1 – Introduction
Toxicology is the study of adverse effects of chemicals on health which we encounter every single
day in our lives. Here are some highlighted cases:
Kilimanjaro Christian Medical Centre, Tanzania
Villagers there take water from the soil but they did not test the water content. Excessive exposure to
fluoride causes an arthritic bone disease called skeletal fluorosis, leading to body deformation.
The Dwale / deadly nightshade plant (Atropine)
In Italy, people used to drop these chemicals into their eyes and their pupils would then dilate. It
could be toxic but at the same time used as a therapeutic for parasympaticolyticum.
Warfarin (dicumarol)
Coumarin is a compound found in the sweet(-scented) woodruff Lievevrouwebedstro plant. It is toxic
as it causes poisoning of livestock (bleeding) after eating moldy sweet clover. Nowadays, depending
on the dose, warfarin is used therapeutically as an anticoagulant or as a rodenticide.
The nature and severity of intoxication is determined by:
- Toxicity of the substance
- Exposure : route, type, size, duration, frequency
- Organism: species, strain, sex, age
- Interactions: physical (temperature, pressure), environmental and social factors,
simultaneous or successive exposure
2 – Biotransformation
Biotransformation is the process of metabolizing drugs. Metabolism of drugs can be misleading as
metabolism is quite referring to food. Thus, we call it biotransformation. Biotransformation makes
compounds active/inactive, and makes water soluble. All cells have transformation enzymes but
especially hepatocytes in the liver. Biotransformation can occur in the enterocytes lining the
intestines but mostly in the liver.
Enterocytes → portal vein → liver → general circulation
Drug metabolism and biotransformation
Compounds need to be biotransformed so they can reach their active metabolite state.
Biotransformation occurs in 3 different phases:
Phase I
This phase of biotransformation is also called functionalization because a functional group (-OH,
-NH2, -SH or -COOH) is introduced to yield polar products. Most times, oxygen is introduced. This
phase involves oxidation, reduction and hydrolysis. The addition of functional groups makes the
compound less stable (active) so it can enter phase II.
,Oxidation is considered the most important Phase I reaction, in some cases involving the cytochrome
P450 (CYP) system. Many different CYPs are involved in drug metabolism and there are a lot of CYP
inhibitors and inducers (increase CYP expression).
Epoxidation
CYP enzymes can also facilitate epoxidation of drug
molecules. Epoxidation can generate many very
reactive compounds as epoxides are very unstable
groups. This reaction occurs in the activation of
benzo[a]pyrene which is present in cigarette
smoke, so everyone is exposed to this compound in
low doses every single day. In the structure of
benzo[a]pyrene, the bay region is important. Firstly,
an epoxide is formed in the bottom of the bay
region and this is so unstable that the epoxide has
, no time to cause any damage in the nucleus. However, we then get another epoxide in the bay
region. This one is more stable than the previous epoxide. Thus, it has time to travel to the nucleus
and attack DNA bases (e.g. guanine) which can lead to mutation and cancer in high concentration.
Phase II
Phase II reactions will make the products hydrophilic through conjugation reactions with many
different substrates (except for methylation as methyl is not water soluble). These substrates include:
- Glutathione via glutathione transferases (from alkyl halides)
Glutathione is a 3 AA peptide with the middle one being a cysteine (S). This can react with the
epoxides, detoxifying them. It is present in large quantities in the cell especially in the liver.
- Acetate via Acetyl-CoA (from -NH2)
- Sulfate via sulfotransferases (from -OH, and amines)
- Glucuronide via glucuronyltransferase/glucuronidase (adding a sugar group onto an -OH)
Phase III: This phase is involved in excretion.
Differences in biotransformation
There are large species and interindividual differences in biotransformation. The metabolism of
xenobiotics can be different across species and therefore it would be very important to see the
metabolism in the other animals before using them as models. For example, Glucuronidation will not
occur in cats. Sulfate conjugation will not occur in pigs.
