Factors in Biochemical Toxicology

Factors in Biochemical Toxicology Tambudzai Phiri Ndashe Maha Farid In the lecture we discussed several responses of the lung to acute injuries. List these responses and discuss one of these responses providing an example of a toxin or a chemical that induces such response in the lung. (5 points) The lung is particularly vulnerable to toxicity because it gets exposed to foreign compounds both in the external environment and internally through the bloodstream. Acute responses of the lung to injury occur in order to protect the lung from further damage. These responses include the following: Irritation following exposure to volatile gases such as ammonia and chlorine may cause bronchitis and changes in permeability. Exposure to gases or irritants may also lead to damage of the epithelial lining of the entire respiratory tract. Irritation of nerve endings in the respiratory epithelium may occur following exposure to gases or irritants to protect from further exposure. Xenobiotic metabolizing enzymes such as Glutathione S-transferase in the lung tissue also play a role in the pathogenesis of pulmonary toxic response. Oxidative burden following exposure to gases such as ozone, nitrogen dioxide or tobacco smoke. Airway reactivity and bronchoconstriction may occur on exposure to nitric oxides, cholinergic drugs, histamine and tobacco smoke. Pulmonary edema may occur as result of high concentrations of acrolein, hydrogen chloride, nitrogen dioxide, ammonia or phosgene. Pulmonary edema Pulmonary edema is the accumulation of fluid in the lung, which collects in the alveoli; it leads to impaired gas exchange and may cause respiratory failure (Medical News Today, 2014). Exposure to ammonia, a volatile and water soluble gas, has been associated with pulmonary edema. The ammonia gets absorbed into the aqueous secretions of the upper airways of the respiratory system, it reacts with the water in aqueous secretions to from ammonium hydroxide, an alkaline and corrosive solution. Though ammonia may not cause permanent damage it leads to impaired permeability and the accumulation of fluid which obstructs the upper airway and collects in the air sacs. This may lead to low blood oxygen content and altered mental status (Center for Disease Control and Prevention, 2014). The dissolving of the ammonia into aqueous solutions on mucous membranes may also result in corrosive injury to the mucus membranes. High concentrations of acrolein, a common component of smoke, can also cause p ulmonary edema following smoke inhalation. Paraquat, is a widely used herbicide that specifically exerts its toxic effect on the lung tissue. Discuss the mechanism of toxicity of paraquat explaining the specificity of lung toxicity induced by this compound. (5 points) Paraquat has been implicated in number of both accidental and intentional cases of poisoning. It causes dose-dependent toxic effects following oral ingestion; and, absorption of a toxic dose usually results in abdominal pain, vomiting and diarrhea. In addition to the lung, other target organs include mainly the kidneys, but may also cause cardiac and liver toxicity if one if exposed to large doses. Mechanism of paraquat toxicity on the lung Paraquat is selectively taken up into type I and II alveolar epithelial cells by active transport, as a result it reaches a higher concentration than in most other tissue. It causes severe lung injury and fibrosis. The mechanism of toxicity involves the initial reaction of paraquat with an electron donor such as NADPH; paraquat accepts the electron to form a stable radical cation (Figure 1); if this occurs under aerobic conditions, this electron is transferred too oxygen giving rise to superoxide; this process gets repeated over and over in the lungs due to the ready supply of oxygen, resulting in the formation of a redox cycle. The formation of the redox cycle is believed to be responsible for the toxicity by causing the following effects: the formation of large amounts of superoxide may overwhelm the neutralizing effects of superoxide dismutase, allowing the superoxide to accumulate, causing a variety of toxic effects such as the peroxidation of lipids leading to the formation of l ipid radicals that may cause membrane damage (Figure 2); and, the depletion of NADPH due to the formation of active oxygen species may compromise the alveolar cells, reducing their ability to carry out their functions. Figure 1: paraquat reduction-oxidation. Figure 2: the proposed mechanism of paraquat toxicity. Figure 1: adapted from http://www.inchem.org/documents/jmpr/jmpmono/v086pr05.gif Figure 2: adapted from http://totalpict.com/imagesb/1818/1818064104502cc34b8ffb7.gif References Timbrell, J.A. (2009). Principles of Biochemical Toxicology, 4th Edition. CRC Press. Pages 204- 205; and, 337-339. Medical News Today (2014, September 15). What is pulmonary edema? What causes pulmonary edema?  