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Carcinogens and their classification

Question:

Discuss about the Pharmacology for Genotoxic and Non-genotoxic Carcinogens.

Carcinogen refers to substances such as radionuclide, radiations or other substance that play an essential role in promoting carcinogenesis, or cancer formation. Carcinogen exerts their action by altering or damaging the genome. Furthermore, these carcinogen also disrupt the cellular metabolic processes. Carcinogens are generally classified into two categories namely, genotoxic and non-genotoxic (Smith et al. 2016). The term genotoxic carcinogen refers to the chemicals that have the property of producing or leading to the onset of cancer by creating direct alterations in the genetic material of major target cells. On the other hand, the term non-genotoxic carcinogen is commonly used for chemicals that are capable of causing cancer by exerting a range of secondary mechanisms that are not directly related to gene damage. 

Genotoxic carcinogen has several properties that are given below:

  • These carcinogens are found to undergo bioactivation to a range of reactive species or electrophilic intermediates. This results in the formation of DNA-adducts in the target tissues or cells.
  • Genotoxic carcinogen have been found to produce positive results when evaluated by several invitor genotoxicity tests (Hernández, van Benthem and Johnson 2013).
  • Genetic damages of the target cells are also induced by these carcinogens, in in-vivo assays that are performed for shorter duration.

On the other hand, major properties of the non-genotoxic carcinogens are given below:

  • These carcinogens often fail to exhibit significant effects related to genotoxicity, when tested in a series of systems
  • They are responsible for inducing target lesions at specific locations. These lesions are generally characterized by increased growth and proliferation of the cells, in addition to sustained hyper-function or dysfunction of the cells (Schaap et al. 2015).
  • These carcinogens also produce several metabolic, hormonal or physiopathological effects that are found responsible for production of target lesions in the body.

While working in conjunction with each other genotoxic and non-geno toxic carcinogens exert a mechanism that is responsible for altering signal transduction pathways. This results in genomic instability, loss of control over proliferation of the cells, hypermutability and an increased resistance to apoptosis. Hence, the characteristic features of cancer cells are exhibited by both the types of carcinogen (Lee et al. 2013). While long term exposure to reduced doses of  genotoxic carcinogen are responsible for non-geno toxic alterations in the cell, weakening of the major checkpoints present in cell cycle occurs due to non-geno toxic environmental carcinogen. Most often these result in certain alterations of the genome that are heritable. Research studies have also provided evidence for the fact that exposure to a large range of genotoxic and non-geno toxic hepatocarcinogens often lead to the development of rapid alterations in cellular epigenome of organisms (Ireno et al. 2014). Their similarities can be attributed to the fact that they result in loss of region specific and global DNA hypomethylation, and hypermethylation of promoters present in tumor suppressor genes. This leads to disruption of balance between apoptosis and proliferation in the cancer cells (Lee et al. 2014).

Chemical carcinogens are often classified into two categories namely, mutagenic and non-mutagenic, based on positive or negative evidences, based on damage to DNA, chromosomal aberration and mutagenicity. Strong positive correlation has been established in mutagenic assays and carcinogenicity. While carcinogenic agents lead to the development of cancer by converting a normal cell into a proliferative cancer cell, they are not always mutagenic (Galloway et al. 2013). This can be attributed to the fact that a mutagen most commonly results in a change in the sequence of DNA. However, carcinogens can lead to a variety of effects, such as, over expression of myc proteins, breaks in DNA, and activation of oncogenes. Furthermore, carcinogenic agents can also manifest themselves in the form of an epigenetic factor, or epigenetic drug that results in bringing about an alteration in gene expression, without changing the genetic sequence (Sutter et al. 2013). Although carcinogens directly increase incidence and prevalence rates of cancer, some of them do not directly cause damage to the DNA and only result in an acceleration of cell division. This leaves less opportunity for the cell to repair the induced mutations or replication errors. Hence, non-mutagenic carcinogens have been found to induce tumors, without directly altering the DNA sequence.

