IngredientesPepsin is the principal proteolytic enzyme of the vertebrate stomach and one of the most thoroughly studied proteins in the history of biochemistry. It is of particular interest as it was the first enzyme ever discovered; the name pepsin was given by Theodor Schwann (1810–1882) in 1836, and came from pepsis, the term for digestion in Hippocratic writings. From its early 19th-century isolation to its contemporary roles as a dietary supplement, industrial processing aid, and clinical biomarker, pepsin occupies a unique intersection of physiology, food science, and medicine.
Pepsin is an acidic protease whose inactive zymogen precursor, pepsinogen, is produced in the stomach mucosa. Its systematic enzyme classification number is EC 3.4.23.1, and its CAS registry number is 9001-75-6. Pepsin is one of the most important digestive enzymes in the human body, primarily responsible for breaking down proteins in the stomach; it is a member of the protease family and plays an essential role in the digestive process, ensuring that proteins consumed in food are adequately degraded into smaller peptides for absorption.
There are four reported pepsin proteins: pepsin A, pepsin B (parapepsin I), pepsin C (gastricsin), and pepsin D (an unphosphorylated version of pepsin A). Pepsin A is the predominant gastric protease; minor amounts of the other pepsins have been detected. Pepsins B and C share a higher degree of homology with each other.
Pepsin A, the major component, has a molecular weight of 35,000 daltons and an optimum pH of approximately 1.0 for substrates such as casein or hemoglobin if the substrate is native protein. Pepsin is a monomeric, two-domain, mainly beta protein with a high percentage of acidic residues. Porcine pepsin has 4 basic residues and 42 acidic residues and is O-phosphorylated at S68.
Pepsin has several functionally important residues. Of paramount importance are Asp-32 and Asp-215, the residues of the catalytic site. These two residues classify pepsin as an aspartic protease. Asp-32 and Asp-215 are each part of two conserved sequences of Asp-Thr-Gly. These sequences converge to form the catalytic site, bringing Asp-32 and Asp-215 together. The polar nature of aspartate allows these residues to hydrogen bond to water and the substrate in order to correctly position the reagents, and the acidity of aspartate functions to cleave the targeted peptide bond of the substrate through a mechanism of general acid-base catalysis.
Pepsinogens consist of two immunological groups: PGI, containing pepsinogens 1, 2, 3, 4, and 5, and PGII, containing pepsinogens 6 and 7. Pepsinogen is a symmetrical molecule with N- and C-terminal lobes with a molecular weight between 40–42 kDa and is stable up to pH values of 10.
Commercial pepsin is extracted from the glandular layer of hog stomachs. Pepsin powder is prepared from the gastric mucosa of pigs, cattle, or sheep. In the supplement and pharmaceutical industries, porcine gastric mucosa is by far the dominant raw material. Traditionally, commercial pepsin has been sourced from the stomach lining of pigs, which has presented food manufacturers with supply and demand challenges. More recently, precision fermentation technology has begun producing animal-free pepsin with equivalent enzymatic function, though this remains largely an industrial food-processing development rather than an established supplement source.
Pharmacopeial standards for pepsin are maintained by the United States Pharmacopeia (USP), the British Pharmacopoeia (BP), the European Pharmacopoeia (Ph. Eur.), and the Japanese Pharmacopeia (JP). The United States Pharmacopeia maintains a reference standard for pepsin with CAS number 9001-75-6, synonymous with Pepsin A from hog stomach sourced from porcine gastric mucosa.
As a dietary supplement or over-the-counter aid, pepsin is available in several physical forms:
The stomach's secretion had been a mystery for centuries. Even after the first indications of its function and role appeared, every formulated idea on the nature of the gastric liquid remained open to controversy. After the ancient Greek perceptions which identified acids as bitter-sour liquids, the physicians of the Iatrochemical School, under the influence of Paracelsus and the alchemists, were the first to point out the physiologic chemistry of secretion. Experiments on animals and humans during the 17th–18th centuries, which mainly included swallowing various substances and observing the process, enhanced knowledge, with Stevens and Spallanzani playing a leading part.
