Carcinogenesis Handouts

Chemical Carcinogenesis
Dr. Christopher Sinal

Room 5E, Tupper Medical Building
csinal@dal.ca
• Email for appointment

• Handouts available online:
http://pharmacology.medicine.dal.ca/undergraduate/courses.cfm
Additional Resource: Luch, A. (2005) Nature and Nurture - Lessons from

Chemical Carcinogenesis. Nature Reviews in Cancer 5:113-125
(www.nature.com)
2008 Sinal - Intro Pharmacol II 1

Cancer in a Pharmacology Course?
1. Chemical carcinogenesis involves the interaction of foreign compounds
(xenobiotics) with the body
2. Chemical carcinogens obey essentially the same pharmacokinetic

principles of absorption, distribution and elimination as therapeutic drugs
3. Chemical carcinogens are metabolized by the same enzymes as therapeutic

drugs
4. Conceptually, the biological effects of chemical carcinogens can be treated

the same as the unwanted side effects of therapeutic drugs
5. Cancer is a human disease treated with pharmacological agents

What is Cancer?
•a disease in which cells of the body divide and proliferate
in an uncontrolled manner
•associated with a loss of normal cell cycle control
•genetic mutation is a required event
Topics we will address:

• chemical carcinogens
• multi-stage model of carcinogenesis
• metabolic activation of carcinogens
• metabolic deactivation of carcinogens
• genetic changes associated with carcinogenesis
• risk assessment
A Brief History of Notable Discoveries in Chemical Carcinogenesis
1700
Bernadini Ramazzini 1895
publishes “Diseases of Workers” Ludwig Wilhelm Carl
1566
a systematic analysis of Rehn reports increased
Paracelsus describes
“peculiar diseases” associated urinary bladder tumours
wasting disease of
with different occupations in aniline dye workers
arsenic
miners in Austria in Germany
1500 1600 1700 1800 1900
1775
Percival Pott links occupational
exposure to soot with
increased incidence of
scrotal cancer in English
chimney sweeps

Chemical Carcinogenesis Research in the 20th Century
1930-50’s
1983
Numerous chemical compounds
1915 Identification of activating
identified as causative agents
Yamagiwa and Ichikawa genetic mutations (ras gene)
for the development of
Direct demonstration of as a consequence of exposure
tumours in animal models
tumour development in to chemical carcinogens
and humans
rabbits after exposure
to coal tar
1900 1925 1950 1975 2000
1930 1950-1960’s 1964

Kennaway and Hieger identify Identification of liver Correlation between
Benzo[a]pyrene as the enzymes that metabolize DNA binding activity
major chemical carcinogen carcinogens to more/ and carcinogenicity of
present in coal tar less toxic metabolites chemical carcinogens

Chemical Carcinogenesis - The Present
• Approximately 200 chemical compounds or mixtures of

chemical compounds are known or are anticipated to be
human carcinogens
• Mutation of approximately 100 genes has been described in

response to exposure to chemical carcinogens
• Exposure to chemical carcinogens is believed to be

responsible for a large proportion of cancer deaths in
Western industrialized societies
– Tobacco
– Diet
– Occupational/environmental exposure
Chemical Carcinogens
Carcinogen - any substance or agent that significantly

increases tumor incidence
Similarity to Drugs and Other Toxins:

• exhibit clear dose-response relationships
• undergo biotransformation (activation, deactivation)
• response varies with species, sex, age
• interact with co-administered substances (enhancement or
inhibition)
Difference from Drugs and Other Toxins:
• biologic effect is persistent, cumulative and delayed

Selected Examples of Known Human Chemical Carcinogens
Organ System Chemical Carcinogen
Lung Metals (As, Be, Cd, Cr, Ni)
Tobacco smoke
Diesel exhaust
Asbestos
Oral Cavity and Esophagous Tobacco smoke
Smokeless tobacco
Skin Cutting oil
Coal soot
Liver Aflatoxin B1
Vinyl chloride
Bladder Aromatic amines (4-aminobiphenyl)
Tobacco smoke
Lymphatics Ethylene oxide
All Benzene

Structures of Some Selected Chemical Carcinogens
Aflatoxins Dioxins Polychlorinated Biphenyls

O
O R R
R R R R
R O R
R R
O R O R
O R R R R R R
OCH3
Aflatoxin B1
R = Cl, H R = Cl, H
Polycyclic Aromatic Hydrocarbons
Alkylating Agents
H3C
Benzo[a]pyrene Cl S Cl
N N O
Cl N Cl
H3C
Aromatic Amines
NH2
Dimethylnitrosamine Sulphur Mustard Nitrogen Mustard
Naphthylamine

