Toxicology
Toxicology
- Toxicology or the doctrine of poisons is the science that deals with adverse effects of chemicals
on the health of living organisms.
- Poisoned means that a chemical substance intervenes with the physiological processes in the
human body in such a way that damage can occur.
- The nature and intensity of the symptoms are depending on 1) the type of poison 2) the
exposure, 3) the manner in which the individual responds to the exposure and 4) the interaction
with other factors (chemical, physical, biological and/or psychosocial).
Biotransformation
- The metabolic conversion of endogenous and xenobiotic chemicals to more water-soluble
compounds.
- Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad
substrate specificities.
- The substances that result from biotransformation (metabolites) may be inactive, or they may
be similar to or different from the original compound in activity or toxicity.
- Especially in the liver (hepatocyte); largest capacity of bio metabolism enzymes
(biotransformation)
- Make compounds inactive or more water soluble to be excreted (lipophilic compounds would
accumulate in fat tissue)
Lipophilic to hydrophilic
- Xenobiotic biotransformation or drug metabolism is the process of converting lipophilic (fat-
soluble) chemicals, which are readily absorbed from the gastrointestinal tract and other sites,
into hydrophilic (water-soluble) chemicals, which are readily excreted in urine or bile.
- There are exceptions even to this most basic rule. For example, acetylation and methylation are
biotransformation reactions that can actually decrease the water solubility of certain
xenobiotics.
- Biotransformation of xenobiotics is catalyzed by various enzyme systems that can be divided
into four categories based on the reaction they catalyze: (1) hydrolysis (e.g., carboxylesterase);
(2) reduction (e.g., carbonyl reductase); (3) oxidation (e.g., cytochrome P450 [CYP]); and (4)
conjugation (e.g., UDP-glucuronosyltransferase [UGT]).
- In general, individual xenobiotic-bio transforming enzymes are located in a single organelle.
1
,Phase one
Polar products
- Oxidation, reduction and hydrolysis
- Introduction of a functional group (e.g., OH, NH2, SH or COOH)
Can produce very reactive compounds and unstable; can bind to all kind of molecules
Introduce an epoxide group: O bound to two different C groups
e.g., CYP reaction: activation of benzo[a]pyrene (cigarette smoke)
Generally, mEH and sEH and cytochrome P450 enzymes, which are often responsible for producing the
toxic epoxides, have a similar cellular localization that presumably ensures the rapid detoxication of
alkene epoxides and arene oxides generated during the oxidative biotransformation of xenobiotics.
ROS
2
, - The biotransformation of some xenobiotics results in the production of reactive oxygen species
(ROS), which can cause cell toxicity (including DNA damage) through oxidative stress and lipid
peroxidation.
- Glutathione (GSH), Glutathione S-transferases (GSTs), and glutathione peroxidases (GPXs) all
limit the toxic effects of ROS just as they limit the toxicity of reactive metabolites formed directly
from xenobiotics
Some non-cytochrome P450 reactions include the metabolism of alcohol, by alcohol dehydrogenase
Phase two
Hydrophilic products
- Conjugation with endogenous substrate (e.g., glucuronide, sulphate, acetyl, methyl and
glutathione)
- Attachment of a small polar molecule onto the drug
- Less lipid soluble and more easily excreted
- With the exception of methylation and acetylation, conjugations result in a large increase in
xenobiotic hydrophilicity, which greatly facilitates excretion of foreign chemicals.
- Glucuronidation, sulfation, acetylation, and methylation involve reactions with activated or
"high-energy" co substrates, whereas conjugation with amino acids or glutathione involves
reactions with activated xenobiotics. Except for the glucuronosyltransferases, most conjugation
enzymes are mainly located in the cytosol.
Lots of O2 = very often water soluble
Species differences
- Very often we use animal models or invitro models (cells)
- The balance between activation (often phase I) and detoxication (often phase II) by xenobiotic-
bio transforming enzymes is often a key determinant of chemical toxicity and is often the basis
for organ or species differences in toxicity.
