Toxin

A toxin (Gk. τοξικόν toxikon "(poison) for use on arrows,") is a poisonous substance produced by living cells or organisms. Toxins are nearly always proteins that are capable of causing disease on contact or absorption with body tissues by interacting with biological macromolecules such as enzymes or cellular receptors. Toxins vary greatly in their severity, ranging from usually minor and acute (as in a bee sting) to almost immediately deadly (as in botulinum toxin).

Biotoxins vary greatly in purpose and mechanism, and can be highly complex (the venom of the cone snail contains dozens of small proteins, each targeting a specific nerve channel or receptor), or relatively small protein.

In the context of biology, poisons, or atters are substances that can cause damage, illness, or death to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism. Paracelsus, the father of toxicology, once wrote: "Everything is poison, there is poison in everything. Only the dose makes a thing not a poison".

In medicine (particularly veterinary) and in zoology, a poison is often distinguished from a toxin and a venom. Toxins are poisons produced via some biological function in nature, and venoms are usually defined as biologic toxins that are injected by a bite or sting to cause their effect, while other poisons are generally defined as substances which are absorbed through epithelial linings such as the skin or gut.

Some poisons are also toxins, usually referring to naturally produced substances, such as the bacterial proteins that cause tetanus and botulism. A distinction between the two terms is not always observed, even among scientists.

Animal toxins that are delivered subcutaneously (e.g. by sting or bite) are also called venom. In normal usage, a poisonous organism is one that is harmful to consume, but a venomous organism uses poison to defend itself while still alive. A single organism can be both venomous and poisonous.

The derivative forms "toxic" and "poisonous" are synonymous.

Within chemistry and physics, a poison is a substance that obstructs or inhibits a reaction, for example by binding to a catalyst.

The phrase "poison" is often used colloquially to describe any harmful substance, particularly corrosive substances, carcinogens, mutagens, teratogens and harmful pollutants, and to exaggerate the dangers of chemicals. The legal definition of "poison" is stricter.

Organisms producing toxic substances

Biotoxins in nature have two primary functions:

• Predation (spider, snake, scorpion, jellyfish, wasp)
• Defense (bee, poison dart frog, deadly nightshade, honeybee, wasp)

Bacteria

(describe endotoxins and exotoxins here)

=Dinoflagellates

Some of the more well known types of biotoxins include:

• Hemotoxins target and destroy red blood cells, and are transmitted through the bloodstream. Organisms that possess hemotoxins include:
  • Pit Vipers, such as rattlesnakes.
• Necrotoxins cause necrosis (i.e., death) in the cells they encounter and destroy all types of tissue. Necrotoxins spread through the bloodstream, but infect all tissues. In humans, skin and muscle tissues are most sensitive to necrotoxins. Organisms that possess necrotoxins include:
  • The brown recluse or "fiddle back" spider.
  • Necrotizing fasciitis (the "flesh eating" bacteria)
• Neurotoxins primarily affect the nervous systems of animals. Organisms that possess neurotoxins include:
  • The Black Widow and other widow spiders.
  • Most scorpions.
  • The box jellyfish.
  • Elapid snakes.
  • The Cone Snail.

Plant Toxins

Ricin is found in the castor bean plant.

Non-technical usage

When used non-technically, the term "toxin" is often applied to any toxic substances. Toxic substances not of biological origin are more properly termed poisons. Many non-technical and lifestyle journalists also follow this usage to refer to toxic substances in general, though some specialist journalists at publishers such as BBC and The Guardian maintain the distinction that toxins are only those produced by living organisms.

In the context of alternative medicine the term is often used nonspecifically to refer to any substance claimed to cause ill health, ranging anywhere from trace amounts of pesticides to common food items like refined sugar or additives like artificial sweeteners and MSG.[1] These claims are often made without a clear scientific basis or conclusive evidence[2], and as such have little to no acceptance in mainstream medicine.