Any existing objections about the nature of gastric acid ceased in 1823 when Prout clearly identified hydrochloric acid as the acid agent of the stomach.
Schwann made most of his important scientific discoveries during the Berlin period (1834–1838). In 1836 he isolated the enzyme responsible for digestive processes in the stomach and coined the name "pepsin" for this newly identified substance. He was the first to isolate a digestive enzyme from animal tissue, naming it pepsin. By studying stomach processes, he determined that a substance besides hydrochloric acid was responsible for breaking down food. Schwann called the substance pepsin after the Greek word pepsis, meaning "digestion." It was the first specific substance ever associated with causing chemical changes within the body. At the time, scientists referred to such substances as ferments; however, the term enzyme was adopted in 1876.
Studies on gastric digestion during 1820–1840 led to the discovery of pepsin as the agent which, in the presence of stomach acid, causes the dissolution of nutrients such as meat or coagulated egg white. Soon afterward it was shown that these protein nutrients were cleaved by pepsin to diffusible products named peptones.
Efforts to isolate and purify pepsin were spurred by its widespread adoption for the treatment of digestive disorders, and highly active preparations were available by the end of the nineteenth century. There was uncertainty, however, as to the chemical nature of pepsin, for some preparations exhibited the properties of proteins while other preparations failed to do so.
Skepticism about its practical therapeutic value was voiced as early as 1870. Dr. E. P. Hurd ridiculed the idea that pepsin could be of the value as an aid to digestion that many seemed to regard it, noting that most of the substance of the pepsin used was starch, and in any case, even a strong preparation could only digest eighty or ninety grains of aliment. Despite such critiques, pepsin preparations remained widely used as digestive remedies into the 20th century.
The chemical properties of pepsin were not fully understood until 1930, when American chemist John Northrop crystallized it in a laboratory. After 1975, the three-dimensional structures of pepsin and many of its relatives were determined by means of x-ray diffraction techniques, greatly extending insight into the mechanism of the catalytic action of these enzymes.
Pepsin is a component of rennet used to curdle milk during the manufacture of cheese. Pepsin is used for a variety of applications in food manufacturing: to modify and provide whipping qualities to soy protein and gelatin, to modify vegetable proteins for use in nondairy snack items, to make precooked cereals into instant hot cereals, and to prepare animal and vegetable protein hydrolysates for use in flavoring foods and beverages. It is used in the leather industry to remove hair and residual tissue from hides and in the recovery of silver from discarded photographic films by digesting the gelatin layer that holds the silver. Pepsin was historically an additive of Beeman's gum brand chewing gum by Dr. Edwin E. Beeman. Pepsin is also commonly used in the preparation of F(ab')₂ fragments from antibodies.
Pepsin is expressed as a zymogen called pepsinogen, whose primary structure has an additional 44 amino acids compared to the active enzyme. In the stomach, gastric chief cells release pepsinogen. This zymogen is activated by hydrochloric acid (HCl), which is released from parietal cells in the stomach lining. The hormone gastrin and the vagus nerve trigger the release of both pepsinogen and HCl from the stomach lining when food is ingested. Hydrochloric acid creates an acidic environment which allows pepsinogen to unfold and cleave itself in an autocatalytic fashion, thereby generating pepsin (the active form).
Upon exposure to the acidic environment of the stomach, pepsinogen undergoes a conformational change that reveals the active site, converting it into active pepsin. This activation can occur autocatalytically, meaning that pepsin can also activate more pepsinogen molecules once it is formed.
Pepsinogen is a symmetrical molecule with N- and C-terminal lobes with a molecular weight between 40–42 kDa and is stable up to pH values of 10. However, when it is exposed to pH levels below 5, which occurs in the gastric glands, an autocatalytic activation occurs. This involves the removal of a section of the pepsinogen's N-terminal.