Alkylating Agents
H3C
Benzo[a]pyrene Cl S Cl
N N O
Genotoxic and Non-Genotoxic

Aromatic Amines
Carcinogens H3C
Cl
NH2
Dimethylnitrosamine Sulphur Mustard Nitrog
Naphthylamine
Metabolism
Genotoxic Non-Genotoxic
• DNA adducts • Inflammation
• Chromosome breakage • Immunosuppression
• Chromosome fusion • Oxygen radicals
• Chromosome deletion • Receptor activation
• Epigentic silencing
Genetic Damage Altered Signal Transduction
Genetic instability
Loss of proliferation control
Resistance to apoptosis
Cancer
Multi-Stage Model of Carcinogenesis

Tumour Initiation
genotoxic
chemical
carcinogen genetic
change
normal cell initiated cell
• genetic damage by a genotoxic chemical carcinogen is a key event

• chemical carcinogens form covalent addition products (adducts) with DNA
• faulty repair of DNA damage leads to mutation
- aberrant levels of gene expression or protein products with
altered function
• in general, a positive correlation exists between the number of detectable
carcinogen:DNA adducts and the development of tumours

Tumour Promotion
clonal
expansion
• expansion of initiated cells to form a preneoplastic lesion

• mutations in genes that control cell growth increases proliferation
(replication, growth) of initiated cell (clonal expansion)
• non-genotoxic carcinogens can increase the proliferation of both normal
and initiated cells
- but, initiated cells have an exaggerated growth response to these
agents
- inflammation, hormones (e.g. estrogen), growth factors, chemicals

Malignant Conversion
genetic
change expansion
preneoplastic
malignant
lesion
tumour
• transformation from “primed” preneoplastic state to
malignant state (conversion to tumour cell)
• associated with additional genetic change and expansion
- affected by genotoxic and non-genotoxic chemicals
• low probability of malignant conversion is increased by
continued exposure to chemical carcinogens

Tumour Progression
genetic change
metastasis
• progression of a malignant tumour to a more aggressive state

• associated with additional genetic change (carcinogen exposure,
genetic instability) and expansion
• invasion beyond the primary tumour (metastasis)
• genotoxic and non-genotoxic agents can accelerate this process

Summary - Multi-Stage Model of Carcinogenesis
• multiple stages are involved in the progression from a

normal cell to metastatic cancer
• conversion to a cancerous phenotype is initiated by genetic

change (genotoxic carcinogen)
• chemical carcinogens (genotoxic and non-genotoxic) have

effects at all stages in the progression of carcinogenesis

Metabolic Fate of Chemical Carcinogens
Tissue
Accumulation Phase I Product
Carcinogen Elimination
Elimination Phase II Product urine

feces
environment

The Liver and Carcinogen Metabolism
• extensive capacity to metabolize a wide variety of chemical
structures
• metabolic capacity of various tissues: liver > lung > kidney ≈
intestine ≈ adrenals > other tissues
• liver metabolism is a primary defense against the
accumulation of toxic chemicals within the body
• but, can also generate reactive carcinogens from non-reactive
precursors
• drug, carcinogen and other xenobiotic metabolism is broadly
classified as Phase I or Phase II
• conversion of lipophilic substances to more water-soluble
metabolites that are more readily eliminated in urine and bile
Phase I Metabolism
• predominant liver metabolism pathway
• usually precedes Phase II reactions
• most common outcome is deactivation (detoxification)
• occasionally compounds are activated to metabolites
with greater biological activity or chemical reactivity
(bioactivation)
Enzymes
• microsomal cytochrome P450 (CYP)
• epoxide hydrolase (EH)
• flavin-containing monooxygenase (FMO)
• alcohol and aldehyde dehydrogenases
• monoamine oxidases
Phase I Bioactivation Reactions
Hydroxylation +H20 OH
OH
OH
CYP O
OO
H
HH
epoxide alcohol
Amine Oxidation O
OO
CYP OH
OH
OH O
OO
H
HH
R
RR N
NN C
CC CH
CH
CH333 R
RR N
NN C
CC CH
CH
CH333
hydroxylamine
Reductive Cl
Cl
Cl
CYP
Cl
Cl
Cl
Cl
Cl
Cl C
CC Cl
Cl
Cl Cl
Cl
Cl C
CC •• ++ HCl
HCl
HCl
Dehalogenation
Cl
Cl
Cl Cl
Cl
Cl
phosgene
Epoxide EH
OH
OH
OH
Hydration O
OO
OH
OH
OH
dihydrodiol

