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.

1. Xenobiotics

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.

5. Biotransformation

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.

15. Glycine conjugation
Aromatic carboxylic acids are conjugated with glycine.
When benzoyl CoA is conjugated with glycine, hippuric
acid is formed.

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.