3
, - Species differences in xenobiotic-bio transforming enzymes are often the basis for species
differences in both the qualitative and quantitative aspects of xenobiotic biotransformation and
toxicity.
- In sexually mature rats and, to a lesser extent, mice there are marked gender differences in the
expression of certain xenobiotic-bio transforming enzymes (both oxidative and conjugating
enzymes). In other species, including humans, gender differences either do not exist or generally
represent less than a twofold difference.
Factors influencing biotransformation
- Environment
- Disease
- Genetics
Decreased CYP enzyme activity can result from
(1) a genetic mutation that either blocks the synthesis of a CYP enzyme or leads to the synthesis of a
catalytically compromised, inactive, or unstable enzyme, which gives rise to the poor and intermediate
metabolizer genotypes.
(2) exposure to an environmental factor (such as an infectious disease or an inflammatory process) that
suppresses CYP enzyme expression.
(3) exposure to a xenobiotic that inhibits or inactivates a preexisting CYP enzyme. By inhibiting
cytochrome P450, one drug can impair the biotransformation of another, which may lead to an
exaggerated pharmacologic or toxicologic response to the second drug.
Increased CYP enzyme activity can result from
(1) gene duplication leading to overexpression of a CYP enzyme.
(2) exposure to drugs and other xenobiotics that induce the synthesis of cytochrome P450.
(3) stimulation of preexisting enzyme by a xenobiotic.
Importance of metabolites and polymorphism
- Large interindividual differences in pharmacokinetic parameters upon administration or
exposure to a chemical can reflect genetically determined differences in the activity of
xenobiotic-bio transforming enzymes or transporters (genetic polymorphisms) or environmental
factors, such as drug-drug interactions. The study of the causes, prevalence, and impact of
heritable differences in xenobiotic-bio transforming enzymes is known as pharmacogenetics.
- Mass spectrometry is widely used to characterize the structure of metabolite
4
Toxicology
- Toxicology or the doctrine of poisons is the science that deals with adverse effects of chemicals
on the health of living organisms.
- Poisoned means that a chemical substance intervenes with the physiological processes in the
human body in such a way that damage can occur.
- The nature and intensity of the symptoms are depending on 1) the type of poison 2) the
exposure, 3) the manner in which the individual responds to the exposure and 4) the interaction
with other factors (chemical, physical, biological and/or psychosocial).
Biotransformation
- The metabolic conversion of endogenous and xenobiotic chemicals to more water-soluble
compounds.
- Xenobiotic biotransformation is accomplished by a limited number of enzymes with broad
substrate specificities.
- The substances that result from biotransformation (metabolites) may be inactive, or they may
be similar to or different from the original compound in activity or toxicity.
- Especially in the liver (hepatocyte); largest capacity of bio metabolism enzymes
(biotransformation)
- Make compounds inactive or more water soluble to be excreted (lipophilic compounds would
accumulate in fat tissue)
Lipophilic to hydrophilic
- Xenobiotic biotransformation or drug metabolism is the process of converting lipophilic (fat-
soluble) chemicals, which are readily absorbed from the gastrointestinal tract and other sites,
into hydrophilic (water-soluble) chemicals, which are readily excreted in urine or bile.
- There are exceptions even to this most basic rule. For example, acetylation and methylation are
biotransformation reactions that can actually decrease the water solubility of certain
xenobiotics.
- Biotransformation of xenobiotics is catalyzed by various enzyme systems that can be divided
into four categories based on the reaction they catalyze: (1) hydrolysis (e.g., carboxylesterase);
(2) reduction (e.g., carbonyl reductase); (3) oxidation (e.g., cytochrome P450 [CYP]); and (4)
conjugation (e.g., UDP-glucuronosyltransferase [UGT]).
- In general, individual xenobiotic-bio transforming enzymes are located in a single organelle.
