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Xenobiochemistry - MC250P24
Title: Xenobiochemie
Czech title: Xenobiochemie
Guaranteed by: Department of Biochemistry (31-250)
Faculty: Faculty of Science
Actual: from 2024
Semester: winter
E-Credits: 3
Examination process: winter s.:
Hours per week, examination: winter s.:2/0, Ex [HT]
Capacity: unlimited
Min. number of students: unlimited
4EU+: no
Virtual mobility / capacity: no
State of the course: taught
Language: Czech, English
Note: enabled for web enrollment
priority enrollment if the course is part of the study plan
Guarantor: RNDr. Věra Černá, Ph.D.
Teacher(s): RNDr. Věra Černá, Ph.D.
RNDr. Mgr. Radka Václavíková, Ph.D.
Annotation -
The aim of the course is to make students familiar with the fate of xenobiotics in organisms. The course is a lecture useful for chemists and especially for biochemists. At first, essential informations on hydrophilic and hydrophobic xenobiotics is given. In addition, the fate of xenobiotics in organisms (entry to organisms, transport in organisms and into the cells, biotransformation, elimination, excretion) is shown in details. The students are also informed on pharmacokinetics of xenobiotics and the effects of hydrophilic and hydrophobic xenobiotics on the metabolic processes (target metabolic pathways for individual xenobiotics - e.g. heavy metals, air pollutants, car exhausts, industrial pollutants, drugs, potential toxicants, mutagens, teratogens, and carcinogens). Metabolic conversion of xenobiotics in organisms (biotransformation - activation and detoxication) is shown in details. Namely, two phases of biotransformation: (i) derivatization and (ii) conjugation of xenobiotics, types of reactions involved in both phases of xenobiotic biotrasformation (oxidative, reductive, conjugative reactions, hydrolysis). Moreover, enzymes participating in xenobiotic biotransformation (the system of microsomal mixed function oxidases/oxygenases containing cytochromes P450 as terminal oxidases, microsomal monooxygenases containing flavine, peroxidases, reductases, amidases, esterases, epoxid hydrolase, UDP-glucuronoside transferase, sulphotransferases, glutathione-S-transferases, aminoacyltransferases) are trained in details, too. Finally, regulation of processes involved in xenobiotic biotransformation is shown.
Lectures - in Czech - and English
Lectures are delivered in Czech to Czech students. For Erasmus students the lectures are in English. Depending on the number of students enroled the course is arranged as lectures or in another way (colloquium, consultations).
Last update: Černá Věra, RNDr., Ph.D. (17.02.2020)
Literature - Czech

Voet D., Voet J.: Biochemistry, John Wiley & Sons, Inc. 1990.

Gibson, G. Gordon Skett, Paul. Introduction to drug metabolism . Cheltenham, UK: Nelson Thornes Publishers, 2001, 256 s. 

Testa B., Kramer S.D.: The biochemistry of Drug metabolism, John Wiley & Sons, Inc. 2010.

Švihovec J., Bultas J., Anzenbacher P., Chládek J., Příborský J., Slíva J., Votava M.: Farmakologie, Grada publishing, a. s., 2018, zejména kapitola farmakokinetika

Skálová L., Boušová I., a kolektiv.: Metabolismus léčiv a jiných xenobiotik, Karolinum, 2011

Ioannides C.: Cytochromes P450: Role in the Metabolism and Toxicity of Drugs and Other Xenobiotics, RSC publishing 2008

Last update: Černá Věra, RNDr., Ph.D. (15.09.2021)
Requirements to the exam -
The exam is written in the scope of the lectured material
Last update: Černá Věra, RNDr., Ph.D. (30.09.2022)
Syllabus -

 

  • Fate of Xenobiotics in Organisms:
    ADME (absorption and transport within organisms, membrane transport, biotransformation, elimination, and excretion).

  • Hydrophilic and Hydrophobic Xenobiotics:
    Characterization of foreign substances based on their solubility properties.