The term is also used commonly in pop psychology to describe things that have an adverse effect on psychological health, such as a "toxic relationship," "toxic work environment" or "toxic shame."

Exotoxin

An exotoxin is a soluble protein excreted by a microorganism, including bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. Both gram negative and gram positive bacteria produce exotoxins. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell.

Most exotoxins can be destroyed by heating. They may exert their effect locally or produce systemic effects. (Nester, 2007). Well known exotoxins include the botulinum toxin produced by Clostridium botulinum, the Corynebacterium diphtheriae exotoxin which is produced during life threatening symptoms of diphtheria.

Exotoxins are susceptible to antibodies produced by the immune system, but many exotoxins are so toxic that they may be fatal to the host before the immune system has a chance to mount defenses against it (Nester, 2007).

Types

Exotoxins can be categorized by their mode of action on target cells.

Type I toxins: toxins that act from the cell surface

Type I toxins bind to a receptor on the cell surface and stimulate intracellular signaling pathways. Two examples are described below.

• Superantigens

Superantigens are produced by several bacteria. The best characterized superantigens are those produced by the strains of Staphylococcus aureus and Streptococcus pyogenes that cause toxic shock syndrome. Superantigens bridge the MHC class II protein on antigen presenting cells with the T cell receptor on the surface of T cells with a particular Vβ chain. Consequently, up to 20% of all T cells are activated, leading to massive secretion of proinflammatory cytokines, which produce the symptoms of toxic shock.

• Heat-stable enterotoxins

Some strains of E. coli produce heat-stable enterotoxins (ST), which are small peptides that are able to withstand heat treatment at 100^oC. Different STs recognize distinct receptors on the cell surface and thereby affect different intracellular signaling pathways. For example, STa enterotoxins bind and activate membrane-bound guanylate cyclase, which leads to the intracellular accumulation of cyclic GMP and downstream effects on several signaling pathways. These events lead to the loss of electrolytes and water from intestinal cells.

Type II toxins: membrane damaging toxins

These toxins are designed primarily to disrupt the cellular membrane. Many type II exotoxins have hemolysin activity, which causes red blood cells to lyse in vitro. Membrane-damaging toxins can be divided into two categories.

• Channel-forming toxins

Channel-forming toxins form pores in the target cell membrane. An example is the α toxin of Staphylococcus aureus.

• Toxins that enzymatically damage the membrane

One example is the α toxin of Clostridium perfringens, which causes gas gangrene. α toxin has phospholipase activity.

Type III toxins: intracellular toxins

Intracellular toxins must be able to gain access to the cytoplasm of the target cell to exert their effects.

• AB toxins

One group of intracellular toxins is the AB toxins. The 'B'-subunit attaches to target regions on cell membranes, the 'A'-subunit enters through the membrane and possesses enzymatic function that affects internal cellular bio-mechanisms. The structure of these toxins allows for the development specific vaccines and treatments. Certain compounds can be attached to the B unit, which is not generally harmful, which the body learns to recognize, and which elicits an immune response. This allows the body to detect the harmful toxin if it is encountered later, and to eliminate it before it can cause harm to the host. Toxins of this type include cholera toxin, pertussis toxin, Shiga toxin and heat-labile enterotoxin from E. coli.

• Injected toxins

Some bacteria deliver toxins directly from their cytoplasm to the cytoplasm of the target cell through a needle-like structure. The effector proteins injected by the type III secretion apparatus of Yersinia into target cells are one example.

Toxins that damage the extracellular matrix

These toxins allow the further spread of bacteria and consequently deeper tissue infections. Examples are hyaluronidase and collagenase.

Endotoxin

Endotoxins are potentially toxic, natural compounds found inside pathogens such as bacteria. Classically, an "endotoxin" is a toxin, which unlike an "exotoxin", is not secreted in soluble form by live bacteria, but is a structural component in the bacteria which is released mainly when bacteria are lysed.