Phase II Metabolism
• usually preceded by Phase I reaction(s)
• addition of polar moieties to exposed functional groups
(e.g. -OH, -COOH, -NH2)
• produces more water-soluble metabolites
• most common outcome is detoxification
• occasionally compounds are bioactivated by this route
Enzymes
• UDP-glucuronyltransferases (UDP-GTs)
• sulfotransferases (STs)
• glutathione S-transferases (GSTs)
• N- and O- acetyltransferases (OATs and NATs)

Phase II Metabolic Reactions
Glucuronidation
O
OH O
UDP-GT COOH
+ UDP-GA + UDP
H H
glucuronide conjugate
Sulfation O
OH O S O
ST
+ PAPs O + 3'-PAP
H H
sulfate conjugate
Mercapturic Acid Biosynthesis H2 H

S C C COOH
GST 2-4
O + GSH NH
OH C O
CH3
mercapturic acid conjugate

Direct and Indirect Chemical Carcinogens
• the carcinogenic potential of a chemical is directly related to the ability to

covalently modify DNA
• for many carcinogens, this process requires metabolism (indirect)
• for others, metabolism is not required (direct)
Procarcinogen: parent compounds which are upstream of the ultimate

mutagen
Ultimate Carcinogen: the reactive metabolite which covalently modifies

DNA
Proximate Carcinogen: an intermediate metabolite between pro and

ultimate

Metabolic Activation of DAB
N
1. N
2. N N
N N N N
N N N N
H3C CH3 H3C OH H3C O H3C
DNA
C O
CH3
Dimethylaminoazobenzene (DAB) Proximate Carcinogen Ultimate Carcinogen DNA Adduct

"Procarcinogen"
• diazo dye used in textile manufacture

• known human hepatocarcinogen
• one of the first characterized procarcinogens (1947)
1. CYP1A2; 2. Acetyltransferase

Metabolic Activation of PAHs
DNA
1 2 3 O
HO
HO HO HO
O
OH OH OH
benzo[a]pyrene “proximate “proximate benzo[a]pyrene-7,8-

"Procarcinogen" diol 9,10-oxide
carcinogen” carcinogen” "Ultimate Carcinogen"
Polycyclic Aromatic Hydrocarbons (PAHs)

• first recognized chemical carcinogens
• formed by incomplete combustion of fossil fuels and vegetable matter
• common environmental contaminant
• chemically inert without metabolic activation
1. CYP1A1; 2. Epoxide Hydrolase; 3. CYP1A1 or CYP3A4

Direct Acting Carcinogens
O HO
+ H2O
N O N CH3+ + N N + H2O
H3C N C NH2 H3C N

methylcarbonium ion
O
N-methylnitrosourea (NMNU)
HC NH2
• do not require metabolic activation

• inherently reactive and unstable compounds
• other examples: free radicals, epoxides, strained-ring systems

An important message regarding chemical
carcinogen metabolism…….
• bioactivation of procarcinogens by phase I or phase II

metabolism is a rare occurrence
• most commonly, metabolism results in the successful

elimination of the procarcinogen without adverse effects

Benzo[a]pyrene is eliminated through metabolism
DNA
1 2 3 O
HO
HO HO HO
O
OH OH OH
benzo[a]pyrene “proximate “proximate benzo[a]pyrene-7,8-

carcinogen” carcinogen” "Ultimate Carcinogen"

Summary - Metabolism of Carcinogens
• the liver is quantitatively the most important site for carcinogen

metabolism
• direct chemical carcinogens do not require metabolic activation
• indirect chemical carcinogens require metabolic activation to generate the

ultimate carcinogenic agent
• phase I and phase II metabolism can result in bioactivation of chemical

carcinogens
• most commonly, metabolism results in the detoxification and elimination

of chemical carcinogens

Genetic Modification by Chemical Carcinogens
• direct and indirect genotoxic chemical carcinogens covalently
modify DNA (adduct formation)
• almost all DNA damage is reversed by very effective and

efficient cellular DNA repair mechanisms
• cells with unrepairable DNA damage usually undergo

programmed cell death (apoptosis)
• errors in DNA repair lead to mutations (alteration of DNA

sequence) that can result in cancer initiation
• mutations can be passed on to daughter cells by mitosis and

clonal expansion
B[a]P-derived DNA-Carcinogen Adducts
N
NH
N N NH
H
HO
HO
OH
benzo[a]pyrene deoxyguanosine adduct

