What are Carcinogens?

Carcinogen is a chemical substance or a combination of chemical substances which increases the risk of cancer or causes cancer. Carcinogens exist naturally in the environment (like ultraviolet rays in sunlight and certain viruses) or may be produced due to man-made activity (like exhaust from automobiles and smoke from cigarettes). These carcinogens interact with the DNA of the cell and cause mutations by damaging the genome.

Types of Carcinogens

There are three different subcategories of carcinogens are

Physical Carcinogens

Ionizing radiation such as γ-rays and X-rays and non-ionizing radiation such as Ultra Violet –rays(UV rays) upon prolonged exposure interact with the genome of organisms leading to mutations expressing their carcinogenic effect.

Chemical Carcinogens

A good example of a chemical carcinogen is Tobacco smoke which causes cancers related to the lung, head, neck, and urinary bladder It contains various carcinogenic agents like Arsenic, polonium-210, nickel, chromium, cadmium, ethyl carbamate ethylene oxide, formaldehyde, benzene, etc.
Chemical carcinogens after metabolic transformation get converted into electrophiles and interact with nucleophiles like DNA  and proteins which leads to mutations.

Biological Carcinogens

Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human papillomavirus (HPV), Epstein–Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), and HIV-1. There are various human RNA and DNA viruses that are carcinogenic to humans. These viruses have developed numerous molecular mechanisms and they alter specific cellular pathways to cause aberrant replication.

Characteristics of Carcinogens

1. It is genotoxic
2. It is electrophilic in nature
3. It leads to genomic instability
4. It causes oxidative stress
5. It is immunosuppressive
6. It causes chronic inflammation
7. It causes epigenetic alterations
8. Alters cell proliferation, cell death, or nutrient supply
9. Causes immortalization
10. Modifies receptor-mediated cells

Alteration in Normal Cell 

• Genotoxic: Carcinogen causes damage to DNA, the cell may or may not convert this damage caused into mutation. An agent that causes DNA damage is  Known as a genotoxicant or a genotoxin, and if the agent also causes mutations in an assay of mutagenicity then it is known as a mutagen.
• Electrophilic Nature: The molecules that seek electrons are known as Electrophiles. They commonly form addition products, these are called adducts, with cellular macromolecules like lipids, proteins, DNA, and RNA. Few chemical carcinogens act directly as electrophiles and few others act after enzymatic biotransformation or metabolic activation.
• Genomic Instability: Normal cells replicate their genomes with high precision and attempt to evade mutations that are deleterious. However, the precision of DNA replication varies depending on the DNA polymerase that is involved, and this may cause an error possibility. most of the mutations that are spontaneous in nature are caused by errors in DNA polymerase. This can leads to genomic instability.
• Induces Oxidative Stress: Many human carcinogens have the ability to alter redox reactions causing redox imbalance within target cells. Any disparity between the formation of reactive oxygen or nitrogen is known as oxidative stress. Oxidative damage is the main factor in the formation of mutations in DNA.
• Immunosuppressive: Immunosuppression is a decrease in the ability of the immune system to fight effectively against foreign antigens. Continuous immunosuppression increases the risk of cancer. Mainly risk of lymphoma is increased when it is accompanied by persistent exposure to foreign antigens after transplantation of an organ or it occurs in individuals who are potentially infected with the oncogenic virus.
• Chronic Inflammation: Chronic inflammation due to repeated infections caused by bacteria like Helicobacter pylori and persistent exposure to fibers of silica or asbestos has been linked with different forms of cancer. Inflammation is suspected  to cause cancer initiation, its promotion, and its a progression
• Persistent infection and chronic inflammation disturb the homeostasis of local tissue, and it disrupts cell signaling, leading to the activation of inflammatory cells that enhance the promotion and progression of tumors.
• Epigenetic alterations: The word “epigenetic” indicates stable changes in the expression of genes and the organization of chromatin. These are not dependent on the DNA sequence and can be mitotic gets inherited over cell divisions. The epigenetic process, includes genomic imprinting,  inactivation of the X chromosome, DNA reconfiguration methylome, and changes in compaction states of chromatin and histone. Many of these processes are disrupted during carcinogenesis.

Properties of Cancer Cell

Alters Cell Proliferation, Cell Death, or Nutrient Supply

DNA damage leads to coding different proteins than normal which causes mutations in proliferating cells, which leads to many changes in the normal cell and makes it different. Evasion of programmed cell death (apoptosis) and autophagy causes cellular proliferation has been suspected to be a factor in increased susceptibility to cancer.

In Neoangiogenesis, new blood vessels grow into a tumor and supply nutrients to it. Agents like arsenic promote or inhibit angiogenesis and will promote or delay tumor growth.

Angiogenesis

Causes Cell Multiplication

There are various human RNA and DNA viruses that are carcinogenic to humans. These include different types of viruses like hepatitis B virus  (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein–Barr virus (EBV), and Kaposi sarcoma-associated herpesvirus (KSHV), and HIV-1. These viruses have evolved numerous molecular mechanisms to 
disturb specific cellular pathways to cause aberrant replication.

These oncogenic viruses belong to various families, they show various similarities in the development of cancer and involve oncoproteins targeting the major proteins of cell that causes cell growth. These viral effects cause multiple changes in the cells in the target tissue which leads to cancer.