  • Impact on Metabolic Processes:
    The influence of hydrophilic and hydrophobic xenobiotics on metabolic processes in organisms, including targeted interventions by heavy metals, airborne and industrial pollutants, exhaust gases, pharmaceuticals, potential toxicants, mutagens, teratogens, and carcinogens within intermediary metabolism.

  • Metabolic Transformation of Xenobiotics:
    Processes of activation and detoxification; the derivatization phase of biotransformation; and the types of reactions involved—oxidation, reduction, and hydrolysis.

  • Conjugation Phase of Biotransformation:
    Mechanisms and significance of the conjugation reactions in xenobiotic metabolism.

  • Membrane Transporters:
    Classification and role of membrane transporters in the transfer of substances.

  • Dioxygenases and Monooxygenases:
    The oxidase/oxygenase system with mixed function, featuring cytochrome P450 as the terminal oxidase (MFO system)—its structure, function, NADPH:cytochrome P450 reductase, and cytochrome b5.

  • Regulation of Xenobiotic Biotransformation:
    Mechanisms controlling the biotransformation processes of xenobiotics.

  • Flavin-Containing Monooxygenases and Peroxidases:
    Structure, function, and regulatory aspects of these enzyme classes.

  • Other Biotransformation Enzymes:
    Alcohol and aldehyde dehydrogenases; molybdenum-containing hydroxylases with flavin; monoamine oxidases; and DT diaphorase.





Last update: Černá Věra, RNDr., Ph.D. (11.03.2025)
Learning outcomes -

I. ADME

  • The student analyzes the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics in the organism and describes how the physicochemical properties of substances and physiological factors influence each phase.
  • The student explains various mechanisms of membrane transport and compares them critically.
  • The student identifies factors that affect the passage of xenobiotics through biological membranes and explains their influence. In addition, the student applies the Henderson–Hasselbalch equation to calculate the ratio of ionized to non-ionized forms of a xenobiotic, depending on the pH of the environment.
  • The student evaluates the significance of drug bioavailability, including the various factors that modulate it.

II. Heavy Metals and Their Toxicological Effects

  • The student defines heavy metals and outlines the properties that render them toxic, describing their environmental sources, applications, and associated health effects.
  • The student explains both general and specific mechanisms by which heavy metals exert their toxic effects, including their impact on enzymes involved in key metabolic pathways, the induction of oxidative stress, and the modulation of membrane activity.
  • The student assesses the defense mechanisms of plants against heavy metal toxicity and applies this knowledge to the prospects of phytoremediation.

III. Air Pollution and Related Toxicological Issues

  • The student defines the fundamental concepts of air pollution and characterizes the main pollutants with respect to their origin and impact on the environment and human health.
  • The student evaluates the toxicological significance of nitrogen oxides and nitrates, identifies at-risk population groups, and enumerates additional substances that may provoke these conditions.
  • The student compares the London and Los Angeles smogs, elucidating the differences in their formation and chemical composition, and evaluates their impacts on human health and the environment.
  • The student analyzes the risks associated with asbestos exposure, describes the types of asbestos fibers, and explains the mechanisms underlying disease development.
  • The student discusses the potential for indoor environmental pollution.

IV. Biotransformation of Xenobiotics – Phase I Reactions

  • The student describes the process of xenobiotic biotransformation, distinguishing between detoxification and activation pathways.
  • The student explains and compares the mechanisms of phase I biotransformation reactions, applies this knowledge to predict the metabolic fate of xenobiotics, and provides examples of the enzymes involved.

V. Conjugation of Xenobiotics

  • The student compares and analyzes the various types of conjugation reactions, specifying the conjugation agents and enzymes involved.
  • The student discusses the activation of xenobiotics through conjugation reactions.
  • The student explains and analyzes the impact of the intestinal microbiota and enterohepatic circulation on conjugation processes and the elimination of xenobiotics.