For the protein to be active, one of the two aspartate residues in the catalytic site has to be protonated and the other deprotonated. This occurs between pH 1 and 5, and above pH 7 pepsin is irreversibly denatured.
Pepsin is an endopeptidase with a broad specificity. The pH optima for some protein substrates, such as cattle hemoglobin, are near pH 2 and are attributable to acid denaturation and solubility of substrates. Pepsin cleaves proteins preferentially at carboxylic groups of aromatic amino acids such as phenylalanine and tyrosine. More precisely, pepsin preferentially cleaves at the C-terminus of phenylalanine, leucine, tyrosine, and tryptophan. Pepsin catalyzes the hydrolysis of peptide bonds between hydrophobic or aromatic residues of a protein substrate; bonds such as Phe-Phe, Phe-Trp, and Phe-Tyr are commonly hydrolyzed.
Pepsin exhibits a broad cleavage specificity and will digest up to 20% of ingested amide bonds.
Treatment of pepsin with chemical reagents indicated the participation in the catalytic mechanism of two aspartyl units widely separated in the linear sequence. Studies on the kinetics of pepsin action on long-chain synthetic peptides suggested that the catalytic site was an extended structure.
Pepsin is inactive at pH 6.5 and above; however, pepsin is not fully denatured or irreversibly inactivated until pH 8.0. Therefore, pepsin in solutions of up to pH 8.0 can be reactivated upon re-acidification. The stability of pepsin at high pH has significant implications for disease attributed to laryngopharyngeal reflux. Pepsin remains in the larynx following a gastric reflux event. At the mean pH of the laryngopharynx (pH = 6.8), pepsin would be inactive but could be reactivated upon subsequent acid reflux events, resulting in damage to local tissues.
The negative charge of the enzyme in the pH of the gastric juice (pH 2–3) is thought to favor the interaction with protein substrates which are positively charged in gastric juice. Pepsin is irreversibly inactivated above pH 7, implying that the enzyme is digested by the pancreatic proteases and reabsorbed as amino acids.
In terms of proteolytic activity, pepsin should not be regarded as simply a low-pH protease, as it has activity close to neutral. Pepsin has a key function in the gastric juice as an antimicrobial agent via its proteolytic activity, but the activation peptides from pepsinogen can also act as antimicrobial peptides.
Pepsin breaks down proteins into smaller peptides and amino acids that can be easily absorbed in the small intestine. In a normal gastrointestinal digestion process, proteolysis in the stomach by the enzyme pepsin is understood to be the first step in the breakdown of dietary proteins. The second step takes place in the small intestine, in the duodenum and jejunum located immediately downstream of the stomach.
Of the components in gastric juice, pepsin is the principal enzyme involved in protein digestion. It breaks down proteins into smaller peptides and amino acids that can be easily absorbed in the small intestine. Specific cells within the gastric lining, known as chief cells, release pepsin in an inactive form, or zymogen form, called pepsinogen. Since chief cells release pepsin as a zymogen, activation by an acidic environment is necessary. Hydrochloric acid (HCl), another component of gastric juice, plays a crucial role in creating the pH required for pepsin activity.
Hypochlorhydria — reduced secretion of gastric acid — is a physiological condition in which both pepsinogen activation and protein digestion are impaired. Data suggest that a diminution of gastric acid secretion may gradually worsen with aging, which cannot be readily detected in the fasted state (i.e., independent of atrophic gastritis/achlorhydria). This extended mealtime/postprandial hypochlorhydria may contribute to poor protein digestion, reduced micronutrient absorption, increased risk of dysbiosis, small intestinal bacterial overgrowth (SIBO), or other symptoms associated with functional dyspepsia.
Esophagectomy patients are left with significant anatomical changes to the GI tract, including the cutting of the vagus nerve, which regulates gastric secretions, gastric acid pH, and motility. Gastric acid is needed for the active absorption of iron, zinc, B complex vitamins especially B12, and digestion of consumed proteins.
