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L Vereczkey

Publications and source records attributed to L Vereczkey.

At least 19 recordsLinked to original sources
PubMed2000

Glucuronidation of thyroxine in primary monolayer cultures of rat hepatocytes: in vitro induction of UDP-glucuronosyltranferases by methylcholanthrene, clofibrate, and dexamethasone alone and in combination.

Induction of UDP-glucuronosyltransferases (UGTs) toward thyroxine (T4) and p-nitrophenol (pNP) by 3-methylcholanthrene (MC), dexamethasone (DEX), clofibrate (Cl), and MC combined with DEX or Cl was studied in rat hepatocyte culture. We have developed a sensitive method for the measurement of glucuronide conjugates of the two substrates based on HPLC analysis of culture medium. MC, Cl, or DEX increased the activity of T4 UGT. Combination of MC and Cl showed additive effect, enzyme activity was enhanced compared with either MC or Cl treatment alone (617, 441, and 217% of the control, respectively). Combination of MC and DEX did not result in higher T4 UGT activity than MC treatment alone. Both MC and DEX enhanced the pNP UGT activity (182 and 162% of the control, respectively). Combination of MC with DEX resulted in additive effect. Cl treatment did not affect pNP conjugation either alone or in combination with MC. Western blot analysis revealed that only the amount of UGT1A1 was elevated by Cl and DEX. In contrast, concentration of UGT1A6 was increased by MC. Previous studies demonstrated that UGT1A1 inducers like phenobarbital have no effect on T4 conjugation (). Our results suggest that Cl, a known inducer of UGT1A1, enhances the activity of other enzyme(s) involved in T4 glucuronidation as well. It is well documented that DEX potentiates the inductory effect of polycyclic aromatic hydrocarbon on UGT1A6 (). In our study, MC increased the rate of T4 glucuronidation, and DEX had no additional effect on this reaction, suggesting that UGT1A6 is not the only enzyme inducible by MC that can catalyze T4 conjugation.

Animals↗
PubMed1999

[Human drug metabolizing enzymes III. Epoxide hydrolases, esterases, and amidases].

In this review we focus on human hydrolytic enzymes that participate in the metabolism of xenobiotics. Although hydrolysis in most of the cases result in detoxication, in some cases hydrolysis may lead to activated molecules that may attack macromolecules (proteins, RNAs, DNAs), resulting in toxicity. We have summarised the data available on these enzymes concerning their catalytic profile and specificity, inhibition, induction properties, their possible role in the generation of toxic compounds, their importance in clinical practice and drug development.

Amidohydrolases↗
PubMed1998

[Mass spectrometry in the verification of pyrimethamine poisoning].

A 17 years old male patient with Pyrimethamin therapy was released from our department by emphasising the necessity of continuous control. A month later the patient was accepted again with serious anaemia. Since the patient did not follow the instructions Pyrimethamin intoxication was presumed, but it had to be proved. At last the drug in the plasma was identified and quantified by mass spectrometry. The plasma concentration of Pyrimethamin was five times higher than the therapeutic level. The rapid analysis (4 hours after taking of blood) and adequate treatment resulted in rapid improvement with the concomitant decrease of plasma Pyrimethamin concentration. During clinical treatment the level of Pyrimethamin in the plasma was followed by mass spectrometry.

Adolescent↗
PubMed1998

Ipriflavone as an inhibitor of human cytochrome P450 enzymes.

1. Reduction of theophylline metabolism and elimination were observed in a theophylline-treated patient during ipriflavone administration. After withdrawal of ipriflavone, the serum theophylline level decreased to an extent similar to that found before administration of ipriflavone. The effects of ipriflavone and its major metabolites 7-hydroxy-isoflavone and 7-(1-carboxy-ethoxy)-isoflavone on cytochrome P450 activities were studied in vitro in human liver microsomes from three donors. 2. Ipriflavone and 7-hydroxy-isoflavone competitively inhibited phenacetin O-deethylase and tolbutamide hydroxylase activity. The parent compound and its dealkylated metabolite were strong inhibitors exhibiting Ki values around 10-20 microM, while 7-(1-carboxy-ethoxy)-isoflavone had no effect on the cytochrome P450 activities investigated. 7-Hydroxy-isoflavone is the only one that influenced nifedipine oxidase activity. It competitively inhibited this activity with a Ki value of 129.5 microM. 3. The steady state concentrations of ipriflavone and 7-hydroxy-isoflavone in plasma of patients receiving 3 x 200 mg daily doses of ipriflavone for 48 weeks were found to be 0.33 +/- 0.32 microM and 1.44 +/- 0.77 microM, respectively. 4. The results indicate that the decrease in theophylline metabolism observed in a patient treated with ipriflavone may be due to a competitive interaction of ipriflavone or its metabolite, 7-hydroxy-isoflavone with CYP1A2. On the other hand, our in vitro findings predict some more interaction with CYP2C9.

