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PHL 472 Chemical Carcinogens Abdelkader Ashour, Ph.D. 3 rd Lecture.

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Presentation on theme: "PHL 472 Chemical Carcinogens Abdelkader Ashour, Ph.D. 3 rd Lecture."— Presentation transcript:

1 PHL 472 Chemical Carcinogens Abdelkader Ashour, Ph.D. 3 rd Lecture

2 Common Chemical Carcinogens CarcinogenType of Cancer Occupational carcinogens Soot and mineral oilSkin cancer ArsenicLung cancer, skin cancer AsbestosLung cancer, mesothelioma Hair dyes and aromatic aminesBladder cancer BenzeneLeukemia NickelLung cancer, nasal sinus cancer FormaldehydeNasal cancer, nasopharyngeal cancer Vinyl chlorideHepatic angiosarcoma Painting materials, non-arsenic pesticides, diesel exhaust, chromates chromates Lung cancer Lifestyle carcinogens AlcoholEsophageal cancer, oropharyngeal cancer Tobacco Head and neck cancer, lung cancer, esophageal cancer, bladder cancer Drug carcinogens Alkylating agentsLeukemia Diethylstilbestrol Liver cell adenoma, vaginal cancer in exposed female fetuses Oxymetholone (Anadrol)Liver cancer

3 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

4 Structure of Representative Chemical Carcinogens

5 Classification of Carcinogens According to the Mode of Action, Based on Reactivity with DNA I.Genotoxic Carcinogens II.Non-Genotoxic (Epigenetic) Carcinogens

6 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

7 Genotoxic Carcinogens, Mechanism

8 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-7,8,9,10- tetrahydro-benz[a]pyrene} yl] - deoxyguanosine; BPdG)

9 Metabolic Activation of Benzo(a)pyrene, as a Representative Example for Chemical Carcinogens (Genotoxic) (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-7,8,9,10- tetrahydroxybenz[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 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

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