Pepsin plays a well-documented role in the pathogenesis of laryngopharyngeal reflux. One of the main mucosal irritants in LPR is pepsin, which digests proteins and impairs the functions of the upper respiratory tract cells by affecting carbonate anhydrase (CAIII) and the Sep 70 protein. Pepsin initiates inflammatory changes within the larynx, nasopharynx, and nasal cavity.
Studies show that the gastroduodenal mucosal barrier is damaged by pepsin under conditions in which it is resistant to acid alone. The continuous layer of adherent mucus gel provides a diffusion barrier to luminal pepsin, preventing its access to the underlying epithelium. Pepsin has mucolytic activity and will progressively digest the adherent mucus layer at its luminal surface, although normally this is balanced by secretion of new mucus to maintain a continuous barrier.
Serum pepsinogen has certain clinical value in determining Helicobacter pylori infection and its treatment monitoring, in identifying the location and extent of gastric mucosal lesions, and in diagnosing and screening gastric cancer and precancerous lesions. Altered levels of serum pepsinogens, which are mainly produced by the chief cells of the fundic glands of the stomach, reflect the atrophic status (i.e., gland loss) of gastric mucosa. Serum pepsinogen levels not only reveal the past infection status or current atrophy of the stomach but have also been shown to be predictive of gastric cancer risk.
Established physiology (very strong): The role of pepsin as the dominant stomach protease is established beyond reasonable scientific dispute through more than a century of biochemical, physiological, and clinical research. Of the components of gastric juice, pepsin is the principal enzyme involved in protein digestion; it breaks down proteins into smaller peptides and amino acids that can be easily absorbed in the small intestine. Its mechanism of action at the molecular level — two-aspartate catalysis, pH dependence, and substrate specificity — has been fully elucidated by structural and kinetic studies.
Supplemental use in hypochlorhydria (limited clinical evidence): Despite the physiological plausibility of using exogenous pepsin to compensate for impaired endogenous secretion, high-quality randomized controlled trials are sparse. The available human evidence consists largely of case reports and small observational studies. In one published case report in the Journal of Medicinal Food (2024), a 76-year-old male patient 9 months post-esophagectomy, who presented with chronic nausea, fatigue, weight loss, and dumping syndrome, had a functional nutritional assessment suggesting gastric hypochlorhydria. A digestive supplement — betaine hydrochloric acid with pepsin (BHClP) — was introduced; the patient ingested 1 capsule containing 500 mg betaine hydrochloride and 23.5 mg pepsin prior to protein-containing meals and reported a substantial decrease in GI symptoms while eating a regular diet. This is a single case report and cannot establish causality or generalizability.
The evidence base for supplemental pepsin in functional hypochlorhydria, while mechanistically supported, lacks large-scale randomized controlled trials. Current evidence is rated as preliminary and insufficient to make firm efficacy claims for supplemental pepsin independently of its acid co-factors.
Salivary pepsin as a diagnostic biomarker (moderate to strong evidence, growing): A rapid lateral flow test (Peptest) to detect pepsin in saliva/sputum has been considered a valuable method for diagnosing laryngopharyngeal reflux (LPR) and gastroesophageal reflux disease (GERD). A systematic review and meta-analysis that analyzed 16 articles including 2,401 patients and 897 controls examined the utility of salivary pepsin detection. The presence of pepsin in the saliva acts as a marker for reflux, considering that pepsin is only produced in the stomach. Twenty-four-hour multichannel intraluminal impedance with double-probe pH monitoring, though considered the most sensitive tool for the diagnosis of GERD, is invasive, time-consuming, not widely available, and unable to detect non-acid reflux.
In a prospective study of 120 adult patients with clinical LPR, when considered along with clinical indicators of reflux finding score (RFS) and reflux symptom index (RSI) of more than 7 and 13, respectively, and/or with a response to treatment, a positive salivary pepsin test indicates a statistically significant chance of the presence of LPR.