Lipopolysaccharide and other endotoxins

The prototypical examples of endotoxin are lipopolysaccharide (LPS) or lipo-oligo-saccharide (LOS) found in the outer membrane of various Gram-negative bacteria. The term LPS is often used exchangeably with endotoxin, owing to its historical discovery. In the 1800s it became understood that bacteria could secrete toxins into their environment, which became broadly known as "exotoxin". The term endotoxin came from the discovery that portions of Gram-negative bacteria itself can cause toxicity, hence the name endotoxin. Studies of endotoxin over the next 50 years revealed that the effects of "endotoxin" was in fact due to lipopolysaccharide.

There are, however, endotoxins other than LPS:

• For example, delta endotoxin of Bacillus thuringiensis makes crystal-like inclusion bodies next to the endospore inside the bacteria. It is toxic to larvae of insects feeding on plants, but is harmless to humans (as we do not possess the enzymes and receptors necessary for its processing followed by toxicity).
• The only gram positive bacteria that produces endotoxin is Listeria monocytogenes.

LPS consist of a polysaccharide (sugar) chain and a lipid moiety, known as lipid A, which is responsible for the toxic effects. The polysaccharide chain is highly variable amongst different bacteria. Endotoxins are approximately 10 kDa in size but can form large aggregates up to 1000 kDa. Humans are able to produce antibodies to endotoxins after exposure but these are generally directed at the polysaccharide chain and do not protect against a wide variety of endotoxins. Injection of a small amount of endotoxin in human volunteers produced fever, a lowering of the blood pressure, and activation of inflammation and coagulation. Endotoxins are in large part responsible for the dramatic clinical manifestations of infections with pathogenic Gram-negative bacteria, such as Neisseria meningitidis, the pathogen that causes fulminant meningitis.

Mechanism

In humans, LPS binds to the lipid binding protein (LBP) in the serum which transfers it to CD14 on the cell membrane, which in turn transfers it to another non-anchored protein, MD2, which associates with Toll-like receptor-4 (TLR4).

CD14 and TLR4 are present in several immune system cells (including macrophages and dendritic cells), triggering the signaling cascade for macrophage/endothelial cells to secrete pro-inflammatory cytokines and Nitric oxide that lead to "endotoxic shock".

Other than TLR4, components of gram negative cell wall may also activate other pathways which may contribute to the overall endotoxic effect.

Endotoxin contamination

Endotoxins are frequent contaminants in plasmid DNA prepared from bacteria, and must be removed from the DNA to avoid unwanted inflammatory responses prior to in vivo applications such as gene therapy.

In pharmaceutical production, it is necessary to remove all traces of endotoxin from drug product containers as even small amounts of endotoxin will cause illness, but not disease, in humans. A depyrogenation oven is used for this purpose. Temperatures in excess of 300 degrees celsius are required to break down this substance. A defined endotoxin reduction rate is a correlation between time and temperature. Based on primary packaging material as syringes or vials a glass temperature of 250°C and a holding time of 30min is typical to achieve 3log reduction on endotoxin levels.

A very sensitive assay for detecting presence of endotoxin is the Limulus Amebocyte Lysate assay, utilizing blood from the Horseshoe crab. Very low levels of LPS can cause coagulation of the limulus lysate due to a powerful amplification through an enzymatic cascade.

See also

• Bioaerosol
• Exotoxin

References

ISBN links support NWE through referral fees

• Textbook of Bacteriology
• Sofer, G.; Hagel, L. (1997). Handbook of Process Chromatography: A guide to Optimization, Scale-up, and Validation. Academic Press, 158-161. ISBN 0-12-654266-X

References

• Lerner, K. L., and B. W. Lerner. 2004. Encylcopedia of espionage, intelligence, and security. Detroit: Thomson/Gale. ISBN 0787675466.

External links

• Society of Toxicology
• The Journal of Venomous Animals and Toxins including Tropical Diseases
• Cycad toxicity
• Corrections and clarifications, The Guardian, 30 May, 2005.

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