i want mindmap for Outlines • Definition & Types of xenobiotics
• Metabolism of xenobiotics: ❑Purpose & Consequences ❑Site ❑Phases of xenobiotics metabolism ❑Cytochrome P450
• Effects of xenobioticsDefinition & Types of Xenobiotics
❑ A xenobiotic is a compound that is foreign to the body (from the
Greek xenos "stranger" and biotic "related to living beings").
❑ Xenobiotics can be exogenous or endogenous
a) Exogenous xenobiotics as drugs, food additives, pollutants, insecticides
and chemical carcinogens.
b) Endogenous xenobiotics: Though they are not foreign substances but have
effects similar to exogenous xenobiotics. These are synthesized in the body
or are produced as metabolites of various processes in the body. Examples:
Bilirubin, Bile acids, Steroids and certain fatty acids.Metabolism of xenobiotics – Purpose & Consequences
❑ Generally, xenobiotic metabolism is the set of metabolic pathways that modify the
chemical structure of xenobiotics.
❑ All the biochemical reactions involved in chemical alteration of chemicals such as toxins
and drugs in the body are called biotransformation reactions.
❑ The overall purpose of biotransformation reactions of xenobiotics metabolism is to
convert these lipophilic (non-polar) compounds to hydrophilic (polar) compounds (to
increase its water solubility) and thus facilitates its excretion from the body (in bile or
urine).
❑ The biotransformation reactions involved in the conversion of foreign, toxic and water
insoluble molecules to non toxic, water soluble and excretable forms are called
Detoxification reactions. In certain situations these reactions may instead increase the
activity (Metabolic activation) & toxicity of a foreign compound (Entoxification reactions).
❑ Biotransformation reactions of xenobiotics metabolism are mainly divided into phase I
and phase II (phase III may also present for further modification and excretion).Metabolism of xenobiotics – Purpose & ConsequencesMetabolism of xenobiotics– Purpose & ConsequencesMetabolism of xenobiotics – Purpose & ConsequencesMetabolism of xenobiotics– Purpose & Consequences
(Biotransformation)Metabolism of xenobiotics- Site
❑ The majority of biotransformation takes place within the liver.
❑ However, several of biotransformation reactions can also occur
in extrahepatic tissues, such as adipose tissue, intestine,
kidney, lung, and skin.
❑ The enzymes of biotransformation process found primarily in
cytoplasm, endoplasmic reticulum, and mitochondria.Metabolism of xenobiotics- Phases
(Biotransformation)
(Functionalization)
(Conjugation)Metabolism of xenobiotics - Phases
and/or hydrolysisMetabolism of xenobiotics– Phases- Phase I
• Phase I (Functionalization): It is broadly grouped into three categories:
❑ Oxidation: The most common reactions of phase I resulting in the removal of
hydrogen and/or the addition of oxygen. Hydroxylation is the most common
oxidation reaction in phase I. The main enzymes of hydroxylation in phase I
are called cytochrome P450 enzymes or mixed-function oxidases or
monooxygenases or hydroxylases).
❑ Reduction: Reactions resulting in the addition of hydrogen and/or the
removal of oxygen. Enzymes involved in reduction reactions are called
reductases.
❑ Hydrolysis: A bond in the compound is broken by water, resulting in two
compounds. The enzymes of hydrolysis reactions include esterases, peptidases,
amidases.Metabolism of xenobiotics– Phases- Phase I
• The enzyme-catalyzed reactions of phase I metabolism serve to expose or
introduce a polar functional group (functionalization) as hydroxyl (-OH),
amino (-NH2), sulfhydryl (-SH), or carboxyl (-COOH), resulting in an increase
in the water solubility of the parent drug. This functional group also serves as
an active center for conjugation in phase II reaction.
• Drugs that have already have -OH, -NH2 or COOH groups can bypass Phase I
and enter Phase II directly.
• Oxidation is the most common phase I reaction (hydroxylation is the most
common oxidation reaction in phase I). The cytochrome P450 system is the
most important enzymes of the phase I oxidation reactions.
• Phase I reactions can create active metabolites and which is beneficial in
activating prodrugs into their active and therapeutic state.Metabolism of xenobiotics – Phases- Phase I
For understandingMetabolism of xenobiotics – Phases- Phase IMetabolism of xenobiotics– Phases- Phase II (Conjugation)
Phase II (Conjugation):
• Conjugation is a process by which the original drug or its phase I
metabolite is coupled with a charged agent (such as glucuronic acid
,glutathione (GSH), sulfate, or glycine) and is converted to soluble, non
toxic derivative (conjugate) which is easily excreted in bile or urine.
• Products of conjugation reactions tend to be less active than their
substrates, unlike Phase I reactions which often produce active
metabolites.
• Conjugation reactions can occur independently or can follow phase I
(hydroxylation) reactions.
• These reactions are catalyzed by a large group of broad-specificity
transferases.Summary of biotransformation reactionsSummary of biotransformation reactionsMetabolism of xenobiotics– Cytochrome P450- General properties
For readingMetabolism of xenobiotics – Cytochrome P450 – Naming & classificationMetabolism of xenobiotics – Cytochrome P450 – Naming & classificationMetabolism of xenobiotics – Cytochrome P450– Chemical reactionMetabolism of xenobiotics– Cytochrome P450 – Clinical importance
❑ Cytochrome P450 enzymes can be repressed or induced by drugs, resulting in
clinically significant drug-drug interactions that can cause adverse reactions or
therapeutic failures.
- Interactions with warfarin, antidepressants, antiepileptic drugs and statins
often involve the cytochrome P450 enzymes.
- Most isoforms of cytochrome P450 are inducible. Phenobarbital (anticonvulsant)
is a potent inducer of the cytochrome P450 system.
- Drug Interactions between phenobarbital and warfarin (anticoagulant):
Phenobarbital increases the rate at which warfarin is metabolized and thus
reduce the effect of a previously adjusted dose. Phenobarbital can reduce the
blood levels of warfarin, which may make the medication less effective in
preventing blood clots.Metabolism of xenobiotics– Cytochrome P450 – Clinical importance
❑ Certain cytochrome P450s exist in polymorphic forms (genetic isoforms),
some of which has low catalytic activity. These observations are one
important explanation for the variations in drug responses noted among
many patients.
- One of the P450s which exhibits polymorphism is CYP2D6 which catalyzes the
metabolism of a large number of clinically important drugs as antidepressants.Metabolism of xenobiotics– Cytochrome P450 – Clinical importance
❑ Certain isoforms of cytochrome P450 are particularly involved in the
bioactivation of procarcinogens to active carcinogens.
- CYP1A1 plays a key role in the conversion of inactive procarcinogens in
cigarette smoke to active carcinogens.
- CYP1A1 is induced through exposure to cigarette smoke. So, smokers have
higher levels of this enzyme than non smokers.Effects of xenobiotics
Xenobiotics can produce a variety of biological effects including:-
❑ Pharmacological responses
❑ Cell injury (Cytotoxicity)
❑ Immunological responses
❑ CancersGSH Conjugation
Immunological
responseSuggested videos
• Drug Metabolism (chemical reactions are for reading only) https://youtu.be/oCPRi5JFMdg
• CYP450 Enzymes Drug Interactions https://youtu.be/vle_0dN3bwA