Properties of genotoxic and non-genotoxic carcinogens

Research evidences have shown that these agents often act on cellular targets, apart from DNA and modulate epigenetic mechanism that often plays a role in tumor evolution. Most common non-mutagenic carcinogens include phenobarbital and DDT. Furthermore, administration of several non-mutagenic carcinogens such as, sodium nitrite and hydroxylamine has failed to induce tumor in animal models (Ferrari et al. 2013). Thus, it can be stated that these non-mutagenic cancer causing agent promote development of cancer by exiting a stimulating effect on the rates of cell mitosis. Increased rates of mitosis weaken opportunities for the repair of the DNA that has been damaged during replication, thereby increasing the likelihood of replication errors. Such mistakes that occur during mitosis often result in wrong number of chromosomes getting incorporated in the daughter cells, which might lead to aneuploidy or cancer (Martins et al. 2013).

In vitro carcinogenicity tests are often designed to predict or evaluate the carcinogenic potential of certain chemicals in order to assess the risk that these chemicals pose to human health. In vitro tests have often been considered as the gold standard method for evaluating carcinogenic potential of certain chemicals (Kirkland et al. 2014). However, there are several disadvantages or challenges associated with their use. Positive in vitro tests are often irrelevant to demonstrate development of tumor, owing to the fact that carcinogen for which tumorigenicity does not occur, due to a recognisable genotoxic mechanism, is often categorised as non-geno toxic.  Research evidences have shown that genotoxicity data produced by these tests are often misleading, and exclude nucleoside analogues and chemotherapeutics from the results, which are most often genotoxic by their design (Schug et al. 2013). Moreover low specificity of these tests lead to misleading positive results as specificity and sensitivity often depend on reliability of identifying the mechanism of carcinogenicity. While the test that focuses on mammalian cell assay demonstrates increased sensitivity, they have poor specificity. On the other hand, reasonable specificity and sensitivity is demonstrated by Ames tests (Ghallab 2013). Hence, the in vitro experiments are often not reliable for determining carcinogenicity of a particular substance.

Hepatotoxicity or gastrointestinal toxicity refers to chemical driven damage of the gastrointestinal tract and liver. They often lead to development of chronic and acute liver diseases (Poorvu et al. 2013). Toxic effects in the gastrointestinal tract mostly comprise of intestinal and gastric ulcer and can be regarded as undesirable effects of non-steroidal anti inflammatory drugs (NSAIDs). These non-steroidal anti inflammatory drugs belong to a class of drugs that work with the aim of decreasing fever, reducing pain, and preventing formation of blood clot. Major function of these drugs is also related to production of inflammation. However, the major side effects are associated with an increase susceptibility to development of gastrointestinal bleeding and cancer. This gastrointestinal toxicant acts in the form of a non selective inhibitor of a particular enzyme cyclooxygenase (COX), by inhibiting cyclooxygenase-1 and cyclooxygenase-2 isoenzymes (Harirforoosh, Asghar and Jamali 2014).

The aforestated enzyme is responsible for catalyzing prostaglandin and thromboxane formation, from arachidonic acid. The enzymes further constitutively express in the lining of the stomach, where prostaglandin prevents erosion of stomach mucosa, from gastric juices. Administration of NSAIDs such as, ibuprofen and aspirin, levels of prostaglandin in the stomach get lower, thereby resulting in internal bleeding and ulcers of the duodenum or stomach (Sostres, Gargallo and Lanas 2013). Moreover, these drugs also interact with the endocannabinoid system and are also used for the management of acute pain that is caused due to gout.

