Liver toxicity and nervous system PDF

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Describe, with examples, the mechanisms by which toxic damage to either the liver or the nervous system may occur.  

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The liver is of great importance in drug metabolism and hepatocytes are exposed to high concentrations of nascent metabolites. Drugs and their polar metabolites are concentrated in renal tubular fluid as water is reabsorbed, so renal tubules are exposed to higher concentrations than are other tissues. Several hepatotoxic drugs (e.g. paracetamol) are also nephrotoxic. Consequently, hepatic or renal damage are common reasons for abandoning development of drugs during toxicity testing and chemical pathology tests of hepatic damage (usually levels of transaminase enzymes measured in blood plasma or serum) and renal function (usually creatinine concentration) are routine. The liver lobes are made up of microscopic units called lobules which are roughly hexagonal in shape. These lobules comprise of rows of liver cells (hepatocytes) which radiate out from a central point. The hepatic cells are in close contact with blood-filled sinusoids and also lie adjacent to canaliculi into which bile is secreted.

Various types that causes liver toxicity : steatosis ( fatty liver), cytotoxic damage a) direct , b) immune mediated, cholestasis, cirrhosis and carcinogenesis.

Steatosis ( Fatty Liver)       

Steatosis (fatty liver) is an accumulation of triglycerides in the liver. One of the toxic effects of ethanol is seatosis. The increased acetate and NADH produced ethanol metabolism can promote increased fatty acid synthesis. Alcohol can also stimulate the expression of lipogenic enzymes and metabolism of alcohol can result ROS production (reactive oxygen species). Carbon tetrachloride (CCl4) treatment can cause steatosis in rats that models both alcoholic and non-alcoholic fatty liver disease in humans. It is damage of the endoplasmic reticulum. Oxidation is not possible. Causes inhibition of protein synthesis and lipoprotein assembly.

Cytotoxic Damage 

Cytotoxic damage is caused by Methylenedianiline (MDA) which is epoxide hardener. It causes for humans liver toxicity while in animals they are carcinogenic.

Halothane 

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Halothane and other halogenated inhalational anesthetic agents, such as enflurane, isoflurane, sevoflurane, and desflurane, are known to cause severe liver dysfunction. It is nonflammable, potent and well tolerated. It has a somewhat slow onset of action and, therefore, like other halogenated inhalational anesthetics, it is used to maintain anesthesia after induction with other agents

Extasy    

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Ecstasy is an amphetamine derivative that causes subclinical liver damage in regular users. Delayed causes severe liver injury. This causes feelings of euphoria, emotional intimacy, increased sensuality, and loss of inhibition, as well as distorted sensory perceptions. Although often used in combination with other drugs, it is usually not taken with alcohol since alcohol is believed to reduce its effects. Ecstasy is widely used in the mistaken belief that it is a harmless drug with minimum chance of toxicity. Although it may not be addictive to all users, serious physical complications are possible, even leading to death. The main effect of ecstasy is on the neurons in the brain that use the neurotransmitter serotonin for transmitting information to other neurons. The serotonin pathway is important for mood regulation, aggression, sexual activity, sensitivity to pain, and sleep. MDMA can cause massive release of serotonin (5hydroxytryptamine or 5-HT) as well as inhibit its uptake.

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Ecstasy toxicity may occur due to other cheaper substances being mixed with the drug, such as amphetamine, methamphetamine, caffeine, or ephedrine. Also, drugs sold as ecstasy may not contain any MDMA at all but may instead contain a combination of other unspecified drugs or substances which can produce toxic reactions.

Cholestasis 

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Cholestasis can be simply defined as the loss of bile flow. This may be the result of obstruction ( e.g. gallstones) or changes in bile formation or transport due to effects on the hepatocytes. Chlorpromazine is a phenothiazine that was once the most commonly prescribed antipsychotic agent, but that is now rarely used. Chlorpromazine can cause mild and transient serum enzyme elevations and is also a well known cause of clinically apparent acute and chronic cholestatic liver injury. Chlorpromazine is also a well known cause of acute cholestatic liver injury It interferes with the sinusoidal bile acid uptake and canalicular acid secretion.

Cirrhosis 

Cirrhosis is a condition that results from permanent damage or scarring of the liver. This leads to a blockage of blood flow through the liver and prevents normal metabolic and regulatory processes.

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As liver function decreases, fewer proteins such as albumin are produced resulting in fluid accumulation in the legs (edema) or abdomen (ascites). Individuals with cirrhosis may bleed and bruise easily due to a decrease in proteins required for blood clotting. Some people may even experience intense itching due to products that are deposited in the skin. It is irreversible.

Carcinogenesis

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The mycotoxin aflatoxin B1 (AFB1) is one of the most potent rodent and human liver carcinogens Upon cytochrome P450-specific metabolism, it induces mutations as well as mitotic recombination events in in vitro systems. It is potent liver carcinogen that causes chronic exposure.

The Nervous System 

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In vertebrate species it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS contains the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or axons, that connect the CNS to every other part of the body. The nervous system is well protected mechanically ( skull, backbone), blood brain barrier( CNS) and blood nerve barrier (PNS) and little internal metabolism of potential toxins. Vulnerable of poor regenerative ability and sensitive to deprivation of oxygen and nutrients.