Cytochrome P-450 CYP3A↗
PubMed1998

[Human drug metabolizing enzymes. I. Oxidative enzymes].

In this review we focus on human oxidative enzymes that are responsible for the metabolism of xenobiotics. More and more publications prove that the reactions catalysed by these enzymes very often lead to activated molecules that may attack macromolecules (proteins, RNAs, DNAs), resulting in toxicity (liver, neuro-, embryotoxicity, allergy, carcinogenecity). We have summarised the data available on these enzymes, concerning their catalytic profile and specificity, inhibition, induction properties, their possible role in the generation of toxic compounds, their importance in clinical practice and drug development.

Alcohol Dehydrogenase↗
PubMed1998

[Human drug metabolizing enzymes. II. Conjugation enzymes].

In this review we focus on human conjugation enzymes (UDP-glucuronyltransferases, methyl-trasferases, N-acetyl-transferases, O-acetyl-transferases, Amidases/carboxyesterases, sulfotransferases, Glutation-S-transferases and the enzymes involved in the conjugation with amino acids) that participate in the metabolism of xenobiotics. Although conjugation reactions in most of the cases result in detoxication, more and more publications prove that the reactions catalysed by these enzymes very often lead to activated molecules that may attack macromolecules (proteins, RNAs, DNAs), resulting in toxicity (liver, neuro-, embryotoxicity, allergy, carcinogenecity). We have summarised the data available on these enzymes concerning their catalytic profile and specificity, inhibition, induction properties, their possible role in the generation of toxic compounds, their importance in clinical practice and drug development.

Glucuronosyltransferase↗
PubMed1997

Species differences in metabolism of panomifene, an analogue of tamoxifen.

In vitro metabolism of panomifene (E-1,2-diphenyl-1--4-(2-(2-hydroxyethyl-amino)-ethoxy)-phenyl--3,3,3- trifluoropropene), a novel antiestrogen against hormone dependent tumors, has been investigated using liver microsomes from mouse, rat, dog, and human. Hydroxylation and side chain modifications were the routes of panomifene metabolism. Microsomal biotransformation showed some qualitative similarities, but several differences were observed in the metabolic profiles of the four species tested. Seven metabolites were detected in the incubation mixtures analyzed by thin layer chromatography and autoradiography, although there was only one produced by all species that had lost the side chain. Among the side chain shortened metabolites, the compound that had lost the hydroxyethyl-amino group was formed by the microsomal system of rodents, whereas the one that had lost the hydroxyethyl group was detected in the incubation mixtures with rat, dog, and human microsomes. Three metabolites (M1, M3, and M4) were produced exclusively by the dog. The structure of M3 was identified by mass spectroscopy as 4-hydroxy-panomifene. Furthermore, human liver microsomes formed a metabolite (M8) that was not detectable in the mixtures with mouse, rat, or dog microsomes. Its structure is suspected to be an oxidized form of panomifene with a double bound in the side chain. The structure of panomifene is analogous to tamoxifen, an antiestrogen currently used as a therapeutic agent against breast cancer, and there are some similar routes in their metabolism. The main difference is that the rate of tamoxifen biotransformation seems faster than that of panomifene. On the other hand, 4-hydroxy-panomifene is produced by only dog, while 4-hydroxylated derivative is one of the main metabolites of tamoxifen that has potent antiestrogenic activity and is considered to be responsible for the formation of DNA-adducts.

Animals↗
PubMed1996

Ion-pair high-performance liquid chromatographic separation of two thyroxine glucuronides formed by rat liver microsomes.

A simple reversed-phase ion-pair high-performance liquid chromatographic separation method has been developed for thyroxine (T4) and its glucuronide metabolites formed by liver microsomes of untreated and 3-methylcholanthrene-treated rats. Besides the phenol-T4-glucuronide, another, probably acyl-T4-glucuronide, formation has been detected. The effect of pH and temperature on the stability of the acyl-T4-glucuronide was also investigated. The lowering of pH to 2 and cooling the samples to 5 degrees C is necessary to prevent the hydrolysis of acylglucuronide, while both pH and temperature do not affect the stability of the phenol-T4-glucuronide. The retention times of T4 and phenol-T4-glucuronide are highly influenced by the pH of the mobile phase, but not that of acyl-T4-glucuronide.