In a separate study examining 60 LPR patients, pepsin was detected in the saliva of 63% of subjects and 78% of those with a high reflux finding score. Salivary pepsin had a sensitivity of 78% and specificity of 53% for predicting a high RFS. There was a correlation between the severity of laryngeal inflammation and the concentration of pepsin (r = 0.28, p = 0.01). The relatively modest specificity of 53% indicates that salivary pepsin alone is not sufficient for definitive diagnosis and should be used as a screening adjunct.
The use of pepsin detection in upper and lower throat secretions represents a new direction in LPR diagnostics. Overall, this area of evidence is rated as moderate to promising, with the caveat that sampling protocols are not yet standardized across studies.
Experimental and clinical evidence (strong for pathological role, not for supplementation): Esophagitis results from excessive exposure of the esophagus to gastric juice through an ineffective or dysfunctional lower esophageal sphincter mechanism. Examination of pepsin's role in damaging the esophageal mucosa has been undertaken directly by testing pepsin under various conditions in experimental models. Since gastric juice contains both acid and pepsin, experiments examine separately the effects of perfusion of the esophagus by acid without and with pepsin. Acid perfusion alone at concentrations represented by pH 1.3 or above does not produce esophagitis. The addition of pepsin to acid between pH 1 and 3.5 causes considerable acute esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5, pepsin does not damage the esophagus.
The damage caused by acidified pepsin may be made much worse by the further addition of aspirin or other NSAIDs, presumably by further breaking down mucosal barriers.
Studies have shown that the acute stress caused by acid and pepsin exposure can widen the epithelial tight junctions of the esophageal mucosa, increasing its permeability. Reflux pepsin can also induce the expression and excessive proliferation of matrix metalloproteinases (MMPs) as sheddases of E-cadherin. Additionally, acidic gastric juice could also contribute to the elevated expression of MMP-9, further causing the degradation of occludin, a significant protein that constructs endothelial tight junctions. The degradation of tight junction proteins induced by pepsin and gastric acid is another significant GERD pathology.
This evidence firmly establishes pepsin as a co-pathogen in reflux-related esophageal injury. The strength of this evidence is strong, but it pertains entirely to the harmful effects of endogenous pepsin in the wrong anatomical location — not to supplemental pepsin.
Biomarker studies (moderate to strong evidence, used clinically in Asia): A PgI/PgII ratio < 3 was identified as an important risk biomarker for precursor lesions of gastric cancer (OR = 9.171, 95% CI: 1.723–48.799, p = 0.009); however, biomarkers showed low accuracy with histopathological study.
Serum PGI and PGII levels are increased with increasing severity of H. pylori-related chronic gastritis. However, when atrophic changes in the corpus are accompanied by a loss of cells in the corpus — including those secreting PGI — the level of PGI decreases, whereas the level of PGII remains high or stable.
The pepsinogen I/II ratio was significantly different between disease groups among both H. pylori-positive and H. pylori-negative individuals, suggesting the pepsinogen I/II ratio is a robust biomarker for determining both chronic and atrophic gastritis. The cutoffs for detecting chronic and atrophic gastritis for the pepsinogen I/II ratio were 4.65 and 4.95, respectively. In conclusion, pepsinogen levels are useful biomarkers for both chronic gastritis and atrophic gastritis, but they should be used with caution.
Overall, the serum pepsinogen biomarker literature is well-developed — particularly in Japanese and broader Asian populations — but use of these biomarkers for gastric cancer screening in Western populations is less established. The evidence is rated as moderate to strong for the biomarker concept, with population-specific variation requiring caution in generalization.
After 1975, the three-dimensional structures of pepsin and many of its relatives were determined by means of x-ray diffraction techniques, greatly extending insight into the mechanism of catalytic action. That knowledge has led to the design of new inhibitors of aspartyl proteinases, which are participants in the maturation of human immunodeficiency virus and in the generation of Alzheimer's disease. This line of research is active but primarily preclinical; it does not bear directly on the use of pepsin as a dietary supplement.
