Xenobiotics are compounds foreign to the body that are subject to biotransformation. Biotransformation involves two phases: Phase I uses enzymes like cytochrome P450 to introduce functional groups, making compounds slightly more hydrophilic. Phase II involves conjugating compounds with endogenous molecules like glutathione and glucuronic acid, greatly increasing hydrophilicity and facilitating excretion. Biotransformation can activate or inactivate compounds, and is influenced by genetic and environmental factors. The liver is the primary site of biotransformation, though other tissues play roles.
2. Definition of Xenobiotics
• Xenobiotics: is a compound that is foreign to the
body ; is a chemical which is found in an organism
but which is not normally produced or expected to
be present in body.
Endogenous: Pigments , hormone
Non-endogenous: such as drugs , food additives,
pollutants, toxin, etc
• Most of these compounds are subject to
metabolism (biotransformation) in human body
3. Definition of the biotransformation
Conversion of lipophilic xenobiotics to water-soluble chemicals
by a process catalyzed by enzymes in the liver and other tissues.
In most cases, biotransformation lessens the toxicity of
xenobiotics, but many must undergo the process to exert their
toxic effects.
Purpose of biotransformation
Facilitates excretion: Converts lipophilic to hydrophilic
compounds
Detoxification/inactivation: converts chemicals to less
toxic forms
Metabolic activation: converts chemicals to more toxic
active forms
4. Factors affecting drug metabolism
Genetic variations: genetic polymorphisms in drug-metabolizing
enzymes can lead to variable responses to medications.
Age-related changes and sex hormones influence enzyme activity.
Liver and renal function: can impair metabolism and elimination.
Drug-drug interactions: can alter enzyme activity, affecting
metabolism.
Environmental factors, smoking, and alcohol consumption, can
induce specific enzymes.
Disease states and hormonal changes: impact drug metabolism.
And nutritional status: adequate nutrition is essential for optimal
enzyme function.
6. Phase I
Introduction of functional group
Hydrophilicity increases slightly
May inactivate or activate original compound
major player is CYP or mixed function oxygenase
(MFO) system in conjunction with NAD(P)H
Location of reactions is smooth endoplasmic
reticulum
7. Sites of biotransformation
Primary site: Liver
Rich in enzymes which Acts on endogenous and exogenous
compounds
Extrahepatic metabolism sites; Intestinal wall Sulfate conjugation
Esterase and lipases - important in prodrug metabolism Lungs,
kidney, placenta, brain, skin, adrenal glands
8. Phase I- Biotransformation Activation
Biotransformation Activation of xenobiotics is a key
element (e.g. benzene, vinyl chloride) –
Reactive intermediates include epoxides and free radical
species (unpaired electrons) that are short-lived and hence
highly reactive
Protection is provided by endogenous antioxidant
substances, e.g. GSH vitamins C and E antioxidant
enzymes, SOD, GPX, CAT in coupled reactions
Antioxidant molecules are oxidized in the process but have
the capacity to regenerate the reduced form from the
oxidized - NAD(P)H is a key player
9. Cytochrome P450 (CYP) Mixed Function Oxidases (MFO)
Located in many tissues but highly in liver ER Human:
16 gene families CYP 1,2,3 perform drug metabolism >48 genes
sequenced Key forms:
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4
Highly inducible –
AlcoholCYP2E1
Dioxin/PCBs CYP1A
Barbiturates
Microsomal Mixed Function Oxidases (MFOs) Flavoprotein,
NADPH-monooxygenase Cytochrome P450
Non-cytochrome oxidizing enzymes.
Xanthine oxidase Alcohol/aldehyde dehydrogenase
Cytochrome P450 (CYP) Mixed Function Oxidases
(MFO)
Phase I metabolizing enzymes
10. Metabolic enzymes
Drug metabolism Refers to enzyme-mediated biotransformations
(detoxication) that alter the pharmacological activity of both
endogenous and exogenous compounds.
Examples
11. Quizzes
Describe hydrolysis process of
esters and amides
Organophosphates
Epoxides
Describe the reductions of Azo and Nitro compounds
Elaborate on benezene transformation to leukemia causing
metabolites
12. Phase II
Conjugation with endogenous molecules (GSH, glycine, cystein,
glucuronic acid)
Hydrophilicity increases substantially
Neutralization of active metabolic intermediates
Facilitation of elimination
Location of reactions is cytoplasm
Types of reactions
13. PHASE II (CONJUGATION) OR CONJUGATIVE ENZYMES
• Phase II conjugative enzymes
metabolize drugs by attaching
(conjugating) a more polar
molecule to the original drug
molecule to increase water
solubility.
• thereby permitting more rapid
drug excretion.
• This conjugation can occur
following a phase I reaction
involving the molecule, but prior
metabolism is not required.
• The phase II enzymes typically
consist of multiple isoforms,
analogous to the CYPs, but to
date are less well defined.
Glucourinic acid conjugation
Acetylation
glycine conjugation
Sulfonation
Methylation
14. Glucourinic acid conjugation
This is the most common.
The active form of glucoronic acid is UDP-glucoronic acid in
uronic acid pathway.
UDP-glucuronyltransferasesare the enzymes which participate in
glucuronide formation.
It occurs with compounds containing hydroxyl , carbonyl,
sulfhydryl or amino groups.
Strongly acidic compounds which are more soluble in water are
produced – hence more easily excreted.
16. Sulfonation
• The active form 3’-phosphoadenosine 5-
phosphosulfate(PAPS) participates in conjugation.
• Enzyme sulfotransferase in involved.
• Aliphatic & aromatic compounds undergo sulfation.
17. Methylation
Methyl group of S-adenosylmethionine is used to methylate
many compounds.
Enzyme methyl transferase is used.
18. Acetylation
Acetyl CoA is the active form .
Drugs like sulfanilamide are converted to acetyl
derivatives.