SVIBOR - Project code: 3-04-319

MINISTRY OF SCIENCE AND TECHNOLOGY

Strossmayerov trg 4, HR - 10000 ZAGREB
tel.: +385 1 459 44 44, fax: +385 1 459 44 69
E-mail: ured@znanost.hr

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Project code: 3-04-319


INVESTIGATIONS OF MECHANISMS OF BIOLOGICAL ACTIVATIONS, AND STRUCTURE-PROPERTY-ACTIVITY STUDIES IN VIVO AND IN VITRO


Main researcher: RENDIĆ, SLOBODAN (40820)


Assistants
Type of research: applied
Duration from: 01/01/91. to 12/31/96.
Papers on project (total): 84
Papers on project quoted in Current Contents: 12
Institution name: Farmaceutsko-biokemijski fakultet, Zagreb (6)
Department/Institute: Department of pharmaceutical chemistry
Address: A. Kovačića 1
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (01)448-516
Fax: 385 (01)445-117
Summary: Investigation of the mechanisms of biotransformations, interactions with proteins, and biological activations of chemicals, including environmental chemicals, chemicals used as explosives, and drugs with a goal to determine biologically active metabolites in vitro and in vivo. Development and methodological standardization of the procedures of analysis and confirmation of drugs of abuse (stimulans such as are mephentermine, mefenorex, amphetamine, and anabolic steroids testosterone, stanozolol and metabolites) in the urine samples, development and publication of the POSITION PAPER for the International Federation of Clinical Chemistry. Investigations are focused on enzymatic reactions catalyzed by the cytochrome P450 superfamily of enzymes in laboratory animals and humans. Optimisation of the analytical procedures (TLC, HPLC, GC, GC-MS) and of the reaction conditions is performed by using methods of the numerical taxonomy and the theory of information. Following model proteins and systems are used for study of the mechanisms of interactions of environmenatal chemicals, chemicals used as explosives and drugs with proteins and protein systems: humane serum albumin, cytochromes P450, and other hemproteins (such as are peroxidases). Reactions kinetic is followed by the stopped flow cryoscopic spectrometry. The compounds used for the study are imidazole and furane drugs (H2-receptor antagonists), enantiomeric compounds such as are enantiomers of a new antidiabetic drug etomoxir, natural (testosterone, epitestosterone) and synthetic steroids (stanozolol, metandienone, and endogenous compounds such are, for instance, fatty acids). Structure-physicochemical properties (QSPR) and structure-biological activity (QSAR) studies of the chemicals studied as well as hydrophobic parameters (log P and RM) calcullated according to Hansch and/or Rekker are used for correlation with different molecular descriptors such as are W(G), X(G), J(G) and I(G).

Keywords: cytochrome(s) P450, CYP enzymes, peroxidases, drugs, chemicals, ligands, human serum albumune, binding, stereoselectivity, mechanisms of binding, QSAR, QSPR, analysis of, drugs, environmental chemicals, explosives, drugs of abuse, analysis, urine, position document

Research goals: The goal of this project is to study the mechanisms of interactions of chemicals including environmental chemicals, explosives and drugs, with biological macromolecules, with a goal to get better insight to understanding of the mechanisms of biological effects (therapeutic and toxic) as a consequence of such interactions. Therapeutic as well as toxic properties of a chemical compoundmight be changed influencing the activities of enzymes containing protoporphirine ring. In these enzyme the ring as prostetic group (cytochromes P450 and peroxidazes) represents actually the active site of the enzyme for activation of molecular oxigen and/or the chemical. Such activations results in mechanisms of toxicity. Following model compounds will be used: phenylalkylamines, H2-receptor antagonists (cimetidine and ranitidine), and steroid hormones, environmental chemicals (explosives). The model compounds are important therapeutical agents and environmental pollutants that ellicitsignificant toxic and side effects. These effects are repeatedly shown to be connectedwith changed activity and/or the content of the enzymes under study. Interactions of the compounds with toxicologically important enzymes such as peroxidases should bring additional information about possible mechanisms of interactions. The goal is to get additional information for clinically important toxic reactions following administration of the drugs. Also influence of environmental chemicals such as are policyclic aromatic hydrocarbones and explosive chemicals will be tested. Human serum albumin is aprincipal binding protein in plasma for a number of drugs and endogenous compounds exerting stereoselectivity of interaction with enantiomeric as well as with prochiral compounds. Study of the binding of new drugs (enantiomers of etomoxir) with HSA should reveal binding parameters of the racemate and of theenantiomers, and to indicate possible clinical interactions with endogenous compounds and exogenous drugs represented by stearic acid and anabolic hormone stanozolol. Metabolic interactions on the level ofcytochrome P450 following administration of endogenous steroid testosterone as well as other anabolic synthetic compounds (i.e.stanozolol) is under invesigation in both in vivo (in clinical studies and following administration to rats) and in vitro condition. The results should give answers about interactions on the level of biosynthesis of endogenous steroids referring to testosterone and its inactive isomer epitestosterone. Already preliminary results indicate repressionof the biosynthesis of epitestosterone following testosterone and synthetic steroids. The methodological approach to the analysis of drugs in the urine samples and metabolites subject of the "Position Paper" prepared by the expert group (see publications) for InternationalFederation of Clinical Chemistry. Numerical taxonomy foroptimisation of the analytical as well as reaction kinetic conditions is under study for analysis of testosterone and other steroids and metabolites. QSPR and QSAR studies are succesfully applied foranalysis the biological activities of phenylalkylamines as well as other compounds (see publications).

COOPERATION - INSTITUTIONS


  1. Name of institution: Clinical Pharmacology, Departments of medicine and Pharmacology, University of California, UCLA Medical center
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 90024 - Los Angeles, USA

  2. Name of institution: Facul…t f—r Biologie, Universit…t Konstanz
    Type of institution: University/Faculty
    Type of cooperation: Systematic exchange of experts
    City: 7750 - Konstanz, Njemačka

  3. Name of institution: Byk Goulden, Konstanz
    Type of institution: Economical/Production
    Type of cooperation: Systematic exchange of information
    City: 7750 - Konstanz, Njemačka

  4. Name of institution: Pliva, Istraživački institut
    Type of institution: Economical/Production
    Type of cooperation: Joint publishing of scientific papers
    City: 10000 - Zagreb, Croatia

  5. Name of institution: Deutsche Sporthochschule, Institut f—r Biochemie
    Type of institution: University/Faculty
    Type of cooperation: Systematic exchange of information
    City: 5000 - K•ln, Njemačka

  6. Name of institution: Institut Rudjer Bošković
    Type of institution: University/Faculty
    Type of cooperation: Joint publishing of scientific papers
    City: 10000 - Zagreb, Croatia

  7. Name of institution: Institute for molecular biophysics, Florida State University
    Type of institution: University/Faculty
    Type of cooperation: Occasional exchange of experts
    City: 32306 - Tallahassee, USA

  8. Name of institution: GlaxoWellcome Research Institute
    Type of institution: Economical/Production
    Type of cooperation: Systematic exchange of information

  9. Name of institution: GlaxoWellcome Research and Development
    Type of institution: Economical/Production
    Type of cooperation: Systematic exchange of information
    City: SG12ODP - Ware, United Kingdom
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Last update: 10/03/95
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