General Toxicology Non-Organ Directed Toxicity Carcinogenesis & Mutagenesis Lec.6 4th Year 2017-2018 College of Pharmacy/University of Mustansiriyah Department of Pharmacology & Toxicology Lecturer: Rua Abbas Al-Hamdy

Objectives of this lecture are to: Determine chemical carcinogenesis in humans. Identify some occupational human carcinogens. Identify some human carcinogenic chemicals associated with medical therapy. Define mutagenesis & its mechanisms. Explain damage to DNA caused by alkylating electrophiles. Explain DNA repair mechanisms.

Chemical carcinogenesis in humans: Infectious agents, lifestyle, medical treatments, & environmental & occupational exposure account for the majority of cancers seen in humans. The component that contributes the most to human cancer induction & progression is lifestyle: tobacco use, alcohol use, & poor diet.

Tobacco usage is estimated to be responsible for 25% to 40% of all human cancers. In particular, a strong correlation between tobacco usage & mouth, larynx, lung, esophageal, & bladder cancer exists. Alcohol consumption contributes anywhere from 2% to 4% of cancers of the esophagus, liver, & larynx.

High-fat & high-calorie diets have been linked to breast, colon, & gallbladder cancer in humans. Diets poor in antioxidants &/or vitamins such as vitamin A & vitamin E probably also contribute to the onset of cancer. The method of cooking may also influence the production of carcinogens produced in the cooking process.

Carcinogenic heterocyclic amines & polycyclic aromatic hydrocarbons are formed during broiling & grilling of meat. Acrylamide, a suspected human carcinogen, has been found in fried foods at low concentrations.

Table 1. Occupational human carcinogens A number of occupations associated with the development of specific cancers are listed in (Table 1). Agent Industrial process Neoplasms Asbestos Construction & asbestos mining Peritoneum, bronchus Benzene Chemical manufacturing Bone marrow Wood dust Cabinet making Nasal sinus Formaldehyde Plastic & chemical Nasal sinus, & bronchus Table 1. Occupational human carcinogens

Human carcinogenic chemicals associated with medical therapy: A number of medical therapeutics have also been linked to the induction of human cancer (Table 2). Drug Associated neoplasms Cyclophosphamide Bladder, & leukemia Azathioprine Lymphoma, reticulum cell sarcoma,& skin Chloramphenicol Leukemia Estrogens Liver cell adenoma, endometrium, & skin Table 2. Human carcinogenic chemicals associated with medical therapy

Mutagenesis: The reaction of a carcinogen with genomic DNA either directly or indirectly may result in DNA adduct formation or DNA damage, & frequently produces a mutation.

Mechanisms of mutagenesis: Transitions & transversions Frame shift mutations Broken DNA strands

Transitions & transversions: Transitions are a substitution of one pyrimidine by the other or one purine by the other (changes within a chemical class), A transversion occurs when a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine (changes across a chemical class).

Frame shift mutations: Frame shifting mutations are the addition or deletion of one or a few base pairs in protein coding regions.

Broken DNA strands: These may arise either as a result of: excision repair mechanisms that are incomplete during DNA replication, or via direct alkylation of the phosphodiester backbone leading to backbone cleavage.

Damage by alkylating electrophiles: Most chemical carcinogens require metabolic activation to exert a carcinogenic effect. The ultimate carcinogenic forms of these chemicals are frequently strong electrophiles (e.g., carbonium ions, free radicals, epoxides & sulfonates) that can readily form covalent adducts with nucleophilic targets. An important & abundant source of nucleophiles is contained not only in the DNA bases, but also in the phosphodiester backbone.

Another common modification to DNA is the hydroxylation of DNA bases. Oxidative DNA adducts have been identified in all our DNA bases. The source of oxidative DNA damage is typically formed from free radical reactions that occur endogenously in the cell or from exogenous sources.

Chemical carcinogens may inhibit DNA methylation by several mechanisms including: forming covalent adducts, single-strand breaks in the DNA, & inactivation of the DNA methyltransferase responsible for methylation.

DNA repair mechanisms: Although cells posses mechanisms to repair many types of DNA damage, these are not always completely effective. These mechanisms include: Mismatch repair of single-base mispairs Excision repair, & Double-strand break repair

Mismatch repair of single-base mispairs: Depurination is a fairly common occurrence & spontaneous event in mammals, & results in the formation of apurinic sites. All mammalian cells possess apurinic endonucleases that function to cut DNA near apurinic sites. The cut is then extended by exonucleases, & the resulting gap repaired by DNA polymerase & ligase.

Excision repair: DNA regions containing chemically modified bases, or DNA chemical adducts, are typically repaired by excision repair processes.  

Double-strand break repair: There are two general pathways for repair of DNA double-strand breaks: homologous recombination & nonhomologous end-joining (NHEJ).

Homologous recombination: In homologous recombination, the double-strand break on one chromosome is repaired using the information on the homologous, intact chromosome.

Nonhomologous end-joining (NHEJ): A cell that has double-strand breaks can be repaired by joining the free DNA ends. The joining of broken ends from different chromosomes, however, will lead to the translocation of DNA pieces from one chromosome to another, translocations that have the potential to enable abnormal cell growth.

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