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L Vereczkey

Publications and source records attributed to L Vereczkey.

At least 19 recordsLinked to original sources
PubMed2003

Some aspects of interindividual variations in the metabolism of xenobiotics.

Differences in drug metabolism among individuals are caused by numerous factors: differences in production and stability of mRNA of xenobiotic metabolizing enzymes, differences in the rate of enzyme synthesis and degradation, or enzyme inhibition. One of the most important reasons is genetic polymorphism of cytochrome P450 genes or cytochrome P450 regulatory factors. Nuclear receptors play great role in the regulation of these genes. The presence of the ligand induces the nuclear receptor to bind to the dimerisation partner and as a hetero/homodimer it can activate the DNA responsive element. In addition, several co-activators, co-repressors and other factors can modulate the effect of nuclear receptors. Hepatic levels of cytochrome P450 enzymes are reduced in multiple models of inflammation or infection. Cytochrome P450 enzymes of four families (CYP1-CYP4) are known to be involved in xenobiotic metabolism. Their genetic polymorphism and regulation are discussed in this review.

Cytochrome P-450 Enzyme System↗
PubMed2001

The effect of dexamethasone on P450 activities in regenerating rat liver.

The aim of our study was to detect four P450s (CYP1A, CYP2B, CYP2E1, CYP3A) on the basis of selective enzyme activities and protein amount, and to investigate the effect of dexamethasone treatment during liver regeneration. Partial hepatectomy of rats resulted in the loss of CYP1A, CYP2B, CYP2E1, and CYP3A activities. The reduction of enzyme activities and the loss of enzyme protein of CYP2B1/2, CYP2E1, and CYP3A1/2 were the most pronounced. In the case of CYP1A1, only slight decrease was observed. Dexamethasone treatment seems to counteract this loss mainly in the first 12 h.

Animals↗
PubMed2001

Effect of alpha-methyldopa on pentoxyresorufin O-dealkylation in liver microsomes from rats treated with phenobarbital.

Loss of pentoxyresorufin O-dealkylation (PROD) was observed when microsomes from PB-treated rats were preincubated in the presence of NADPH. PROD proved to be quite sensitive towards inactivation. Decrease in cytochrome P450 (CYP) dependent activity was accompanied by simultaneous formation of thiobarbituric acid reactive substances (TBARS) indicating the occurrence of lipid peroxidation. The presence of 50 microM alpha-methyldopa (AMD) during preincubation with NADPH resulted in complete protection against enzyme activity loss and the extent of lipid peroxidation was also diminished. Addition of ascorbate or GSH in combination with AMD reduced the protective effect of the drug on PROD. AMD probably exerts its effect by scavenging reactive oxygen species but chelation of ferric ions can also contribute to the protective effect of the drug on PROD activity.

Animals↗
PubMed2001

[About paracetamol again].

The mechanism of hepatotoxicity caused by paracetamol (acetaminophen) overdose and the treatment of patients is reviewed. Paracetamol is widely used over-the-counter drug with analgesic and antipyretic properties. Although it is considered to be safe at therapeutic doses, the incidence of hepatotoxicity caused by overdose or inadvertent application has been increasing lately. N-acetyl-p-benzoquinonimine, one of the metabolites formed from paracetamol is responsible for the hepatotoxicity. Until now there is no complete therapeutic strategy for the effective treatment of hepatotoxicity caused by paracetamol. Gut decontamination, N-acetylcysteine antidote administration and enhancement of elimination is used for the management of paracetamol overdose. Those with severe hepatotoxicity and neurological symptoms can benefit from removal of necrotic liver and undergo transplantation.

Acetaminophen↗
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↗