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S Yanev

Publications and source records attributed to S Yanev.

At least 19 recordsLinked to original sources
PubMed2002

Quantitative structure-activity relationship (QSAR) and three-dimensional QSAR analysis of a series of xanthates as inhibitors and inactivators of cytochrome P450 2B1.

1. Various xanthates (R-OCS2) were found to be mechanism-based inactivators of cytochrome P450 2B1 (CYP2B1) and CYP2B6 via formation of reactive metabolites. 2. In the present study, quantitative structure-activity relationships (QSARs) were derived with inhibitory and inactivation potencies of 15 xanthates (R = two to 20 methylene groups, allyl, cyclohexyl or O-tricyclo[5.2.1.0(2,6)]dec-9-yl (D609)) against purified, reconstituted rat liver CYP2B1. Factor, regression and comparative molecular field analyses (CoMFA) were used. 3. The compounds formed two groups whose activities depended on different structural features: the first group consisted of compounds with ethyl, propyl, allyl, cyclohexyl and D609 substituents; the second involved compounds with eight to 20 methylene groups. 4. High correlation between the molecular volume and inhibitory potency of the xanthates of the second group was found. The inactivation potency in the first group correlated with the charge of the first carbon atom of R, identifying this atom as a potential target for metabolic attack. A decrease in the inactivation potency with an increase in the size of R was observed in the second group. This finding could be explained by a decreased rate of metabolism of the long alkyl chain compounds and/or by difficulty in binding of the resulting metabolite(s) to the enzyme molecule.

Animals↗
PubMed2002

Propranolol as an inhibitor of some cytochrome P450-dependent monooxygenase activities in native and induced rat liver microsomes.

The in vitro effect of propranolol (10(-3) M and 10(-4) M), a nonselective and extensively metabolized beta-adrenergic blocking agent, on rat liver drug metabolism in native and induced (with phenobarbital and beta-naphthoflavone [beta-NF]) microsomes was studied. The type of inhibition and the inhibitory constants of some cytochrome P450-dependent microsomal enzyme reactions (hexobarbital oxidation [HBO], ethylmorphine-N-demethylation [EMND], aniline hydroxylation [AH], ethoxycoumarin-O-deethylation [ECOD], ethoxyresorufin-O-dealkylation [EROD] and penthoxyresorufin-O-dealkylation [PROD]) were estimated. The results showed that propranolol competitively inhibited AH activity in native microsomes. The type of inhibition was changed from competitive to noncompetitive in all other enzyme activities studied. This inhibition was more pronounced after phenobarbital induction in PROD (Ki = 0.11 +/- 0.01 mM), ECOD (Ki = 0.40 +/- 0.09 mM) and EMND (Ki = 0.59 +/- 0.1 mM), and after beta-NF induction in AH (Ki = 0.28 +/- 0.05 mM) and in HBO (Ki = 0.35 +/- 0.1 mM) in native microsomes. It was assumed that the noncompetitive type of inhibition is due to the covalent binding of reactive metabolites derived from propranolol to hepatic microsomal proteins. The competitive type of inhibition of AH suggested a common P450 isoenzyme in the metabolism of propranolol and aniline. Thus, in this study, propranolol has been found to be not only a selective inhibitor of CYP2D6 isoenzyme-dependent reactions, but also a nonspecific inhibitor of other cytochrome P450 isoenzymes.

Adrenergic beta-Antagonists↗
PubMed1999

Mechanism-based inactivation of cytochromes P450 2B1 and P450 2B6 by n-propylxanthate.

n-Propylxanthate (nPX) inactivated the 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) O-deethylation activity of purified, reconstituted rat hepatic P450 2B1 or human P450 2B6 in a mechanism-based manner. The inactivation followed pseudo-first-order kinetics and was entirely dependent on both NADPH and nPX. The maximal rate constant for inactivation of P450 2B1 at 30 degrees C was 0.2 min-1. The apparent KI was 44 microM, and the half-time for inactivation was 4.1 min. Purified, reconstituted human P450 2B6 was also inactivated by nPX with a KI of 12 microM. The kinactivation for P450 2B6 was 0.06 min-1, and the t1/2 was 11 min. Incubations of P450 2B1 with nPX and NADPH for 20 min resulted in a 75% loss in enzymatic activity and a concurrent 25% loss of the enzyme's ability to form a reduced CO complex. Little loss in the absolute spectrum of nPX-inactivated P450 2B1 was observed. With P450 2B6, an 83% loss in enzymatic activity and a 12% loss in the CO-reduced spectra were observed. The extrapolated partition ratio for nPX with P450 2B1 was 32. P450 2B1 could be protected from inactivation by nPX by adding an alternate substrate to the reaction mixture. Removal of unbound nPX by dialysis did not reverse the inactivation. The alternate oxidant iodosobenzene was able to partially restore enzymatic activity to nPX-inactivated P450 2B1 samples. A stoichiometry for labeling of 1.2:1 for binding of radiolabeled nPX metabolite to P450 2B1 was seen. These results indicated that nPX inactivated P450 2B1 and P450 2B6 in a mechanism-based manner. P450 2B1 was inactivated primarily by a nPX reactive intermediate that bound to the apoprotein.