1
,Phase one
Polar products
- Oxidation, reduction and hydrolysis
- Introduction of a functional group (e.g., OH, NH2, SH or COOH)
Can produce very reactive compounds and unstable; can bind to all kind of molecules
Introduce an epoxide group: O bound to two different C groups
e.g., CYP reaction: activation of benzo[a]pyrene (cigarette smoke)
Generally, mEH and sEH and cytochrome P450 enzymes, which are often responsible for producing the
toxic epoxides, have a similar cellular localization that presumably ensures the rapid detoxication of
alkene epoxides and arene oxides generated during the oxidative biotransformation of xenobiotics.
ROS
2
, - The biotransformation of some xenobiotics results in the production of reactive oxygen species
(ROS), which can cause cell toxicity (including DNA damage) through oxidative stress and lipid
peroxidation.
- Glutathione (GSH), Glutathione S-transferases (GSTs), and glutathione peroxidases (GPXs) all
limit the toxic effects of ROS just as they limit the toxicity of reactive metabolites formed directly
from xenobiotics
Some non-cytochrome P450 reactions include the metabolism of alcohol, by alcohol dehydrogenase
Phase two
Hydrophilic products
- Conjugation with endogenous substrate (e.g., glucuronide, sulphate, acetyl, methyl and
glutathione)
- Attachment of a small polar molecule onto the drug
- Less lipid soluble and more easily excreted
- With the exception of methylation and acetylation, conjugations result in a large increase in
xenobiotic hydrophilicity, which greatly facilitates excretion of foreign chemicals.
- Glucuronidation, sulfation, acetylation, and methylation involve reactions with activated or
"high-energy" co substrates, whereas conjugation with amino acids or glutathione involves
reactions with activated xenobiotics. Except for the glucuronosyltransferases, most conjugation
enzymes are mainly located in the cytosol.
Lots of O2 = very often water soluble
Species differences
- Very often we use animal models or invitro models (cells)
- The balance between activation (often phase I) and detoxication (often phase II) by xenobiotic-
bio transforming enzymes is often a key determinant of chemical toxicity and is often the basis
for organ or species differences in toxicity.
3
, - Species differences in xenobiotic-bio transforming enzymes are often the basis for species
differences in both the qualitative and quantitative aspects of xenobiotic biotransformation and
toxicity.
- In sexually mature rats and, to a lesser extent, mice there are marked gender differences in the
expression of certain xenobiotic-bio transforming enzymes (both oxidative and conjugating
enzymes). In other species, including humans, gender differences either do not exist or generally
represent less than a twofold difference.
Factors influencing biotransformation
- Environment
- Disease
- Genetics
Decreased CYP enzyme activity can result from
(1) a genetic mutation that either blocks the synthesis of a CYP enzyme or leads to the synthesis of a
catalytically compromised, inactive, or unstable enzyme, which gives rise to the poor and intermediate
metabolizer genotypes.
(2) exposure to an environmental factor (such as an infectious disease or an inflammatory process) that
suppresses CYP enzyme expression.
(3) exposure to a xenobiotic that inhibits or inactivates a preexisting CYP enzyme. By inhibiting
cytochrome P450, one drug can impair the biotransformation of another, which may lead to an
exaggerated pharmacologic or toxicologic response to the second drug.
Increased CYP enzyme activity can result from
(1) gene duplication leading to overexpression of a CYP enzyme.
(2) exposure to drugs and other xenobiotics that induce the synthesis of cytochrome P450.
(3) stimulation of preexisting enzyme by a xenobiotic.
Importance of metabolites and polymorphism
- Large interindividual differences in pharmacokinetic parameters upon administration or
exposure to a chemical can reflect genetically determined differences in the activity of
xenobiotic-bio transforming enzymes or transporters (genetic polymorphisms) or environmental
factors, such as drug-drug interactions. The study of the causes, prevalence, and impact of
heritable differences in xenobiotic-bio transforming enzymes is known as pharmacogenetics.
- Mass spectrometry is widely used to characterize the structure of metabolite
4