Acylation↗
PubMed1996

Xenobiotic metabolizing enzymes in fish: diversity, regulation and biomarkers for pollutant exposure.

Cytochromes P450 play key roles in biotransformation of pollutant chemicals and in the activation or inactivation of many toxic or carcinogenic compounds. Multiple P450 isozymes have been purified from different fish species. Fish monooxygenase activity shows temperature compensation and sex-related variation. Several xenobiotics can induce cytochrome P450 monooxygenases altering toxicity of chemical contaminants. Polycyclic aromatic hydrocarbons can increase transcription of CYP1A gene in fish as it has been observed in mammals, but phenobarbital-type agents do not induce in fish at all. The presence of conjugation enzymes in fish has also been proved, although their induction by xenobiotics is poorly investigated. Since exposure of fish to environmental contaminants can result in the induction of specific cytochrome P450 enzymes, monitoring of their catalytic activities can identify polluted areas.

Animals↗
PubMed1995

[Role of human cytochrome P-450 enzymes in the metabolism of xenobiotics].

Cytochrome P450 enzymes play essential role in metabolism of exogenous compounds. They are found mainly in endoplasmic reticulum of hepatocytes. Purification of different P450 isoforms and determination of their structures and catalytic activities allowed to investigate their participation in metabolism of xenobiotics. Numerous factors cause variations in the expression of these P450: the effect of genetic and environmental factors results in the production of series of enzymes catalyzing biotransformation of xenobiotics. Several genetic polymorphisms have been described: CYP2D6, CYP2C and 'Ah locus' polymorphism. Some P450 (CYP1A, CYP3A, CYP2E1) are inducible by xenobiotics. Additionally, P450 expression and inducibility vary depending on tissues. It is now possible to determine which isoform(s) is (are) responsible for the production of a metabolite and to predict the fate of a compound in vivo.

Biotransformation↗
PubMed1995

[Pharmacokinetic and metabolic studies in the development of drugs].

A system basing mainly on pharmacokinetic investigations has been elaborated by the author for the development of new drugs. The main elements of this system are as follows: 1.1. Screening toxicity investigations: Bacterial mutagenesis tests. Mammalian mutagenesis tests (These tests must be supported by kinetic studies in order to prove the exposure of the animals to the drug in negative cases, or to detect the critical plasma concentration of the drug in positive cases.) Cytochrome P-450 induction studies. In vitro metabolism studies (Incubation of a drug under development with rat, mouse, dog, rabbit and human liver microsomes (S9 fraction) can show the species (dis) similarities of the drugs. In vitro toxicology studies (The use of tissue cultures may answer the mechanism of toxicity. Early in vitro (eye and skin) irritation studies are of primary importance in the development of topical preparations. Acute toxicology studies (Acute toxicity investigations seem to become less important). 28 days (14 days) toxicity testing with pharmacokinetic measurements. 1.2. Long term and reproductive toxicity testing: The scientifically based evaluation of long term and reproductive toxicity studies can only be made in the light of toxicokinetic and metabolism data. 1.3. Human safety studies. Phase I. Study. The pharmacokinetic measurements must be made in order to see the (non) linearity of the kinetics as the function of dose. Phase II. Study. Pharmacokinetic measurements are necessary in order to establish the effective plasma (blood, serum) concentration of the drug. The pharmacokinetics of the drug should be determined in renal and liver patients, and in most of the cases in healthy elderly people.

Aged↗
PubMed1995

Structure activity relationship in toxicology.

One of the basic principles of the modern pharmacological research is that there is a close correlation between the chemical structure and the pharmacological effect. In contrast to pharmacology, in toxicology high doses of the drugs are used in order to provoke toxic symptoms generally realized through other receptors than the pharmacological effect. The evaluation of the structure activity relationship (SAR) in toxicology is hindered by the fact that it is not possible to establish in every case that the toxic effect 1. is developed by the original compound or its metabolite(s) 2. is realized through one or more receptors. Furthermore it is necessary to take into consideration that the studies in toxicology are not carried out with so many compounds as the studies in pharmacology and--horrible dictu--the toxicological data are not always public. Thus the prediction of the toxicity of a compound on the base of its chemical structure is difficult, and the prediction whether a new drug is toxic to such an extent that excludes its development, is impossible. What we can do is trying to predict--in the knowledge of the metabolism of the drug--its possible carcinogenic, hepatotoxic, CNS etc. toxic effect.