Biotransformation factors
- Genetics
- Environment
- Disease
Toxicology is the study of adverse effects of chemicals on health which we encounter every single
day in our lives. Here are some highlighted cases:
Kilimanjaro Christian Medical Centre, Tanzania
Villagers there take water from the soil but they did not test the water content. Excessive exposure to
fluoride causes an arthritic bone disease called skeletal fluorosis, leading to body deformation.
The Dwale / deadly nightshade plant (Atropine)
In Italy, people used to drop these chemicals into their eyes and their pupils would then dilate. It
could be toxic but at the same time used as a therapeutic for parasympaticolyticum.
Warfarin (dicumarol)
Coumarin is a compound found in the sweet(-scented) woodruff Lievevrouwebedstro plant. It is toxic
as it causes poisoning of livestock (bleeding) after eating moldy sweet clover. Nowadays, depending
on the dose, warfarin is used therapeutically as an anticoagulant or as a rodenticide.
The nature and severity of intoxication is determined by:
- Toxicity of the substance
- Exposure : route, type, size, duration, frequency
- Organism: species, strain, sex, age
- Interactions: physical (temperature, pressure), environmental and social factors,
simultaneous or successive exposure
2 – Biotransformation
Biotransformation is the process of metabolizing drugs. Metabolism of drugs can be misleading as
metabolism is quite referring to food. Thus, we call it biotransformation. Biotransformation makes
compounds active/inactive, and makes water soluble. All cells have transformation enzymes but
especially hepatocytes in the liver. Biotransformation can occur in the enterocytes lining the
intestines but mostly in the liver.
Enterocytes → portal vein → liver → general circulation
Drug metabolism and biotransformation
Compounds need to be biotransformed so they can reach their active metabolite state.
Biotransformation occurs in 3 different phases:
Phase I
This phase of biotransformation is also called functionalization because a functional group (-OH,
-NH2, -SH or -COOH) is introduced to yield polar products. Most times, oxygen is introduced. This
phase involves oxidation, reduction and hydrolysis. The addition of functional groups makes the
compound less stable (active) so it can enter phase II.
,Oxidation is considered the most important Phase I reaction, in some cases involving the cytochrome
P450 (CYP) system. Many different CYPs are involved in drug metabolism and there are a lot of CYP
inhibitors and inducers (increase CYP expression).
Epoxidation
CYP enzymes can also facilitate epoxidation of drug
molecules. Epoxidation can generate many very
reactive compounds as epoxides are very unstable
groups. This reaction occurs in the activation of
benzo[a]pyrene which is present in cigarette
smoke, so everyone is exposed to this compound in
low doses every single day. In the structure of
benzo[a]pyrene, the bay region is important. Firstly,
an epoxide is formed in the bottom of the bay
region and this is so unstable that the epoxide has
, no time to cause any damage in the nucleus. However, we then get another epoxide in the bay
region. This one is more stable than the previous epoxide. Thus, it has time to travel to the nucleus
and attack DNA bases (e.g. guanine) which can lead to mutation and cancer in high concentration.
Phase II
Phase II reactions will make the products hydrophilic through conjugation reactions with many
different substrates (except for methylation as methyl is not water soluble). These substrates include:
- Glutathione via glutathione transferases (from alkyl halides)
Glutathione is a 3 AA peptide with the middle one being a cysteine (S). This can react with the
epoxides, detoxifying them. It is present in large quantities in the cell especially in the liver.
- Acetate via Acetyl-CoA (from -NH2)
- Sulfate via sulfotransferases (from -OH, and amines)
- Glucuronide via glucuronyltransferase/glucuronidase (adding a sugar group onto an -OH)
Phase III: This phase is involved in excretion.
Differences in biotransformation
There are large species and interindividual differences in biotransformation. The metabolism of
xenobiotics can be different across species and therefore it would be very important to see the
metabolism in the other animals before using them as models. For example, Glucuronidation will not
occur in cats. Sulfate conjugation will not occur in pigs.
Biotransformation factors
- Genetics
- Environment
- Disease