Animals↗
PubMed1999

Selective mechanism-based inactivation of cytochromes P-450 2B1 and P-450 2B6 by a series of xanthates.

Fifteen xanthates with carbon chains of different lengths or substitutions, including the antiviral compound D609 (O-tricyclo[5.2. 1.0(2,6)]dec-9-yl-dithiocarbonate), were tested for their ability to inactivate cytochromes P-450 (P-450s) 2B1 and 2B6. All of the xanthates tested were found to inactivate P-450 2B1 in a time- and concentration-dependent manner. The rates of inactivation at 30 degrees C ranged from 0.22 min-1 to 0.02 min-1. The concentrations required for half-maximal inactivation were between 2.4 and 69 microM. A general trend in the inactivation kinetics could be observed with an increasing chain length of the xanthates. Longer carbon chains resulted in slower rates of inactivation with longer half-times of inactivation and higher partition ratios. For P-450 2B1, the most effective inactivators were xanthates with substitutions of intermediate length. The best inactivator for P-450 2B1 was the C8 xanthate, with an inactivation potency (KI) of 2.4 microM, a rate of inactivation of 0.07 min-1, and a partition ratio of 4. Four xanthates were further examined for their effect on the 7-ethoxy-4-(trifluoromethyl)coumarin activity of P-450 2B6. The C8 xanthate was again the most effective inactivator, with a KI of 1 microM. Although the KI values were generally lower than those found with P-450 2B1, the rates of inactivation for P-450 2B6 with the various xanthates were 3- to 5-fold slower. In addition, the isozyme selectivity of xanthates was tested with P-450s 2E1, 1A1, 3A2, 3A4, 2C9, and 2D6. P-450 2E1 was inactivated by xanthates at concentrations 15- to 100-fold higher than those required to inactivate either P-450 2B1 or 2B6. P-450 1A1 was not inactivated by xanthates. However, all of the xanthates tested were able to inhibit the enzymatic activity of P-450 1A1 to a different extent, depending on the length of the xanthate carbon chain. Virtually no inactivation of P-450s 2D6 or 2C9 was seen, except that C8 and D609 were inhibitory at high concentrations (0.2-0.6 mM). None of the xanthates studied had any effect on the activities of P-450s 3A2 or 3A4.

Animals↗
PubMed1988

Effects of potassium ethylxanthogenate on nitrosodiethylamine-induced DNA damage and on liver carcinogenesis.

BD-6 rats were injected with 80 mg/kg N-nitroso-diethylamine weekly for 10 weeks. Addition of 270 mg/kg potassium ethylxanthogenate weekly reduced significantly the number of rats developing NDEA-induced malignant liver tumors. Ethylxanthogenate decreased the total number of liver tumors induced by the carcinogen to 6 as compared to a total of 29 neoplasms in animals treated only with NDEA. In acute experiments potassium ethylxanthogenate markedly decreased the exhalation of 14CO2 derived from 14C-NDEA. The amount of the nonmetabolized carcinogen increased in the urine of ethylxanthogenate protected rats only 4% of the given dose. Initial DNA damage, single strand breaks and alkali-labile sites, was determined by alkaline sucrose gradients and in protected animals was minimal for at least 24 hours after NDEA administration. It appears that the production of less initial DNA damage may be important for the further course of liver carcinogenesis induced by relatively large doses of nitrosodiethylamine.

Animals↗
PubMed1987

No evidence for an interaction of the bacterial immunomodulator trehalose dimycolate (TDM) with liver drug-metabolizing system in mice.