Spontaneous Decomposition of NMNU
O HO
+ H2O
N O N
CH3+ + N N + H2O
H3C N C NH2 H3C N

methylcarbonium ion
O
N-methylnitrosourea (NMNU)
HC NH2

Metabolic Activation of Benzo[a]Pyrene
DNA
1 2 3 O
HO
HO HO HO
O
OH OH OH
benzo[a]pyrene benzo[a]pyrene-7,8-
"Ultimate Carcinogen"

Carbonium ion-DNA Adducts
OCH3
N
NH
O
N N NH2
H
N
NH
+ CH3+ O6-methylguanosine
N N NH2
H
CH3 O
guanosine N
NH
N N NH2
H
N7-methylguanosine

Repair of DNA-Carcinogen Adducts
1. Nucleotide Excision
- elicited by bulky adducts (e.g. B[a]P)
- large stretch of DNA surrounding the adduct is removed
(10-12 bp total) and replaced
2. Base Excision
- elicited by small DNA adducts (e.g. alkylating agents)
- removal and replacement of a single modified base or a very short
stretch of DNA surrounding the adduct
3. O6-alkylguanine Transferase
- specifically removes alkyl groups from the O6-position of modified
guanosine bases (e.g. carbonium ion)
- no DNA is removed or replaced

Mutations Resulting From Faulty DNA Repair
AGG TGT GTG GAG A

Arg Cys Val Glu
AGG TGG GTG GAG A
Arg Trp Val Glu Substitution
carcinogen -single AA
substitution
-short protein
AGG TGA GTG GAG A
Arg STOP --- ---
AGG TGT GTG GAG A
Arg Cys Val Glu
T AGG TGG TGG AGA

successful Arg Trp Trp Arg Frameshift
repair -multiple AA
T substitutions
-short protein
AGG TGT GTG GAG A AGG TGT TGT GGA GA
Arg Cys Val Glu Arg Cys Cys Gly

Implications of Faulty Repair of DNA-Carcinogen Adducts
DNA repair errors

DNA replication errors
MUTATION
mutations -proto-oncogene
-tumour suppressor gene
aberrant gene regulation

incorrect gene products
REPAIR NO REPAIR
altered cell
function and growth
tumour development
NO CANCER CANCER

Proto-Oncogenes
Function:
• normal cellular genes that control cell:
- growth (proliferation)
- specialization (differentiation)
- death (apoptosis)
• almost all proto-oncogenes encode signal transduction proteins
• activated proto-oncogene = oncogene
Activation:
Proto-oncogene Oncogene

Mechanisms of Proto-Oncogene Activation
1. Overexpression of the gene leading to increased

concentration and biological activity of the protein product
- regulatory mutation
2. Expression of the gene at an inappropriate time or context

3. Expression of the gene in an inappropriate cell type

- regulatory muation
4. Expression of an altered protein product

- structural mutation

Ras Proto-Oncogenes
Ras Proteins
• large family of membrane-bound guanine nucleotide binding proteins (G-proteins)
• GTP binding promotes formation of signal transduction complexes with other proteins
• hydrolysis of GTP -> GDP terminates activity (transient activation)
• exert a powerful proliferative influence in many cell types
Incidence of Ras Mutations

in Human Cancers
Pancreas 90%
Colon 50%
Thyroid 50%
Lung 30%
Myeloid Leukemia 30%
Ovarian 15%
Bladder 6%
http://fig.cox.miami.edu/~cmallery/150/gene/c7.19.12a.Ras.jpg
Ras and Human Cancers
• activation is very common in human cancers
• in animal models of chemical carcinogenesis and in human cancers
arising from environmental exposure:
- most mutations occur within the 12th
or 61st codons
- amino acid substitution
Why the specificity of these sites?