Anticonvulsants↗
PubMed1994

The effect of phenobarbital and dexamethasone coadministration on the activity of rat liver P450 system.

Phenobarbital, the potent inducer of CYP2B and CYP3A, and dexamethasone, that induces CYP3A, are not able to elevate p-nitrophenol hydroxylase activity of CYP2E1. However, rats treated with phenobarbital and dexamethasone in combination showed threefold increase in p-nitrophenol hydroxylation and the activity correlates with an elevated amount of a 53.000 dalton protein. Biosynthesis of mRNA and P450 protein is required for the induction. 3-amino-1,2,4-triazole and anti CYP2E1 IgG inhibition studies show that CYP2E1 is not responsible for enhanced p-nitrophenol hydroxylation, but the residual activity indicates the participation of other isozyme(s). As a result of double induction, changes in the amount of CYP2E1 of microsomes were not detected by Western blot analysis compared to untreated rat liver microsomes.

Aminopyrine N-Demethylase↗
PubMed1994

Pharmacokinetic study on a new antiischaemic agent (BRLP-42).

In the present study the pharmacokinetics of BRLP-42--a new antiischaemic agent--was investigated in dogs and rats. Plasma concentrations were measured by HPLC. After intravenous application the curves can be characterized by a two-compartment open pharmacokinetic model. The central volume of distribution (Vcentr.) is large (1.07 +/- 0.14 l/kg in dogs and 2.74 l/kg in rats), the first elimination half-life (t1/2 alpha) is 5.47 +/- 1.67 min in dogs and 13.7 min in rats. These facts indicate rapid and large tissue distribution. The excretion and/or metabolic elimination of BRLP-42 resulted in short second elimination half-life (t1/2 beta = 41.45 +/- 2.34 min in dogs and 43.8 min in rats). After oral application high individual variability can be seen. This fact may be due to the different rate and/or extent of absorption process. The plasma level curves can be characterized by a one-compartment open pharmacokinetic model. The absorption seems to conceal the distribution phase of the kinetic curve. The absorption half-life was short (t1/2a = 17.36 +/- 5.90 min in dogs and 2.7 min in rats). The bioavailability was 40 +/- 8% in dogs and 28% in rats. The elimination half-life (t1/2e = 28.77 +/- 0.88 min in dogs and 30.1 min in rats) is connected dominantly with metabolic elimination and/or excretion of BRLP-42. In the cases of intravenous as well as oral administrations the plasma concentrations decreased under the limit of quantitation by 4-6 hours in dogs and 4 hours in rats after treatments.

Administration, Oral↗
PubMed1993

Combined action of phenobarbital and dexamethasone on the activity of rat liver P450 system.

Phenobarbital and dexamethasone are potent inducers of the same cytochrome P450 form, CYP3A1, but the mechanism of action is not quite clear. If the mechanism of induction by phenobarbital and dexamethasone is different, additive effect may be observed in the specific activities of CYP3A1: ethylmorphine or aminopyrine N-demethylation of liver microsomes from rats treated with phenobarbital and dexamethasone in combination. The results of recent work could not display differences in CYP3A1 activities between the groups of animals single-administered and coadministered with phenobarbital and dexamethasone. However, p-nitrophenol hydroxylation surprisingly increased threefold as a result of double induction. 3-amino-1,2,4-triazole inhibition study shows that CYP2E1 is responsible for 60% of enhanced p-nitrophenol hydroxylase activity, but the residual 40% indicates the participation of other isoenzyme(s).

Animals↗
PubMed1993

[Pharmacokinetic studies of 14C-labeled epervudine in rats].

The characteristics of absorption, distribution and elimination of 14C-labelled epervudine were studied in rats treated with 10 mg/kg doses orally and intravenously. The blood level curves were analyzed by appropriate pharmacokinetic models. The results of oral treatment showed a rapid absorption of the radioactivity from the gastrointestinal tracts of the animals (tmax (0.75 h). The elimination rate of radioactivity from blood was fast (t1/2 el = 5.53 h). Blood level curves were characterized by a rapid initial distribution phase after intravenous treatment (t1/2 alpha = 0.17 h). Subsequently, the rate of elimination became slower and the concentration of radioactivity remained at a low level between 2 and 24 hours after the treatment. Studies of distribution did not reveal any specific tissue accumulation. As shown by excretion studies, the elimination of the radioactivity was fast following both the oral and intravenous administration. Within 24 hours ca. 50% excreted with urine and ca. 20% with feces. The ratio areas under blood level curves demonstrated an absorption of 70% (AUCpo: AUCiv x 100).

Administration, Oral↗