spin forms of cytochrome P-450 determined by ESR was increased according to BP less than PB less than control less than IS approximately 4-MP; Vmax values increased according to BP less than PB less than control less than IS less than 4-MP. Thus, reaction of NADPH-dependent anaerobic amaranch reduction may be used for determination of low spin forms of cytochrome P-450 at physiological conditions.

[The effect of finoptin on the metabolism and pharmacological action of cyclophosphane in vivo and in vitro]. / Vliianie finoptina na metabolizm i farmakologicheskoe deistvie tsiklofosfana in vivo i in vitro.

Phynoptin (Ph) and cyclophosphamide (CP) gave rise to a type I spectral changes with liver microsomal fraction. KS were 15 microM and 2150 microM, respectively. Ph increases the concentration of NBP product(s) of CP and acrolein in the blood plasma of animals. Ph increases a toxicity of CP. LD50 was 388.0 +/- 13.9 mg/kg for CP and LD50 was 342.8 +/- 16.9 mg/kg for CP in combination with Ph. Ph changes a therapeutic action of CP in mice with hemocytoblastosis La. Pharmacokinetic interactions have been demonstrated between calcium antagonists Ph and CP.

Application of electron-donor properties of glucose oxidase and xanthine oxidase for reduction of microsomal NAD(P)H-dependent electron-transport chains.

The reduction of cytochromes b5 and P-450 in mammalian hepatic microsomes by glucose oxidase and xanthine oxidase has been investigated. Under anaerobic conditions cytochrome b5 is reduced by glucose oxidase to the "dithionite" level, while cytochrome P-450 remains oxidized. Under the same conditions xanthine oxidase completely reduces both hemoproteins. Besides, neither glucose oxidase nor xanthine oxidase reduces isolated cytochromes. They can be reduced only after addition of microsomes to incubation media. Only in this case are the cytochromes, both isolated and included in microsomal membranes, reduced. The participation of microsomal flavoproteins in the reduction reaction is discussed. The method suggested makes it possible to substantially decrease the rates of reduction of microsomal hemoproteins, thus permitting the investigation of interactions between microsomal NADH- and NADPH-dependent electron-transport chains and electron carriers.

[A photoplethysmo-tonomanometer for examination of the vascular system and measuring hemodynamic parameters]. / Fotopletizmotonomanometr dlia issledovanii sosudistoi sistemy i izmereniia pokazatelei gemodinamiki.

A new method and an apparatus for noninvasive medical investigations of the vascular system are considered. During the investigations, the two known methods of arterial pressure measuring, namely Korotkov's method and Penaz's method were used. The combination of the methods and a special procedure algorithm allow the measuring, in addition to arterial pressure, of the other important hemodynamic parameters such as venous pressure, the characteristic time parameters of blood redistribution between arterial and venous vessels and pulse wave velocity. The diagram of the photoplethysmo-tonomanometer and the measuring algorithm procedure are provided.

[The role of secondary metabolism in formation of benz(a)pyrene dihydrodiol profile in microsome membranes]. / Rol' vtorichnogo metabolizma v formirovanii profilia digidrodiolov benz(a)pirena v membranakh mikrosom.

4,5-, 7,8- and 9,10-dihydrodiols of benz(a)pyrene (BP) were separated by thin-layer chromatography and their influence on BP-hydroxylase activity was studied in liver microsomes isolated from rats treated with phenobarbital (PB-microsomes) and 3-methylcholanthrene (MC-microsomes). All diols studied inhibited hydroxylation of BP by the competitive type. Accumulation of BP-diols in the incubation media correlated with their affinity to cytochrome P-450 isoenzymes which catalyzed the secondary metabolism of these diols. This correspondence allowed to formulate the kinetic and temperature dependence of BP oxidation suggesting that two main groups of hemoprotein isoforms were contained which were dissimilar in the active site orientation. Treatment with 3-methylcholanthrene induced specifically those hemoproteins which had the active site directed inside the membrane lipids; treatment with phenobarbital involved induction of two groups of hemoproteins active site of which was directed both to lipid and to water. The primary metabolism of the hydrophobic BP involved cytochrome P-450 isoenzymes which had the active site directed inside the lipids; the secondary metabolism of more polar diols was realized using both groups of hemoprotein isoenzymes with active sites oriented into lipids and water.

The ratio of two isozyme groups in microsomal cytochrome P-450 under exogenous influence of carbon tetrachloride and cyclophosphamide.

A method for measuring the content of two groups of microsomal cytochrome P-450 isozymes--cytochromes P-450W and P-450L--with the active sites directed into the water phase and membrane lipids, respectively, has been developed. The method is based on the ability of the xanthine oxidase-menadione complex to reduce microsomal cytochromes b5 and P-450 under anaerobic conditions by transferring electrons to hemoproteins with the active sites directed into the water phase. Cytochrome b5 is completely reduced (to the dithionite level) and cytochrome P-450 is reduced partially (only a group of cytochromes P-450W). The amount of cytochromes P-450L is estimated using the difference between the total content of cytochrome P-450 reduced by sodium dithionite and the content of cytochromes P-450W. The possibility of controlling the ratio of these two isozyme groups in cytochrome P-450 in vivo in membranes of the endoplasmic reticulum by pretreatment of animals with a variety of chemicals has been demonstrated. The ratio of cytochromes P-450W and P-450L has been shown to decrease two-fold 18 days after three injections of phenobarbital into mice. Carbon tetrachloride and cyclophosphamide also decrease this ratio in vivo.

[The role of vitamin K3 in the hydroxylation of benz(a)pyrene in rat liver mitochondria after induction with 3-methylcholanthrene and phenobarbital]. / Uchastie vitamina K3 v gidroksilirovanii benz(a)pirena v mikrosomakh pecheni krys pri induktsii 3-metilkholantrenom i fenobarbitalom.

The "fast" phase reduction of microsomal cytochromes P-450 and P-448 and their benz(a)pyrene (BP) hydroxylase activity was investigated as a function of menadione concentrations. Within a narrow concentration range (1.5-3 microM) menadione activates cytochrome P-448 reduction and the BP hydroxylase activity. At higher concentrations menadione inhibits cytochromes P-450 and P-448 reduction and BP hydroxylation with participation of the both cytochromes. These data suggest that menadione molecules present in membrane lipids serve as an additional electron carrier to cytochrome P-448, the active site of which is embedded into lipids. The activating effect is unobserved is case of cytochrome P-450 with an active site localized in the aqueous phase. The number of different BP metabolites formed at low (3 microM) menadione concentrations in the microsomes of rats induced with 3-methylcholanthrene (MC) and phenobarbital (PB) was compared. In PB-induced microsomes the amount of 7,8-dihydrodiol rises whereas the total content of BP metabolites decreases. Contrariwise, in MC-induced microsomes the synthesis of all BP metabolites is augmented. Menadione has a very weak effect on the ratio of different BP metabolites in PB- and MC-microsomes, but strongly inhibits the formation of more polar metabolites. This results in a marked reduction of the number of "dangerous" BP diolepoxides.