1. Selectivity of ultimate carcinogen for these sites
- accessibility, nucleotide preference, physiochemiststry
2. Functional effect of mutations
- growth advantage to cells possessing mutation
- reduced or absent GTPase activity (activation)

Tumour Suppressor Genes
Function:
• normal cellular genes that :
- limit tissue growth
- contribute to the destruction of cells with damaged
genomes
• almost all tumour suppressor genes encode signal transduction

proteins
Deactivation:
Tumour Suppressor Gene Loss of function

Mechanisms of Tumour Suppressor Gene Deactivation
1. Expression of a protein with altered or absent function

- structural mutation
2. Absence of gene expression


p53 Tumour Suppressor Gene
• cell cycle control

• DNA repair
• differentiation
• apoptosis
• most well studied tumour

suppressor gene
• fully functional p53 can
overcome the effects of
http://fig.cox.miami.edu/~cmallery/150/gene/c7.19.12b.p53.jpg one or more activated
oncogenes

p53 Mutations
• point mutations resulting in amino acid substitutions or chain termination are
extremely common in human cancers (50%)
• mutational spectra exhibits “hot spots”
• chemical carcinogens frequently cause mutations at codon 249 (AGG)
AGT
(serine)
Protein with
AGG O
(arginine)
reduced or absent
function
ATG
(methionine)

Selectivity of p53 Mutations?
1. Unusual susceptibility of codon 249 to ultimate carcinogens

- accessibility, nucleotide preference, physiochemiststry
- bulky PAHs form N7-deoxyguanosine adducts
2. Functional effect of mutations

- growth advantage to cells possessing mutation
- reduced or absent protein activity (deactivation)

Proto-Oncogene Activation and Tumour Suppressor
Deactivation is Rare:
• there are approximately 35 000 genes in the human

genome
• there are approximately 100 known human proto-

oncogenes and tumour suppressor genes
• DNA repair is an extremely efficient and effective process
• genetic changes resulting in proto-oncogene activation and

tumour suppressor gene deactivation are rare events

Summary - Genetic Modification by Chemical Carcinogens
• genotoxic chemical carcinogens covalently modify DNA, a process

which can be reversed by cellular DNA repair
• faulty repair of DNA adducts results in changes in the structure and/or

regulatory properties of affected genes and the corresponding protein
products
• proto-oncogene activation and loss of tumour suppressor genes are

important outcomes of the genotoxic actions of carcinogens
• the vast majority of genetic changes are efficiently repaired, have no

oncogenic consequence, or are lethal to the host cell

Genetics and Cancer Susceptibility
• interindividual variability in cancer susceptibility exists
• arises from subtle differences in gene sequence between
individuals (polymorphisms)
• can affect the level of expression of the gene or the
function of the protein product
• exhibits familial patterns of inheritance
Example: Polymorphisms of Carcinogen Metabolism

Polymorphisms of Carcinogen Metabolism
Glutathione S-transferases
- variant GST genes encoding proteins with reduced function have been
linked to increased susceptibility to PAH-induced (tobacco smoke) lung
cancer
UDP-glucuronyltransferases
- variant UDP-GTs genes encoding proteins with reduced function have been
linked to increased susceptibility to various chemical induced cancers
N-acetyltransferases
- variant NAT1 and NAT2 genes with encoding proteins with reduced activity
have been linked to increased risk for aromatic amine induced bladder cancer
Phase I Bioactivation Enzymes
- no conclusive evidence exists linking polymorphisms of genes encoding Phase I
enzymes with human cancers, but
- evidence exists for interaction with other polymorphisms

Risk
The probability of a particular adverse effect (e.g. cancer)
after exposure to a chemical agent
Example:
The lifetime risk of cancer of is 2.5 x 10-4 from exposure to 1 part per million (ppm) of
chemical “X” present in the air, when breathed 24 hours a day for 70 years.
Is equivalent to:
There is a risk of 1 additional cancer in a population of 1 x 106 individuals from

exposure to 1 part ppm of chemical “X” present in the air, when breathed 24 hours a
day for 70 years.
• a probabilistic statement based upon short, high-dose exposure

• not derived from direct measurement
• assumptions and uncertainties

Dose-Response Assessment
A quantitative description of the relationship between the
dose of the agent of interest and a detrimental effect
• Description of potency (EC50) and efficacy (Emax)

• Considers modifiers of response such as sex, age, species, route of exposure,
exposure pattern
• Data derived from animal studies with high-dose, short-term exposure
Potential Problems:
1. Extrapolation from animals to humans
2. Extrapolation from acute to chronic exposure
3. Extrapolation from high dose to low dose

Dose-Response Curves
Net Linear Threshold Hormetic

Effect
Damage = Repair Damage < Repair
Damage > Repair
Damage > Repair Damage > Repair
+
Dose Dose Dose

