Bithionol: Difference between revisions

{{short description|Chemical compound}}

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| image2 = Bithionol molecule ball.png

| alt2 = Ball-and-stick model of the bithionol molecule

| width2 = 240

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| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 97-18-7

| IUPHAR_ligand = 2338

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| KEGG = C07967

| smiles = Clc2cc(Cl)cc(Sc1cc(Cl)cc(Cl)c1O)c2O

| C=12 | H=6 | Cl=4 | O=2 | S=1

| melting_point = 188

'''Bithionol''' is an antibacterial, [[anthelmintic]], and [[algaecide]]. It is used to treat ''[[Anoplocephala perfoliata]]'' (tapeworms) in horses<ref>{{cite journal | vauthors = Sanada Y, Senba H, Mochizuki R, Arakaki H, Gotoh T, Fukumoto S, Nagahata H | title = Evaluation of marked rise in fecal egg output after bithionol administration to horse and its application as a diagnostic marker for equine Anoplocephala perfoliata infection | journal = The Journal of Veterinary Medical Science | volume = 71 | issue = 5 | pages = 617–620 | date = May 2009 | pmid = 19498288 | doi = 10.1292/jvms.71.617 | format = pdf | doi-access = free }}</ref> and ''[[Fasciola hepatica]]'' (liver flukes).

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==Mechanism of action==

Bithionol has been shown to be a potent inhibitor of [[soluble adenylyl cyclase]],<ref>{{cite journal | vauthors = Kleinboelting S, Ramos-Espiritu L, Buck H, Colis L, van den Heuvel J, Glickman JF, Levin LR, Buck J, Steegborn C | display-authors = 6 | title = Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site | journal = The Journal of Biological Chemistry | volume = 291 | issue = 18 | pages = 9776–9784 | date = April 2016 | pmid = 26961873 | pmc = 4850313 | doi = 10.1074/jbc.M115.708255 | doi-access = free }}</ref> an intracellular enzyme important in the catalysis of [[Adenosine triphosphate|adenosine triphosphate (ATP)]] to [[cyclic adenosine monophosphate|cyclic adenosine monophosphate (cAMP)]]. [[Soluble adenylyl cyclase]] is uniquely activated by [[bicarbonate]]. The [[cyclic adenosine monophosphate|cAMP]] formed by this enzyme is associated with capacitation of sperm, eye pressure regulation, acid-base regulation, and [[astrocyte]]/[[neuron]] communication.{{cn|date=December 2022}}

It is related to the [[organochlorine]] [[hexachlorophene]], 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.{{cn|date=December 2022}}

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.{{cn|date=December 2022}}

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.{{cn|date=February 2023}}

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 [[Michaelis–Menten kinetics|Vmax]] and a larger [[Michaelis–Menten kinetics|Km]]. This translates to a decreased rate of reaction and a decreased affinity between substrates when bithionol is in higher concentrations.{{cn|date=December 2022}}

However, concentrations of bithionol that are required inhibit soluble adenylyl cyclase at clinically relevant levels are also [[cytotoxic]] [[in vivo]]. 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.{{cn|date=February 2023}}

==Safety and regulation==

[[LD50]] (oral, mouse) is 2100 mg/kg.<ref name="a">{{Ullmann| vauthors = Fiege H, Voges HW, Hamamoto T, Umemura S, Iwata T, Miki H, Fujita Y, Buysch HJ, Garbe D, Paulus W | display-authors = 6 | contribution=Phenol Derivatives | year=2007 | doi=10.1002/14356007.a19_313}}</ref>

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.<ref>{{cite book| vauthors = Morton IK, HallJM |date=1999 |title=Concise Dictionary of Pharmacological Agents |doi=10.1007/978-94-011-4439-1 |isbn=978-94-010-5907-7 |s2cid=25401949}}</ref>

== References ==

{{Glutamate metabolism and transport modulators}}

{{Xenobiotic-sensing receptor modulators}}

[[Category:Chlorobenzene derivatives]]

[[Category:Phenols]]