Effects of carcinogens on the genome and cellular processes

Exposure to a range of blood toxicants have been found to create adverse effects on the hematopoietic or cardiovascular system, thereby contributing to increased rates of mortality and morbidity. One major blood toxicant is carbon monooxide that results in poisoning typically from its inhalation. Common symptoms of this toxicity include weakness, dizziness, headache, pain, vomiting, and loss of consciousness. Carbon monoxide (CO) displays increased diffusion coefficient when compared to oxygen. Heme oxygenase located in the cells is responsible for producing this toxicant. Upon binding to hemoglobin, the pigment found in red blood cells, CO produces a compound termed as carboxyhemoglobin (Wu and Juurlink 2014). This carboxyhemoglobin decreases oxygen carrying capacity of the blood, thereby inhibiting appropriate transport, distribution and utilisation of oxygen.

This can be attributed to the fact that affinity between CO and haemoglobin is approximately 230 times higher, than that between oxygen and the pigment. The toxicant also binds to the heme protein myoglobin, and impairs its capability for utilising oxygen. This directly leads to reduction in cardiac output and causes hyotension, thereby contributing to brain ischemia (Roderique et al. 2015). Furthermore, it also binds to cytochrome oxidase and interferes with the process of aerobic metabolism, resulting in lactic acidosis, anoxia, and subsequent cell death. Its mechanism also involves release of nitric oxide and formation of oxygen free radicals in the central nervous system that leads to mitochondrial dysfunction, leukocyte sequestration, and apoptosis (Kudo et al. 2014).

Dermal toxicity often occurs when the skin comes in direct contact with the toxicant that leads to hypersensitivity, skin cancer or other damage in the body.  One major skin toxicant is Poison Ivy or Toxicodendron radicans. It is a poisonous flowering plant that is responsible for causing urushiol induced contact dermatitis that often involves irritation itchiness and painful rashes in the skin. Urushiol often exerts detoxing effects that are mediated by induced immune response inside the human body (Colbeck, Clayton and Goenka 2013) Oxidized urushiols often act as haptens tutorials and chemically react with, or bind to integral membrane proteins, thereby changing their shape on the surface of skin cells that have been exposed to the plant. The sap of the plant contains oleoresin that results in development of allergic reactions in the body.  

A blackish lacquer develops at the site, after it comes in contact with oxygen. The effective proteins are also known to interfere with the immune system of the person exposed to it, thereby impairing its ability to recognise the exposed cells as a part of the body (Hsu et al. 2013). This results in development of a T-cell mediated immune response that is most commonly directed at the complex formed by urushiol derivatives. One common urushiol derivative is pentadecacatechol that generally binds to the proteins present on the skin surface, and attacks cells of the body, by considering them to be foreign particles (Honda et al. 2013).

Exposure to a range of chemical substances has often showed adverse effects on the ureters, kidney and urinary bladder, thereby contributing to nephrotoxicity. Cadmium often results in kidney toxicity in the human body. It is found to accumulate in the lining of the renal tubular cells, and is generally bound to metallothionein. The latter is a small protein that contains approximately 30% cysteine.  Metallothionein plays an important role in protecting the kidney against nephrotoxicity, by binding to cadmium in its non-toxic form. This non-toxic cadmium metallothionein complex is generally filtered by the glomerulus and often taken up by the epithelial cells that line the proximal tubule (Thévenod and Wolff 2016).

In vitro tests for evaluating carcinogenic potential

This creates a paradoxical effect, and facilitates distribution of cadmium from delivered to the kidneys, thereby mediating its toxic effects. This results in loss of kidney function, to remove waste acids from the blood, thereby contributing to proximal renal tubular dysfunction. The irreversible damage inflicted by cadmium poisoning results in low phosphate levels in the blood, and often accounts for muscle weakness, fatigue, and coma. It also leads to the development of gout, due to accumulation of excess uric acid crystals in the joints. This can often be attributed to hyperuricemia, or high acidity levels in the blood (Yang and Shu 2015). Further defects are related to shrinkage of the kidneys by 30% and development of kidney stones.

