jeudi 8 décembre 2011

Tunneling through life.

Imagine being completely drained by the formation of holes all over your body. That is what a cell should feel when encountering the drug Amphotericin B. It is an antifungal agent typically used against athletes foot and systematically against life-threatening fungal diseases. Athletes foot is the kind of fungal infection one can get when walking barefoot in moisty places as saunas, bathhouses, swimming pool, etc. It is also called ringworm of the foot because of the holes appearing.

The compound is a natural product derived from a microorganism: Streptomyces nodosus. These are bacteria that often produce spores and have an "earthy" odor. Secondary metabolism in Streptomyces bacteria is responsible for a large range of antifungals, antibacterials, antiparasites, immunosuppressant and even herbicide or piscicide drugs. All involved in a survival instinct mechanism.

This fascinating molecule contains an hydrophobic part made up of double bonds in a long carbon chain. The other part formed by the different hydroxyl groups is hydrophilic.
The fungal membrane cell is built of a lipidic bilayer. Several amphotericin molecules cluster together such that the alkene chains are to the exterior and interact favourably with the hydrophobic center of the cell membrane.
The tunnel resulting from this cluster is lined with the hydroxyl groups and so it is hydrophilic, allowing the polar (aqueous) contents of the cell to drain away.

This drug drills literally in the cell and because of forces as coalescence, electrostatic interactions and gradient concentration, every constituent is sucked out of it.

vendredi 18 novembre 2011

Warfare: Arsenite poisoning.

Lewisite (2-chlorovinyldichlorarsine) is an arsenic organic compound (halide arsine) that looks like a viscous liquid and has been used as a toxic agent during the first world war and the war between China and Japan (1937-1945). 

Winford Lee Lewis, chemist in the US army found the recipe needed to synthesize this compound in the thesis of a young student (obviously) from Washington DC. Its first nam was "The dew death" because of its activity in cold condition, its unflammability, its almost colorless liquid aspect and because it is almost inodor (scented geranium).

It can easily penetrate ordinary clothing and even rubber; upon skin contact it causes immediate pain and itching with a rash and swelling. Large, fluid-filled blisters develop after approximately 12 hours. These are severe chemical burns. Sufficient absorption can cause systemic poisoning leading to liver necrosis or death.
Inhalation causes a burning pain, sneezing, coughing, vomiting, and possibly pulmonary edema. Ingestion results in severe pain, nausea, vomiting, and tissue damage. The results of eye exposure can range from stinging and strong irritation to blistering and scarring of the cornea. Generalised symptoms also include restlessness, weakness, subnormal temperature and low blood pressure.

Lewisite as all halide arsine compounds reacts with water leading to formation of free Arsenic and ionic arsenite. The effects of Lewisite on the body come from the vesicant (allergic effect leading to the formation of blisters) properties of the halide form and the poisonous arsenic and arsenites molecules. 

Some enzymes need cofactors (other molecules or enzymes) to perform their task. Arsenite and Arsenic reacts with thiol groups (sulphur) of an enzyme cofactor called dihydrolipoate (lipoic acid). The enzymes concerned by this cofactor are responsible for cellular respiration and glycolysis metabolic pathway and are then inhibited by Lewisite. The cell dies because of lack of energy or because of a too high concentration of glucose in the blood (peripheral organes are affected by this glucose toxicity).

The antidote is the 2,3-dimercaptopropanol. This molecule has a structure really close to dihydrolipoate but arsenic derivatives binds tighter to the former. Then, the complex formed can be washed away by the kidneys.

jeudi 17 novembre 2011

Mad as a hatter.

The toxicity of several poisons, toxins and heavy metals result from their action on proteins (most of the time on enzymes). Heavy metals such as lead, cadmium and mercury have teratogenic effects leading to babies being born with malformed limbs.

Mercury nitrate was used by hat makers to soften and shape animal furs, and inevitably some of the chemical was absorbed through the skin. So many in the trade were poisoned in this way that their peculiar manner of behaviour led to the phrase "Mad as a hatter". Mercury poisoning can then, also, affect enzymes in the central nervous system leading to neurological damage.

Acute inhalation of high concentrations causes a wide variety of cognitive, personality, sensory, and motor disturbances. The most prominent symptoms include tremors, emotional lability (characterized by irritability, excessive shyness, confidence loss, and nervousness), insomnia, memory loss, neuromuscular changes, polyneuropathy, and performance deficits in tests of cognitive function.

My interest here, is how emotional lability occurs:
Mercury, because of its effect teratogenic, would act on certain proteins or directly on DNA. It causes disturbances or disruptions of neural networks by destroying neurones responsible for regulating the output of emotions which leads to the disinhibition, or release, of laughing/crying centers, or more generally failure of voluntary control of emotion.

The neurones affected would be then either in the prefrontal cortex (emotional core of the brain), either in the pathway descending from the brain to the brainstem. That is, either the neurones responsible for emotion die or do not work or the ones responsible for the visible response.

How exactly does this happen ?
Mercury modifies DNA of the cell and trigger the synthesis of mutant proteins. Those are either deficient, either unable to play their role. They can be also capable of carrying out new tasks playing against the cell or for instance preventing other proteins from functioning, leading inevitably to the death of the cell.
Mercury could also block other proteins like receptors or empeding them. It impact schemical signaling in the central nervous system.The following response from the next neurone is then modified, inhibited or enhanced (shyness or exhibitionnism, crying or laughing).