Bithionol is an antibacterial,

anthelmintic Anthelmintics or antihelminthics are a group of antiparasitic drugs that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them and without causing significant damage to the host. They may ...

, and

algaecide Algaecide or algicide is a biocide used for killing and preventing the growth of algae, often defined in a loose sense that, beyond the biological definition, also includes cyanobacteria ("blue-green algae"). An algaecide may be used for controlle ...

. It is used to treat '' Anoplocephala perfoliata'' (tapeworms) in horses and ''

Fasciola hepatica ''Fasciola hepatica'', also known as the common liver fluke or sheep liver fluke, is a parasitic trematode (fluke or flatworm, a type of helminth) of the class Trematoda, phylum Platyhelminthes. It infects the livers of various mammals, includi ...

'' (liver flukes). __TOC__

Mechanism of action

Bithionol has been shown to be a potent inhibitor of soluble adenylyl cyclase, an intracellular enzyme important in the catalysis of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Soluble adenylyl cyclase is uniquely activated by

bicarbonate In inorganic chemistry, bicarbonate (IUPAC-recommended nomenclature: hydrogencarbonate) is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion with the chemical formula . Bicarbonate serves a crucial biochem ...

. The

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

formed by this enzyme is associated with capacitation of sperm, eye pressure regulation, acid-base regulation, and

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

communication. It is related to the

organochlorine An organochloride, organochlorine compound, chlorocarbon, or chlorinated hydrocarbon is an organic compound containing at least one covalently bonded atom of chlorine. The chloroalkane class (alkanes with one or more hydrogens substituted by chlo ...

hexachlorophene Hexachlorophene, also known as Nabac, is an organochlorine compound that was once widely used as a disinfectant. The compound occurs as a white odorless solid, although commercial samples can be off-white and possess a slightly phenolic odor. It ...

, which has been shown to be an isomer-specific inhibitor of soluble adenylyl cyclase. Bithionol has two aromatic rings with a sulfur atom bonded between them and multiple chlorine ions and hydroxyl groups attached to the phenyl groups. These functional groups are capable of hydrophobic, ionic, and polar interactions. These intermolecular interactions are responsible for the binding of bithionol to the bicarbonate binding site of soluble adenylyl cyclase efficiently enough to cause competitive inhibition with the usual bicarbonate substrate. The side chain of arginine 176 within the bicarbonate binding site interacts significantly with the aromatic ring of the bithionol molecule. This allosteric, conformational change interferes with the ability of the active site of soluble adenylyl cyclase to adequately bind ATP to convert it into cAMP. Arginine 176 usually interacts with the ATP and other catalytic ions at the active site, so when it turns from its normal position to interact with the bithionol inhibitor, it no longer functions in keeping the ATP bound to the active site. In another form of inhibition, bithionol is a much larger molecule than simple sodium bicarbonate, so it is large enough to reach through a small channel in the soluble adenylyl cyclase and interfere with binding of ATP, preventing its conversion to cAMP. This inhibition of the soluble adenylyl cyclase by bithionol at the bicarbonate binding site is demonstrated through a mixed-inhibition graph, where higher concentrations of bithionol have a lower Vmax and a larger Km. This translates to a decreased rate of reaction and a decreased affinity between substrates when bithionol is in higher concentrations. However, concentrations of bithionol that are required inhibit soluble adenylyl cyclase at clinically relevant levels are also cytotoxic

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

. Thus, it cannot be used as the therapeutic drug needed to inhibit soluble adenylyl cyclase and therefore decrease the accumulation of cAMP within the cell. However, it sheds light on the search for a compound that will eventually be able to target the bicarbonate binding site of soluble adenylyl cyclase. Bithionol is the first known soluble adenylyl cyclase inhibitor to act through the bicarbonate binding site via a mostly allosteric mechanism.

Safety and regulation

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...

(oral, mouse) is 2100 mg/kg. Bithionol was formerly used in soaps and cosmetics until the U.S. FDA banned it for its photosensitizing effects. The compound has been known to cause photocontact sensitization.

References

{{Xenobiotic-sensing receptor modulators Antiparasitic agents Chlorobenzenes Phenols Thioethers