General Toxicology and Principles Samples †MyAssignmenthelp.com

Question: Discuss about the General Toxicology and Principles. Answer: Genotoxic carcinogens are divided into categories: direct and indirect carcinogens that initiate tumours through the production of DNA damage. A primary or direct acting carcinogen is a chemical that do not require any kind of chemical modification or metabolic activation for inducing cancer called activation- independent carcinogens being highly reactive electrophilic molecules act by binding to cellular macromolecules, DNA (Klaunig, 2014). On the other hand, indirect-acting genotoxic carcinogens require metabolic activation from proximate carcinogen or procarcinogen to carcinogen like Nicotine-derived nitrosamine ketone (NNK), benzo[a]pyrene and alfatoxin B1. Direct carcinogens like dimethylcarbamyl chloride and Dimethyl sulphate does not require any chemical transformation for the carcinogenicity production. On a contrary, procarcinogens or indirect acting compounds as polycyclic aromatic hydrocarbons require the metabolic conversion for the final production of carcinogen that has the capability of carcinogenicity or induce tumours (Stanley, 1995). Direct acting carcinogens like alkylating and acylating agents does not uncoil or coil DNA properly or information-decoding enzymes do not process it. As a result, there is cytotoxicity and inhibition of cell growth and initiation of apoptosis or programmed cell death. Direct carcinogens that increase the incidence of cancer after chemical exposure also trigger mutations (Smith et al., 2016). Indirect carcinogens or pro-carcinogens are changed in the body after exposure into carcinogens that cause cancer at other sites except for the exposure site. They are activation dependent and require cellular enzymatic metabolism that exert action just as direct acting carcinogen. In general, metabolism is the attempt made by body to detoxify exogenous chemicals conjugation with water solutes that can be excreted. However, body exposure to chemical and detoxification results in activation of that chemical into ultimate carcinogen that can induce cancers (Oliveira, 2016). Epigenetic carcinogen does not damage the DNA on its own, however, make alterations in the body predispose to cancer. It is different from genotoxic carcinogens as they directly react with DNA or any macromolecule inducing cancer. They are non-genotoxic chemical carcinogens that function to induce tumour formation by modulating the cell growth, inducing cell death or by exhibiting dose dependent relationships between exposure of chemical and tumour formation. Chemicals like arsenite, diethylstilbestrol, nickel compounds and hexachlorobenzene increases the incident of tumours, however, does not show any mutagen activity like pathogens or toxic compounds. The epigenetic carcinogens cause modification of gene expression, functional developmental changes or exogenous factors that induce cancer. DNA hypemethylation causes down-regulation of tumour suppressor genes (TSG) and hypomethylation results in up-regulation of oncogenes in epigenetic mechanism of carcinogenesis where it does not ch ange the basic structure and sequence of DNA. The growth factors, hormones interact with their receptors for production and different differentiation processes and other processes like inflammation, restorative growth and cytotoxicity. Due to the action of epigenetic carcinogens, there is gene repression, activation or derepression, stimulation of cell division and clonal expansion that alters the cell and as a result, cell communication is disrupted. These mechanisms induce normal cell to induce mutation and the initiated cell becomes transformed cell in the promotion stage. After progression, there is survival advantage of the malignant sub-populations resulting in cancer cells and carcinogenesis (Herceg et al., 2013). Proto-oncogenes are normal genes that help in cell growth normally, however, when it undergoes mutations or changes to become activated uncontrollably becoming oncogene. When mutations occur in DNA sequence, it gives rise to oncogene that interferes with normal cell division regulation. The proto-oncogene activation is achieved by mechanisms like chromosomal translocation, enhancer and promoter insertion, point mutations or gene amplification. Mutation in one allele is enough to cause oncogenic activity and often acting as dominant to wild type. There is gain of function of the protein signalling uncontrolled cell division and conversion occurs from proto-oncogene to oncogene. There is some tissue preference in this mechanism. Mutation occurs in somatic cells and therefore, it is not inherited (Hnisz et al., 2016). On the other hand, TSGs are found normally on a cell surface and its function is the regulation of cell division by slowing of division process, coupling to DNA damage in cell cycle, cell repair mechanism or the induction of apoptosis. It is different from proto-oncogene as oncogene is formed due to activation of proto-oncogene whereas TSG cause cancer in activated form. Only one allele of TSG that is mutated is not enough to cause cancer rather two mutant form of TSG alleles are required to cause cancer as one normal allele has the signal for stopping cell division. Examples, p53 protein and Rb gene are TSGs and loss of function mechanism of protein results in malfunctioning of TSGs. There is strong tissue preference in TSGs, for example, the Rb II gene in retina blastoma (Harris, 1996). References Harris, C. C. (1996). p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology, and cancer risk assessment.Environmental health perspectives,104(Suppl 3), 435. Herceg, Z., Lambert, M. P., van Veldhoven, K., Demetriou, C., Vineis, P., Smith, M. T., ... Wild, C. P. (2013). Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation.Carcinogenesis,34(9), 1955-1967. Hnisz, D., Weintraub, A. S., Day, D. S., Valton, A. L., Bak, R. O., Li, C. H., ... Reddy, J. (2016). Activation of proto-oncogenes by disruption of chromosome neighborhoods.Science, aad9024. Klaunig, J. E. (2014). Chemical carcinogenesis.Principles of Toxicology: Environmental and Industrial Applications 2014,259. Oliveira, P. A. (2016). Chemical carcinogens.Oxford Textbook of Oncology, 142. Smith, M. T., Guyton, K. Z., Gibbons, C. F., Fritz, J. M., Portier, C. J., Rusyn, I., ... Hecht, S. S. (2016). Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis.Environmental health perspectives,124(6), 713. Stanley, L. A. (1995). Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes.Toxicology,96(3), 173-194