Salicylic acid

Mechanism of action

Salicylic acid modulates COX-1 enzymatic activity to decrease the formation of pro-inflammatory prostaglandins. Salicylate may competitively inhibit prostaglandin formation.

Salicylic acid, when applied to the skin surface, works by causing the cells of the epidermis to slough off more readily, preventing pores from clogging up, and allowing room for new cell growth. Salicylic acid inhibits the oxidation of uridine-5-diphosphoglucose (UDPG) competitively with NADH and noncompetitively with UDPG. It also competitively inhibits the transferring of glucuronyl group of uridine-5-phosphoglucuronic acid to the phenolic acceptor.

The wound-healing retardation action of salicylates is probably due mainly to its inhibitory action on mucopolysaccharide synthesis.

Safety

In excess, salicylates have toxic effects, which can be fatal. Toxicity is most often due to oral overdose.

Cosmetic applications of the drug pose no significant risk. Even in a worst-case use scenario in which one was using multiple salicylic acid-containing topical products, the aggregate plasma concentration of salicylic acid was well below what was permissible for acetylsalicylic acid (aspirin). Since oral aspirin (which produces much higher salicylic acid plasma concentrations than dermal salicylic acid applications) poses no significant adverse pregnancy outcomes in terms of frequency of stillbirth, birth defects or developmental delay, use of salicylic acid containing cosmetics is safe for pregnant women. Salicylic acid is present in most fruits and vegetables as for example in greatest quantities in berries and in beverages like tea.

In one documented case, a patient applied extreme levels of salicylate ointment topically (40% ointment, over 41% of the total skin surface), and subsequently received hemodialysis to reduce blood salicylate concentration.

Production and chemical reactions

Biosynthesis

Salicylic acid is biosynthesized from the amino acid phenylalanine. In Arabidopsis thaliana, it can be synthesized via a phenylalanine-independent pathway.

Chemical synthesis

Commercial vendors prepare sodium salicylate by treating sodium phenolate (the sodium salt of phenol) with carbon dioxide at high pressure (100 atm) and high temperature (115 °C) – a method known as the Kolbe-Schmitt reaction. Acidifying the product with sulfuric acid gives salicylic acid:

At the laboratory scale, it can also be prepared by the hydrolysis of aspirin (acetylsalicylic acid) or methyl salicylate (oil of wintergreen) with a strong acid or base; these reactions reverse those chemicals' commercial syntheses.

Reactions

Upon heating, salicylic acid converts to phenyl salicylate:

2 HOC₆H₄CO₂H → C₆H₅O₂C₆H₄OH + CO₂ + H₂O

Further heating gives xanthone.

Salicylic acid as its conjugate base is a chelating agent, with an affinity for iron(III).

Salicylic acid slowly degrades to phenol and carbon dioxide at 200–230 °C:

C₆H₄OH(CO₂H) → C₆H₅OH + CO₂

All isomers of chlorosalicylic acid and of dichlorosalicylic acid are known. 5-Chlorosalicylic acid is produced by direct chlorination of salicylic acid.

History

Willow has long been used for medicinal purposes. Dioscorides, whose writings were highly influential for more than 1,500 years, used "Itea" (which was possibly a species of willow) as a treatment for "painful intestinal obstructions", birth control, for "those who spit blood", to remove calluses and corns and, externally, as a "warm pack for gout". William Turner, in 1597, repeated this, saying that willow bark, "being burnt to ashes, and steeped in vinegar, takes away corns and other like risings in the feet and toes". Some of these cures may describe the action of salicylic acid, which can be derived from the salicin present in willow. It is, however, a modern myth that Hippocrates used willow as a painkiller.

Hippocrates, Galen, Pliny the Elder, and others knew that decoctions containing salicylate could ease pain and reduce fevers.

It was used in Europe and China to treat these conditions. This remedy is mentioned in texts from Ancient Egypt, Sumer, and Assyria.

The Cherokee and other Native Americans use an infusion of the bark for fever and other medicinal purposes. In 2014, archaeologists identified traces of salicylic acid on seventh-century pottery fragments found in east-central Colorado.

Edward Stone, a vicar from Chipping Norton, Oxfordshire, England, reported in 1763 that the bark of the willow was effective in reducing a fever.

An extract of willow bark, called salicin, after the Latin name for the white willow (Salix alba), was isolated and named by German chemist Johann Andreas Buchner in 1828. A larger amount of the substance was isolated in 1829 by Henri Leroux, a French pharmacist. Raffaele Piria, an Italian chemist, was able to convert the substance into a sugar and a second component, which on oxidation becomes salicylic acid.

Salicylic acid was also isolated from the herb meadowsweet (Filipendula ulmaria, formerly classified as Spiraea ulmaria) by German researchers in 1839. Their extract caused digestive problems such as gastric irritation, bleeding, diarrhea, and even death when consumed in high doses.

In 1874 the Scottish physician Thomas MacLagan experimented with salicin as a treatment for acute rheumatism, with considerable success, as he reported in The Lancet in 1876. Meanwhile, German scientists tried sodium salicylate with less success and more severe side effects.

In 1979, salicylates were found to be involved in induced defenses of the tobacco plant against tobacco mosaic virus. In 1987, salicylic acid was identified as the long-sought signal that causes thermogenic plants, such as the voodoo lily, Sauromatum guttatum, to produce heat.

Dietary sources

Salicylic acid occurs in plants as free salicylic acid and its carboxylated esters and phenolic glycosides. Several studies suggest that humans metabolize salicylic acid in measurable quantities from these plants. High-salicylate beverages and foods include beer, coffee, tea, numerous fruits and vegetables, sweet potato, nuts, and olive oil. Meat, poultry, fish, eggs, dairy products, sugar, breads and cereals have low salicylate content.

Some people with sensitivity to dietary salicylates may have symptoms of allergic reaction, such as bronchial asthma, rhinitis, gastrointestinal disorders, or diarrhea, so may need to adopt a low-salicylate diet.

Plant hormone

Salicylic acid is a phenolic phytohormone, and is found in plants with roles in plant growth and development, photosynthesis, transpiration, and ion uptake and transport. Salicylic acid is involved in endogenous signaling, mediating plant defense against pathogens. It plays a role in the resistance to pathogens (i.e. systemic acquired resistance) by inducing the production of pathogenesis-related proteins and other defensive metabolites. SA's defence signalling role is most clearly demonstrated by experiments which do away with it: Delaney et al. 1994, Gaffney et al. 1993, Lawton et al. 1995, and Vernooij et al. 1994, each use Nicotiana tabacum or Arabidopsis expressing nahG, for salicylate hydroxylase. Pathogen inoculation did not produce the customarily high SA levels, SAR was not produced, and no pathogenesis-related (PR) genes were expressed in systemic leaves. Indeed, the subjects were more susceptible to virulent – and even normally avirulent – pathogens.

Exogenously, salicylic acid can aid plant development via enhanced seed germination, bud flowering, and fruit ripening, though too high of a concentration of salicylic acid can negatively regulate these developmental processes.

The volatile methyl ester of salicylic acid, methyl salicylate, can also diffuse through the air, facilitating plant-plant communication. Methyl salicylate is taken up by the stomata of the nearby plant, where it can induce an immune response after being converted back to salicylic acid.

Signal transduction

A number of proteins have been identified that interact with SA in plants, especially salicylic acid binding proteins (SABPs) and the NPR genes (nonexpressor of pathogenesis-related genes), which are putative receptors.