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PHL 472
Chemical Carcinogens
Abdelkader Ashour, Ph.D.
3rd Lecture
Common Chemical Carcinogens
Carcinogen
Type of Cancer
Occupational carcinogens
Soot and mineral oil
Skin cancer
Arsenic
Lung cancer, skin cancer
Asbestos
Lung cancer, mesothelioma
Hair dyes and aromatic amines
Bladder cancer
Benzene
Leukemia
Nickel
Lung cancer, nasal sinus cancer
Formaldehyde
Nasal cancer, nasopharyngeal cancer
Vinyl chloride
Hepatic angiosarcoma
Painting materials, non-arsenic pesticides, diesel
exhaust, chromates chromates
Lung cancer
Lifestyle carcinogens
Alcohol
Esophageal cancer, oropharyngeal cancer
Tobacco
Head and neck cancer, lung cancer, esophageal
cancer, bladder cancer
Drug carcinogens
Alkylating agents
Leukemia
Diethylstilbestrol
Liver cell adenoma, vaginal cancer in exposed female
fetuses
Oxymetholone (Anadrol)
Liver cancer
IARC Classification of carcinogens
 IARC (International Agency for Research on Cancer)
 IARC class 1: The substance is carcinogenic to humans, e.g. arsenic, aflatoxin
B1, estrogens
 IARC class 2A: The substance is probably carcinogenic to humans (sufficient
evidence of carcinogenicity in animals, but limited evidence of
carcinogenicity in humans), e.g., benzo[a]pyrene, adriamycin
 IARC class 2B: The substance is possibly carcinogenic to humans , e.g., carbon
tetrachloride, chloroform
 IARC class 3:
The substance is not classifiable as to its carcinogenicity to
humans, e.g., chloroquine, diazepam, 5-fluorouracil
 IARC class 4:
The substance is probably not carcinogenic to humans. This
category is used for agents or mixtures for which there is
evidence suggesting lack of carcinogenicity in humans and in
experimental animals
Structure of Representative Chemical
Carcinogens
Classification of Carcinogens According to
the Mode of Action, Based on Reactivity with DNA
I.
Genotoxic Carcinogens
II.
Non-Genotoxic (Epigenetic) Carcinogens
Classification of Carcinogens According to
the Mode of Action, Based on Reactivity with DNA
I. Genotoxic Carcinogens
 DNA-reactive (direct-acting) or DNA-reactive (indirectly acting ) metabolites
 The interaction with DNA  mutation due to alteration in the structure of DNA 
inaccurate replication of that region of the genome
 Genotoxic Carcinogens  formation of DNA adducts (the most common), DNA
strand breaks, and DNA-protein cross-links
 N7 of G is the most nucleophilic site in DNA, at which many ultimate
carcinogens form covalent adducts
+
= DNA Adduct  Mutation  Cancer
Genotoxic Carcinogens, Mechanism
Chemical Carcinogens and Their Activation
 The first chemically identified carcinogens were the polycyclic aromatic
hydrocarbons (PAHs)
 They are composed of variable numbers of fused benzene rings that form from
incomplete combustion of fossil fuels and vegetable matter (including tobacco),
and they are common environmental contaminants.
 The PAHs are chemically inert, and require metabolism to exert their biologic
effects
 This is a multi-step process, it involves the following: initial epoxidation
(cytochrome P450, CYP1A1 is an inducible isoform), hydration of the epoxide
(epoxide hydrolase), and subsequent epoxidation across the olefinic bond
(CYP1B1; CYP3A4)
 The result is the ultimate carcinogenic metabolite, a diolepoxide
 The arene ring of benzo[a]pyrene-7,8-diol 9,10-oxide opens spontaneously at
the 10 position, giving a highly reactive carbonium ion that can form a covalent
addition product (i.e., adduct) with cellular macromolecules, including DNA
 Several DNA-adducts can be formed, the most abundant being at the exocyclic
amino group of deoxyguanosine ([7R]-N2-[10-{7,8,9-trihydroxy-7,8,9,10tetrahydro-benz[a]pyrene} yl] - deoxyguanosine; BPdG)
Metabolic Activation of Benzo(a)pyrene,
as a Representative
Example for Chemical Carcinogens (Genotoxic)
Procarcinogen
Proximate Carcinogen Ultimate Carcinogen
(1) Cytochrome P450 catalyses initial epoxidation across the 1 - 2, 2 - 3, 4 5, 7 - 8 , 9 - 10 and 11 - 12 positions
(2) With the exception of the 1 - 2 and 2 - 3 oxides that convert to phenols,
epoxide hydrolase may catalyze the formation of dihydrodiols
N7(benzo[a]pyren-6-yl)guanine
(3) Benzo[a]pyrene-7, 8-dihydrodiol is further metabolized at the olefinic double bond by
cytochrome P450 to form a vicinal diolepoxide (7, 8-dihydroxy-9, 10 epoxy-7,8,9,10tetrahydroxybenz[a]pyrene)
(4) The highly unstable arene ring opens spontaneously to form a carbocation
(5) This electrophic species forms a covalent bond between the 10 position of the hydrocarbon and
the exocyclic amino group of deoxyguanosine