Most important cells are nerve cells called neurons. Transmission to the adjacent cell at the synapse. Neurotransmitters: noradrenaline, dopamine, serotonin, acetylcholine

Neurotoxic effects   

Transmission toxicity: interference with the neurotransmission Neuropathy: lesion to the nerve cell body Axonopathy: toxic effect on the axon

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The membrane potential is maintained by active transport of ions against the gradient. Signal transduction  influx of Na+ and efflux of K+

Tetrodotoxin 

Poisoning with the neurotoxin tetrodotoxin (TTX) occurs after ingestion of various species of puffer fish or the blue ringed octopus.

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Tetrodotoxin blocks the sodium channels in the signal transduction. The toxin affects the central nervous system to prevent the dissemination of nerve impulses. The toxic dose is not clear because puffer fish have different concentrations of tetrodotoxin. A dose of 1-2 mg of purified toxin can be lethal. Tetrodotoxin which can very well paralyze the diaphragm and result in death because of respiratory breakdown.

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Organophosphorus esters

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Organophosphorus esters are insecticides that are most frequently involved in fatal human poisoning. DDT, lindane, dieldrin High lipid solubility, low degradation rate Persistence in environment, bioconcentration and biomagnification in food chains Produce disturbances in ion transport across axon leading to increased excitability and seizures Most of the delayed neurotoxic organophosphorus esters are AChE inhibitors, but not all anticholnesterase compounds produce delayed neurotixicity.

 AChE inhibitors or anti-cholinesterases inhibit the cholinesterase enzyme from breaking down ACh, increasing both the level and duration of the neurotransmitter action. According to the mode of action, AChE inhibitors can be divided into two groups: irreversible and reversible . Reversible inhibitors, competitive or noncompetitive, mostly have therapeutic applications, while toxic effects are associated with irreversible AChE activity modulators.

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The underlying mechanism involves the inhibition of acetylcholinesterase (AChE), leading to the build-up of acetylcholine (ACh) in the body. The binding to the enzyme causes protracted blockage of the enzyme, preventing the breakdown of acetylcholine. This is causes an over stimulation of the nervous system including the receptors in the neuromuscular junction. Poisoning with organophosphates can cause weakness in musculature, occasional spasicity and respiratory insufficiency which can lead to coma and death. Several analogues have been developed which vary in their toxicity and their safety profile. This include the thion analogues e.g. malathion Malathion is proinsecticide e.g. the parent compound is not active but requires metabolite to its active for malaxon. Mammals malathion is mainly hydrolysed by esterases to carboxy acids. Thus malathion has a preferential effects on the target species and a better safety profile for the non-target species. Pralidoxime react with organophosphates which are bound to choline esterase and the pralidoxime-organophosphate complex is released from the enzyme. This results in the reactivation of the enzyme activity and reduction of the symptoms.

Amphatamines     

Amphatamines displace the neurotransmitters from the storage vesicles. Then neurotransmitters are released into synaptic cleft. The postsynaptic response, unprovoked neurostimulation. The central nervous system respond within some side effects such as euphoria, excitement, wakefulness, loss of appetite. The peripheral nervous system respond within raised blood pressure and tachycardia wich is abnormal rapid heartbeat.

Botulinum Toxin 

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Botulinum toxin is produced by Clostridium botulinum, a gram-positive anaerobic bacterium. The clinical syndrome of botulism can occur following ingestion of contaminated food, from colonization of the infant gastrointestinal tract, or from a wound infection. Botulinum toxin acts as a neurotoxin. It binds to the nerve ending at the point where the nerve joins a muscle, blocking the release by the nerve of the chemical acetylcholine (the principal neurotransmitter at the neuromuscular junction), preventing the muscle from contracting. The result is weakness and paralysis of the muscle. The muscle atrophies. The blockage of acetylcholine release is irreversible. Function can be recovered by the sprouting of nerve terminals and the formation of new synaptic contacts, which usually takes 2 to 3 months. Botox has since found other medical and cosmetic uses and was FDA approved in 2002 for treatment of moderate-to-severe frown lines between the eyebrows known as glabellar lines. Botox is often used in other areas of the face for cosmetic purposes.

Neuronopathy  

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Neurons are highly dependent on glucose and oxygen. It is also very sensitive to hypoglycaemia and hypoxia or anoxia. 6-hydroxydopamine is a neurotoxic synthetic organic compound used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain. Auto –oxidation of catecholamines especially dopamine results in quinone formation. It is formation of reactive oxygen species such as H2O2, superoxide, anion etc. 6- hydroxydopamine do not cross blood- brain barrier. It only affects PNS. It slows down the heart rate. Hypermotility of gastrointestinal system. Neuronopathy has a similar mechanism associated with neurotoxicity of MDMA. MDMA is associated with neuronal death at recreational levels.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug to the neurotoxin MPP+ which causes permanent symptoms of Parkinson’s disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study disease models in various animal studies. It also a contaminant of a heroin substitute. The Parkinson-inducing effects of MPTP were first discovered following accidental ingestion as a result of contaminated MPPP.

Axonopathy     

Type – n –Hexane which is organic solvent. It is progressive sensorimotor distal axonopathy. It is reactive metabolite 2,5- hexadediene interacts with the cytoskeleton. It causes neurofilament aggregation anf axonal swelling. It is successive weakness in proximal muscle groups....