Trehalose dimycolate (TDM), an immunomodulatory glycolipid component of Mycobacteria, was tested from the point of view of possible effects on drug metabolism. TDM was given intraperitoneally as a single 0.1 mg dose to mice. Basic parameters of the liver mixed-function oxidase system were assayed 1 or 7 days later. No significant changes were found in contents of cytochromes P-450 and b5, as well as in specific activities of microsomal enzymes--aniline hydroxylase, ethylmorphine demethylase, and glucuronide transferase. Similarly, liver microsomal protein concentration and activities of serum aspartate and alanine transaminases remained unchanged. The susceptibility of microsomal membranes to lipid peroxidation was significantly decreased 7 days after TDM administration. TDM may thus be presumed not to influence range and magnitude of effects of concurrently administered drugs.

Animals↗
PubMed1986

Effect of medazepam on benzodiazepine receptors in brain of mice with isolation syndrome.

The effect of medazepam in a model of isolation aggression in mice was studied according to Yen et al. It was established that the mean effective dose of medazepam was 250 micrograms/kg and the therapeutic index (LD50:ED50) 6200. The simultaneous biochemical investigations showed a reduction of the affinity and number of benzodiazepine receptors in the brain of aggressive animals. Medazepam 10 mg/kg p.o. led to the restoration of the number of benzodiazepine receptors at a single and 10-day treatment.

Aggression↗
PubMed1986

Mode of action of cholecystokinin octapeptide on smooth muscles of stomach, ileum and gall bladder.

Mechanical activity of preparations isolated from canine and guinea-pig stomach, ileum and gall bladder was recorded. At least 2 strips were cut out from each organ and investigated simultaneously in thermostatically controlled organ baths. Responses to acetylcholine (ACH) were used for comparison. Octapeptide of cholecystokinin (CCK-OP) at concentrations of 5 X 10(-11) M to 10(-8) M produced dose-dependent tonic concentrations in all muscle strips and showed a higher affinity but lower efficacy as compared to ACH. Atropine (10(-7) M 10(-5) M) had no effect on the CCK-OP responses in stomach and gall bladder muscle strips but it significantly decreased the CCK-OP responses in ileum muscle strips. Dibutyryl cyclic GMP (dbc GMP) at concentrations of 10(-5) M-5 X 10(-4) M did not change the ACH dose-response curves but shifted to the right in parallel to the control the dose-response curves for CCK-OP in all muscle preparations with pA2 values 5, 5.3, 7.2, and 6 for canine stomach and guinea-pig stomach, ileum and gall bladder, respectively. Michaelis-Menten's analysis suggested a competitive type of interaction of dbc GMP on CCK-OP contractile responses of guinea-pig ileum and gall bladder; at a higher concentration (5 X 10(-4) M) the antagonistic effect of dbc GMP in canine and guinea-pig stomach appeared to be a mixed or uncompetitive type. The data suggest that the contractile effects of CCK-OP in the iliac smooth muscle are caused by cholinergic and direct mechanisms whereas on the gall bladder and gastric smooth muscles by direct myogenic mechanisms only.

Animals↗
PubMed1984

Changes in rat liver and brain monoamine oxidase activity after acute treatment with some heavy metal salts.

In in vivo and in vitro experiments the effects of some heavy metal salts (Cu, Co, Cd, Pb, Ni, Zn, Hg, As, Bi and Sn) on rat liver and brain mitochondrial monoamine oxidase (MAO) activity was studied using three different substrates (tyramine, 5-hydroxytryptamine (5-HT) and beta-phenylethylamine (2-PEA). It was established that some of the metals (Cu, Cd, Bi) inhibited MAO activity both in vivo and in vitro experiments, others like Ni, Zn, As and Sn inhibited it only in vivo while Hg exerted inhibitory action only in vitro. The in vivo experiments showed significantly higher sensitivity of brain MAO as compared with liver MAO to the inhibitory action of metals. The same higher susceptibility was shown by liver and brain MAO-A form. It was concluded that the inhibitory effects of some heavy metal salts on MAO activity were not directly connected with their action on enzyme thiol groups but more probably with changes in the enzyme membrane surroundings in the different organs.

Animals↗
PubMed1984

Hepatic mixed-function oxidase system and microsomal lipid peroxidation in rats treated with a synthetic immunomodulator, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP).