Modifies Receptor-Mediated Cells

Agents (hormonally active) that show carcinogenicity usually act as ligands through nuclear receptors and in a few cases these act through receptors situated on the surface of the cell.

This activation of receptors is divided into two types:

• Intracellular receptors activation that migrates into the nucleus and it acts on DNA as transcription factors, and
• Activation of receptors situated on the cell surface and some intracellular receptors. These triggers signal transduction pathways causing biological responses.

Mutagen/Carcinogen Metabolism

Many chemical carcinogens are not genetically cancer-causing without first being metabolized by enzymes inside cells.
Usually, the metabolism of these chemical carcinogens forms less carcinogenic substances, which are in course of eliminated from the body.

However, a small part of metabolism causes the formation of highly carcinogenic byproducts. These highly carcinogenic metabolic byproducts are hydrophobic in nature. The aggregate in cell membranes and fatty tissues of the body causes dysfunction and toxicity. Hence, living organisms have evolved to get rid of these foreign carcinogenic substances. The mechanism usually involves the addition of hydroxyl groups to mutagens or carcinogens by enzymatic action, this enhances their polarity nature and increases their water solubility. This leads to their eventual elimination through excretion.

Metabolism is carried out in different tissues of the body, but extensively metabolism occurs in the liver. Different types of detoxifying enzymes participate in this process, but of them, quantitatively ubiquitous cytochrome P450 plays an important role.

There are 20 different cytochrome P450s known to exist in humans. These help in the addition of hydroxyl groups (OH) to various kinds of chemicals. Cytochrome P450 enzymes generally generate the least toxic substances. and they can also form intermediate products which are highly reactive causing carcinogenic effects.

Identifying Carcinogens

Molecular Structural Analysis

Data regarding the possibility of a chemical being a carcinogen may be evaluated by comparing its structure, chemical characteristics, and physical characteristics with those of already identified carcinogens and noncarcinogens. Some molecular structures are related to carcinogenicity, and the structural resemblance is used in taking decisions regarding agents that are more or less suspect.

Short Term Tests 

The short term requires a short time to perform the experiments. Few studies in which micro-organisms are used require less than one day, many studies require some days to some weeks and in animals, like mice, it takes 8 to 9 months. These times may be correlated to the more than 3 years needed to complete a bioassay and in epidemiologic studies, it takes months to years to complete.

Long-term Chronic Bioassays in Laboratory Animals

Due to ethical reasons, chemicals cannot be evaluated for carcinogenicity in humans. A considerable body of experimentally obtained knowledge and the majority of expert opinion supports the conclusion regarding the testing of chemicals in laboratory animals provides dependable information regarding carcinogenicity. Animal tests include complete mammal systems, and even though they are different from one another, all mammals and including humans have many similar biological characteristics.

Epidemiology Studies

According to Lilienfeld epidemiology is the study of disease distribution in human populations and the factors responsible for this disease distribution. Epidemiology methods are used for detecting causative agents and circumstances that lead to cancer. epidemiology studies can determine the correlation in populations between exposure to agents causing carcinogenicity, details of lifestyle, and increased risk of cancer.

Safety Precautions 

The personnel working or handling the carcinogens, or the people who are regularly exposed to harmful dust must use precautionary steps to protect themselves from risks caused due to harmful chemicals, rays, or biological agents carcinogens. safety equipment includes

• Special Goggles are used for safety to avoid carcinogen contact with the eyes, 
• Impermeable gloves made with proper material that cannot interact with carcinogenic agents respirator is used against harmful vapours and gases. 
• face shield is used to avoid contact of skin with chemical, physical and biological carcinogens. 
• In the lab, the working personnel uses impermeable apron made of proper material, closed-toed shoes, and long-sleeved lab coat that are also worn for protection against potential threats of carcinogens. 

Conceptual Questions

Question 1: What is a Carcinogen?

Answer: 

A chemical substance or a combination of chemical substances which increases the risk of cancer or causes cancer is called a “Carcinogen’

Carcinogens exists naturally in the environment (like ultraviolet rays in sunlight and certain viruses) or may be produced due to man made activity (like exhaust from automobiles and smoke from cigarette ). These carcinogens interact  with a DNA of cell and causes mutations by damaging the genome.

Question 2: What is Neo-angiogenesis?

Answer: 

In Neo-angiogenesis new blood vessels grow into a tumour and supplies nutrients to it. Agents like arsenic promote or inhibit angiogenesis and will promote or delay tumor growth.

Question 3: What is a Genotoxicant?

Answer:

Carcinogen causes damage to DNA, the cell may or may not convert this damage caused into mutation. An agent that causes DNA damage is  Known as a genotoxicant or a genotoxin, and if the agent also causes mutations in an assay of mutagenicity then it is known as a mutagen.

Question 4: What are the examples of biological agents that are carcinogenic?

Answer:

There are various human RNA and DNA viruses that are carcinogenic to humans .These include different types of viruses likehepatitis B virus  (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein–Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV), and HIV-1. These viruses have evolved numerous molecular mechanisms to disturb specific cellular pathways to  cause aberrant replication.