Retrieved from: http://www.medicalnewstoday.com/articles/167533.php The Center for Disease Control and Prevention (2014). Medical Management Guidelines for Ammonia. Retrieved from: http://www.atsdr.cdc.gov/MMG/MMG.asp?id=7tid=2 Maha Farid Discuss the patterns of neurotoxicity and provide one example of a toxin producing each pattern. Examples from the assigned textbooks are recommended. (6 points) The nervous system is a highly complex network of specialized cells and damage to this system may have permanent and serious effects because there is very low capacity to regenerate and little reserve functional capacity. The following are the patterns of neurotoxicity: Neuronopathy: this is the result of the destruction of the peripheral nervous system, or simply put, death of the entire neuron. The drug contaminant 1-mehtyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes specific damage to the substantia nigra area of the brain (Timbrell, 2009). It is highly lipophilic and readily enters the brain where it is readily metabolized to a toxic metabolite that is taken up by dopamine neurons. Methyl mercury also causes Neuronopathy. Axonopathy: this is the degeneration of the axon. Carbon disulfide exposure is a good example of a neurotoxin. Exposure to this solvent usually occurs in industry and causes neuronal damage in the central and peripheral nervous systems. The mechanism is believed to involve the chelation of metal ions essential for enzyme activity by the oxothiazolidine and dithiocarbamate metabolites of carbon disulfide, which result from reaction with glycine and glutathione (GSH) (Timbrell, 2009). Myelinopathy: this is a general term used to describe damage to or disorder of the myelin of peripheral nerve fibers, the myelin sheath or the white matter of the brain, in contrast to that affecting the axons (Axonopathy). A number of substances cause Myelinopathy in both the Schwann cells and the Oligodendrocytes. Lead is a good example of a neurotoxin that causes Myelinopathy, especially in children. Transmission toxicity: this is the disruption of neurotransmission. Organophosphorus pesticides such as malathion, which is used in the treatment of head lice in humans, and parathion, are good examples of neurotoxins that cause transmission toxicity. Exposure is usually accidental, suicidal or associated with homicide; and occurs via the gastrointestinal tract, the skin and the lungs. They are acetylcholinesterase inhibitors and acute toxicity manifests via the overstimulation of the muscarinic and nicotinic acetylcholine receptors. Nicotinic signs and symptoms result from the accumulation of acetylcholine at motor nerve endings in skeletal muscles and automated ganglia. This results in fatigue, involuntary twitching and even muscle weakness which may affect muscles of respiration. Death may occur from respiratory distress partly due to neuromuscular paralysis, central depression and even bronchoconstriction (Timbrell, 2009). Discuss the vulnerability of the nervous system to toxicity. (4 points) There are multiple characteristics of the nervous system that make it vulnerable to toxicity; in fact the nervous system is highly susceptible to changes in its environment. The characteristics of the nervous system that make it vulnerable to toxicity include the following: Neurons can have very long axons, making them more vulnerable to toxicity. The nervous system is also highly dependent on glucose, which is the sole source of energy to the central nervous system. This high dependence on glucose is demonstrated through fatal irreparable damage to the nervous system, even in brief obstruction of blood flow to the central nervous system. Energy shortage to the nervous system can lead to glutamate leakage which can cause severe brain injury. The long axons and large cell volume in the nervous system require high metabolic activity due to the electrical transmission of action potential and chemical transmission in the nervous system. Proper axonal transport is very essential for normal brain function. There are multiple fast and slow, anterograde and retrograde transport systems that exist in the nervous system, which complicate the process and add to the sensitivity of this area. Reference Timbrell, J.A. (2009). Principles of Biochemical Toxicology, 4th Edition. CRC Press. Pages 206; and, 339-346.