An Example of Hormesis?
Global
Average
2 Exposure • relative risk of leukemic
Global cancer is lower in certain
Average geographical areas with
Risk higher than average
1 background radiation
levels
• mechanism?
• confounding factors?
0
0.1 1 10 100
Annual Radiation Exposure (cSv)

The Big Picture
• cancer is a disease of uncontrolled cell growth characterized by defects in the
expression of proto-oncogenes and tumour suppressor genes
• cancer is a multistage disease which requires genetic change for transition from one
stage to another
• chemical carcinogens act by causing genetic mutations (genotoxic) and/or by
stimulating the growth of cancerous cells (non-genotoxic)
• metabolism of chemical carcinogens most commonly results in deactivation and
elimination - bioactivation is rare
• genetic modification of proto-oncogenes and tumour suppressor genes by chemical
carcinogens at regions that affect protein structure/function is a rare event
• mutation is rare due to efficient and effective repair by DNA repair mechanisms
• chemical carcinogenesis requires the occurrence of multiple rare events
• the probability of cancer development from exposure to a chemical carcinogen is
affected by genetic polymorphisms, dose and time
• the linear dose-response model is preferred for risk assessment

Carcinogenesis Handouts

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Carcinogenesis Handouts

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Chemical Carcinogenesis

Dr. Christopher Sinal

• Email for appointment

Additional Resource: Luch, A. (2005) Nature and Nurture - Lessons from

2008 Sinal - Intro Pharmacol II 1

2. Chemical carcinogens obey essentially the same pharmacokinetic

3. Chemical carcinogens are metabolized by the same enzymes as therapeutic

4. Conceptually, the biological effects of chemical carcinogens can be treated

5. Cancer is a human disease treated with pharmacological agents

2008 Sinal - Intro Pharmacol II 2

Topics we will address:

1500 1600 1700 1800 1900

2008 Sinal - Intro Pharmacol II 4

1900 1925 1950 1975 2000

1930 1950-1960’s 1964

2008 Sinal - Intro Pharmacol II 5

• Approximately 200 chemical compounds or mixtures of

• Mutation of approximately 100 genes has been described in

• Exposure to chemical carcinogens is believed to be

Carcinogen - any substance or agent that significantly

Similarity to Drugs and Other Toxins:

2008 Sinal - Intro Pharmacol II 7

2008 Sinal - Intro Pharmacol II 8

Aflatoxins Dioxins Polychlorinated Biphenyls

Polycyclic Aromatic Hydrocarbons

2008 Sinal - Intro Pharmacol II 9

Genotoxic and Non-Genotoxic

Genetic Damage Altered Signal Transduction

2008 Sinal - Intro Pharmacol II 11

normal cell initiated cell

• genetic damage by a genotoxic chemical carcinogen is a key event

2008 Sinal - Intro Pharmacol II 12

• expansion of initiated cells to form a preneoplastic lesion

2008 Sinal - Intro Pharmacol II 13

2008 Sinal - Intro Pharmacol II 14

• progression of a malignant tumour to a more aggressive state

2008 Sinal - Intro Pharmacol II 15

• multiple stages are involved in the progression from a

• conversion to a cancerous phenotype is initiated by genetic

• chemical carcinogens (genotoxic and non-genotoxic) have

2008 Sinal - Intro Pharmacol II 16

Elimination Phase II Product urine

2008 Sinal - Intro Pharmacol II 17

2008 Sinal - Intro Pharmacol II 20

2008 Sinal - Intro Pharmacol II 21

Mercapturic Acid Biosynthesis H2 H

mercapturic acid conjugate

2008 Sinal - Intro Pharmacol II 22

• the carcinogenic potential of a chemical is directly related to the ability to

Procarcinogen: parent compounds which are upstream of the ultimate

Ultimate Carcinogen: the reactive metabolite which covalently modifies

Proximate Carcinogen: an intermediate metabolite between pro and

2008 Sinal - Intro Pharmacol II 23

Dimethylaminoazobenzene (DAB) Proximate Carcinogen Ultimate Carcinogen DNA Adduct

• diazo dye used in textile manufacture

2008 Sinal - Intro Pharmacol II 24

benzo[a]pyrene “proximate “proximate benzo[a]pyrene-7,8-

Polycyclic Aromatic Hydrocarbons (PAHs)

1. CYP1A1; 2. Epoxide Hydrolase; 3. CYP1A1 or CYP3A4

2008 Sinal - Intro Pharmacol II 25

H3C N C NH2 H3C N

• do not require metabolic activation

2008 Sinal - Intro Pharmacol II 26