VI. Membrane Transporters and Their Role in Pharmacokinetics

  • The student classifies transporters into the ABC and SLC families, describes their structure, mechanisms of action, and energy requirements, and provides examples of significant transporters from both families along with their roles in drug transport.
  • The student analyzes the role of transporters in drug pharmacokinetics and explains how the expression and activity of transporters in various tissues affect drug bioavailability and efficacy.
  • The student describes the mechanisms underlying multidrug resistance (MDR).
  • The student explains the principles and compares various laboratory methods used to profile membrane transporters.

VII. Enzymatic Systems in Biotransformation – The MFO System

  • The student analyzes the differences between dioxygenases and monooxygenases, classifying them into groups based on their mechanisms and substrate specificities.
  • The student describes the composition of the mixed-function oxidase (MFO) system and explains the function of its individual components, providing structural characterizations and detailing their mutual interactions.
  • The student interprets the reaction mechanisms of the MFO system using various substrate types and compares these mechanisms.
  • The student describes the structure and function of NADPH:cytochrome P450 oxidoreductase (CPR), including the roles of the coenzymes FAD and FMN, and explains the mechanism of electron transfer from NADPH to cytochrome P450.

VIII. Cytochrome P450 – Regulation and Variability

  • The student classifies cytochrome P450 enzymes into families and subfamilies, providing examples of significant CYP isoenzymes, and describes their localization, prevalence, and substrate specificity in relation to the metabolism of xenobiotics and drugs.
  • The student analyzes the factors that influence the expression and activity of CYP isoenzymes and explains how these factors contribute to inter- and intra-individual variability in xenobiotic metabolism.
  • The student describes the mechanisms of CYP induction via various nuclear receptors and provides examples of inducers and potential drug interactions.
  • The student evaluates the significance of CYP inhibition, describes the different types of inhibition, and provides examples of inhibitors along with the associated risks of drug interactions.
  • The student demonstrates the impact of genetic polymorphism in CYP enzymes on the pharmacokinetics and pharmacodynamics of drugs and explains how CYP isoenzyme genotyping can be used to individualize pharmacotherapy.

IX. Other Enzymes and Peroxidases

  • The student compares flavin-containing monooxygenases (FMO) and cytochrome P450 enzymes (CYP) in terms of their structure, catalytic mechanisms, substrate specificity, and regulatory properties, elucidating how these differences affect their roles in xenobiotic biotransformation.
  • The student analyzes the mechanism of the catalytic cycle of FMOs.
  • The student classifies peroxidases and describes the structure of representative model enzymes.
  • The student explains the mechanisms of peroxidase reactions while considering the structural differences among various types.
  • The student identifies other significant peroxidase representatives and describes their functions and specific characteristics.
  • The student compares the structure of the active sites of peroxidases with those of cytochrome P450 enzymes.

X. Metabolism of Ethanol and Other Biotransformation Enzymes

  • The student describes the metabolism of ethanol via both oxidative and non-oxidative pathways, explains the differences compared to the metabolism of methanol and other alcohols, evaluates the risks associated with their consumption, and elucidates the mechanisms of action of agents used in the treatment of methanol poisoning or alcoholism.
  • The student assesses the impact of genetic polymorphisms in key biotransformation enzymes on the metabolism of alcohol.
  • The student describes the structure and function of xanthine oxidoreductase, explains the mechanism of conversion from xanthine dehydrogenase (XD) to xanthine oxidase (XO), and outlines its catalytic cycle.
  • The student provides examples of additional biotransformation enzymes (e.g., aldehyde oxidase [AO], monoamine oxidase [MAO], NAD(P)H:quinone oxidoreductase 1 [NQO1], esterases, hydrolases, etc.), describes their structure and function, compares their mechanisms of action, and identifies key differences and similarities.
Last update: Černá Věra, RNDr., Ph.D. (28.03.2025)
 
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