Cardiotoxicity often refers to this function of the electrophysiology of the heart that directly leads to damage of the cardiac muscles. Anthracyclines belong to the class of drugs that are used in cancer chemotherapy and extracted from several species of Streptomyces bacterium. The principal adverse effect associated with these drugs is cardiotoxicity that is found to limit their usefulness in enhancing health outcomes. A critical component of anthracycline induced cardiotoxicity can be related to generation of free radicals, and presence of redox related damages. These are found to occur by non-enzymatic and enzymatic pathways, which often result in iron accumulation (Lotrionte et al. 2013).

The free radicals that are generated by anthracycline lead to the formation of lipid peroxidation that is ultimately responsible for producing membrane damages. In addition to causing damage of the mitochondria, this cardiotoxicity also increases calcium current and inhibits function of the sarcoplasmic reticulum. Further mechanism is associated with bringing about a reduction in the activity of Na and K-ATPase. Greater susceptibility of the heart to get affected by anthracycline induced damage can be attributed to high affinity of this drug for cardiolipin (Št?rba et al. 2013). These are unique mitochondrial phospholipids that are involved in mitochondrial membrane dynamics and apoptosis.

References

Colbeck, C., Clayton, T.H. and Goenka, A., 2013. Poison ivy dermatitis. Archives of disease in childhood, 9(12), p.1022.

Ferrari, T., Cattaneo, D., Gini, G., Golbamaki Bakhtyari, N., Manganaro, A. and Benfenati, E., 2013. Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction. SAR and QSAR in Environmental Research, 24(5), pp.365-383.

Galloway, S.M., Reddy, M.V., McGettigan, K., Gealy, R. and Bercu, J., 2013. Potentially mutagenic impurities: analysis of structural classes and carcinogenic potencies of chemical intermediates in pharmaceutical syntheses supports alternative methods to the default TTC for calculating safe levels of impurities. Regulatory Toxicology and Pharmacology, 66(3), pp.326-335.

Ghallab, A., 2013. In vitro test systems and their limitations. EXCLI journal, 12, p.1024.

Harirforoosh, S., Asghar, W. and Jamali, F., 2014. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. Journal of Pharmacy & Pharmaceutical Sciences, 16(5), pp.821-847.

Hernández, L.G., van Benthem, J. and Johnson, G.E., 2013. A mode-of-action approach for the identification of genotoxic carcinogens. PLoS One, 8(5), p.e64532.

Honda, T., Egawa, G., Grabbe, S. and Kabashima, K., 2013. Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. Journal of Investigative Dermatology, 133(2), pp.303-315.

Hepatotoxicity and gastrointestinal toxicity

Hsu, T.W., Shih, H.C., Kuo, C.C., Chiang, T.Y. and Chiang, Y.C., 2013. Characterization of 42 microsatellite markers from poison ivy, Toxicodendron radicans (Anacardiaceae). International journal of molecular sciences, 14(10), pp.20414-20426.

Ireno, I.C., Baumann, C., Stöber, R., Hengstler, J.G. and Wiesmüller, L., 2014. Fluorescence-based recombination assay for sensitive and specific detection of genotoxic carcinogens in human cells. Archives of toxicology, 88(5), pp.1141-1159.

Kirkland, D., Zeiger, E., Madia, F., Gooderham, N., Kasper, P., Lynch, A., Morita, T., Ouedraogo, G., Morte, J.M.P., Pfuhler, S. and Rogiers, V., 2014. Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? I. Reports of individual databases presented at an EURL ECVAM Workshop. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 775, pp.55-68.

Kudo, K., Otsuka, K., Yagi, J., Sanjo, K., Koizumi, N., Koeda, A., Umetsu, M.Y., Yoshioka, Y., Mizugai, A., Mita, T. and Shiga, Y., 2014. Predictors for delayed encephalopathy following acute carbon monoxide poisoning. BMC emergency medicine, 14(1), p.3.

Lee, S.J., Yum, Y.N., Kim, S.C., Kim, Y., Lim, J., Lee, W.J., Koo, K.H., Kim, J.H., Kim, J.E., Lee, W.S. and Sohn, S., 2013. Distinguishing between genotoxic and non-genotoxic hepatocarcinogens by gene expression profiling and bioinformatic pathway analysis. Scientific Reports, 3, p.2783.