Effects of synthetic muramyl dipeptide (MDP) on activity of liver microsomal mixed-function oxidase system and on the susceptibility of liver microsomes to lipid peroxidation, were tested in rats at intervals of 1 or 24 hours after single i.p. injection of MDP (1 mg per animal). No significant changes were found in levels of cytochrome P-450 and b5, microsomal heme, or in activities of aniline hydroxylase, ethylmorphine demethylase, glucuronide transferase or cytosol glutathione-S-transferase. However, significantly less (about 45%) TBA-reactive material accumulated in microsomal samples at the 1 h-interval after the MDP administration. The same inhibitory effect of MDP on lipid peroxidation was shown in vitro (in 1 mM concentration) after incubation of microsomes with the NADPH/ADP/Fe system.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Effects of glaucine and some glaucine derivatives and of their combination with L-DOPA on the brain level of biogenic monoamines.

Glaucine and two of its structural analogues exerted an inhibitory effect on phosphodiesterase activity in different tissue homogenates. In experiments on rats glaucine applied intraperitoneally significantly increased the brain level of dopamine (DA) and did not change the content of noradrenaline and serotonin (5-HT). The combined application of L-DOPA and glaucine or glaucine derivatives produced a higher increase in brain DA than the increase which would be expected by simple summation of the effects of L-DOPA and glaucine and of the glaucine derivatives respectively. At the same time L-DOPA and glaucine, applied together, caused a slighter decrease of brain 5-HT than the decrease produced by the same dose of L-DOPA when the latter was applied alone. It is suggested that the higher increase of brain DA produced by the combination of L-DOPA and the phosphodiesterase inhibitor glaucine or its structural analogues is mainly due to the increased cAMP level.

Animals↗
PubMed1981

Effect of chronic para-chlorophenylalanine treatment on convulsive-seizure reactions.

The effect of chronic para-chlorphenylalanine (PCPA) treatment was investigated in two different seizure models: the pentylenetetrazole (PTX) seizure model in rats and the kindled seizures from rabbit amygdala. Chronic PCPA treatment (21 days) in male albino rats caused a progressive decrease in the 5-hydroxytryptamine (5-HT) brain level between the 1st and the 7th day of PCPA administration. Then the 5-HT level remained low until the end of the experiment. On the background of the low 5-HT level there occurred changes in PTZ convulsive reactions: after the 3rd day of PCPA treatment the convulsive-seizure reactivity was significantly increased and after the 7th, 14th and 21st day the increased seizure reactivity performed only as a tendency, though the 5-HT level was still low. Chronic PCPA treatment (16 days) of rabbits delayed the development of the behavioural kindled seizures. This treatment also reduced the duration of bioelectrical seizures until the 8th day of treatment, especially in the motor cortex. The observed different effect of the chronic PCPA treatment in both seizure models: pentylenetetrazole in rats and kindling in rabbits might be explained by essential differences in the origin and mechanisms of development of the two seizure models.

Amygdala↗
PubMed1979

Motor estimation of short time intervals under the effect of some psychotropic drugs.

A study is made of the human ability to estimate short time intervals (up to 1 s) by a simple motor response under the effect of stimulants (Amphetamine, Caffeine) and depressants (Chlorazin, Diazepam, Phenobarbital). Of all psychotropic drugs used only Chlorazin causes a statistically significant increase in the mean values of the reaction time of all subjects compared with the controls. The psychotropic drugs in the doses used have no influence on the ability of the subjects to produce a light interval of a given duration. In the task requiring reproduction of a 900 ms interval, Amphetamine schortens significantly the response times, which is explained by earlier organization of their motor responce and lack of feedback.

Adult↗
PubMed1978

A rapid and sensitive assay for monoamine oxidase activity.

Based on the Berthelot reaction, a new sensitive and rapid procedure for monoamine oxidase (MAO) determination with substrate tyramine has been developed. The saturation with oxygen and the separation of ammonia from the substrate were omitted. At the end of incubation the samples were deproteinized with ethanol and consecutive centrifugation. The newly-formed ammonia is converted into the coloured compound indophenol, using the procedure of Fenton (1962). The indophenol concentration, respectively NH3 is determined by spectrophotometry at 625 nm, and calculated by comparison with a set of standard amounts of NH3. The enzyme activity is expressed as nanomoles ammonia, formed by 1 mg protein for 1 min. The method was tested for studying the relationship between the enzyme activity, time of incubation and protein concentration, as well as the effect of pargyline. The kinetics of MAO, using both liver and brain mitochondria as enzyme material was also studied. Considering the specificity, simplicity, versatility and rapid performance, the new method showed several advantages in comparison with the other known methods for MAO determination.

Animals↗