Lee, W.J., Kim, S.C., Lee, S.J., Lee, J., Park, J.H., Yu, K.S., Lim, J. and Kwon, S.W., 2014. Investigating the different mechanisms of genotoxic and non-genotoxic carcinogens by a gene set analysis. PloS one, 9(1), p.e86700.

Lotrionte, M., Biondi-Zoccai, G., Abbate, A., Lanzetta, G., D'Ascenzo, F., Malavasi, V., Peruzzi, M., Frati, G. and Palazzoni, G., 2013. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. American Journal of Cardiology, 112(12), pp.1980-1984.

Martins, M., Costa, P.M., Ferreira, A.M. and Costa, M.H., 2013. Comparative DNA damage and oxidative effects of carcinogenic and non-carcinogenic sediment-bound PAHs in the gills of a bivalve. Aquatic toxicology, 142, pp.85-95.

Poorvu, P.D., Sadow, C.A., Townamchai, K., Damato, A.L. and Viswanathan, A.N., 2013. Duodenal and other gastrointestinal toxicity in cervical and endometrial cancer treated with extended-field intensity modulated radiation therapy to paraaortic lymph nodes. International Journal of Radiation Oncology• Biology• Physics, 85(5), pp.1262-1268.

Roderique, J.D., Josef, C.S., Feldman, M.J. and Spiess, B.D., 2015. A modern literature review of carbon monoxide poisoning theories, therapies, and potential targets for therapy advancement. Toxicology, 334, pp.45-58.

Schaap, M.M., Wackers, P.F., Zwart, E.P., Huijskens, I., Jonker, M.J., Hendriks, G., Breit, T.M., van Steeg, H., Van de Water, B. and Luijten, M., 2015. A novel toxicogenomics-based approach to categorize (non-) genotoxic carcinogens. Archives of toxicology, 89(12), pp.2413-2427.

Schug, M., Stöber, R., Heise, T., Mielke, H., Gundert-Remy, U., Godoy, P., Reif, R., Blaszkewicz, M., Ellinger-Ziegelbauer, H., Ahr, H.J. and Selinski, S., 2013. Pharmacokinetics explain in vivo/in vitro discrepancies of carcinogen-induced gene expression alterations in rat liver and cultivated hepatocytes. Archives of toxicology, 87(2), pp.337-345.

Smith, M.T., Guyton, K.Z., Gibbons, C.F., Fritz, J.M., Portier, C.J., Rusyn, I., DeMarini, D.M., Caldwell, J.C., Kavlock, R.J., Lambert, P.F. and Hecht, S.S., 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environmental health perspectives, 124(6), p.713.

Sostres, C., Gargallo, C.J. and Lanas, A., 2013. Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis research & therapy, 15(3), p.S3.

Št?rba, M., Popelová, O., Vávrová, A., Jirkovský, E., Kova?íková, P., Geršl, V. and Šim?nek, T., 2013. Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection. Antioxidants & redox signaling, 18(8), pp.899-929.

Sutter, A., Amberg, A., Boyer, S., Brigo, A., Contrera, J.F., Custer, L.L., Dobo, K.L., Gervais, V., Glowienke, S., van Gompel, J. and Greene, N., 2013. Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities. Regulatory Toxicology and Pharmacology, 67(1), pp.39-52.

Thévenod, F. and Wolff, N.A., 2016. Iron transport in the kidney: implications for physiology and cadmium nephrotoxicity. Metallomics, 8(1), pp.17-42.

Wu, P.E. and Juurlink, D.N., 2014. Carbon monoxide poisoning. Canadian Medical Association Journal, 186(8), pp.611-611.

Yang, H. and Shu, Y., 2015. Cadmium transporters in the kidney and cadmium-induced nephrotoxicity. International journal of molecular sciences, 16(1), pp.1484-1494.

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