Pepsin is not approved as a standalone prescription drug in most jurisdictions but is sold as a dietary supplement and, in some markets, in over-the-counter digestive combination products. The activity and dose of pepsin products vary widely depending on the source, the activity standardization method (USP units, FIP units, or NF/BP potency expressions), and the intended use.
Robust, replicated clinical trials in humans establishing an evidence-based optimal dose for supplemental pepsin for any condition have not been published in the peer-reviewed literature as of the time of this writing. Dosages cited in marketing materials are not drawn from controlled human studies and are therefore not presented here.
Administration of HCl/pepsin is contraindicated in peptic ulcer disease. Pepsin has mucolytic activity and will progressively digest the adherent mucus layer at its luminal surface, although normally this is balanced by secretion of new mucus to maintain a continuous barrier. In peptic ulcer disease, the proportion of peptic activity in gastric juice attributable to pepsin type 1 is significantly raised (four to five-fold). Exogenous pepsin supplementation in individuals with active peptic ulceration could plausibly worsen mucosal injury, though direct supplementation studies on this specific risk are not available in the current peer-reviewed literature.
The addition of pepsin to acid between pH 1 and 3.5 causes considerable acute esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5, pepsin does not damage the esophagus. For individuals with pre-existing GERD or active reflux esophagitis, supplemental pepsin could theoretically augment the proteolytic damage already mediated by refluxed gastric contents.
The damage caused by acidified pepsin may be made much worse by the further addition of aspirin or other NSAIDs, presumably by further breaking down mucosal barriers. This interaction — pepsin combined with NSAIDs — has direct clinical relevance for individuals who take both supplemental pepsin/betaine HCl combinations and anti-inflammatory medications.
Administration of HCl/pepsin is contraindicated in peptic ulcer disease. HCl can irritate sensitive tissue and can be corrosive to teeth; therefore, capsules should NOT be emptied into food or dissolved in beverages.
Commercial pepsin is extracted from the glandular layer of hog stomachs. Individuals observing religious dietary laws that prohibit pork (e.g., halal or kosher restrictions) or those adhering to vegetarian or vegan diets must be aware that the vast majority of commercial pepsin supplements are derived from porcine tissue. Animal-free alternatives derived from precision fermentation have been developed but are predominantly available in the food ingredient market rather than in dietary supplement form at present.
Pepsin is inactive at pH 6.5 and above; however, pepsin is not fully denatured or irreversibly inactivated until pH 8.0. Therefore, pepsin in solutions of up to pH 8.0 can be reactivated upon re-acidification. This property means that ingested supplemental pepsin, if it reaches extraesophageal tissues during a reflux episode, could be reactivated by subsequent acid exposure — potentially contributing to tissue damage at sites such as the larynx, pharynx, and airways.
There are no extensively studied pharmacokinetic drug-drug interactions specific to oral supplemental pepsin in the peer-reviewed clinical literature. However, the following interactions are physiologically plausible and supported by mechanistic evidence:
In the United States, pepsin is sold as a dietary supplement regulated under the Dietary Supplement Health and Education Act (DSHEA, 1994) and is not required to demonstrate pre-market efficacy. The USP, BP, and Ph. Eur. maintain official reference standards for pepsin potency in pharmaceutical and compounding contexts. In some countries, pepsin-containing combination products are classified as over-the-counter medicines and are regulated accordingly.
Condiciones de salud que pepsina puede ayudar a apoyar.
A 2017 non-interventional observational study published in BMC Gastroenterology evaluated a fixed combination of pepsin and amino acid hydrochloride (Enzynorm®f) in 97 patients with functional dyspepsia (FD) over 6 weeks. The validated Gastrointestinal Symptom Score (GIS©) decreased significantly from a mean of 11.6 to 7.4 (p<0.0001), including improvements in upper abdominal pain and discomfort. Pepsin has also been traditionally used to support gastric proteolytic function in dyspepsia, though placebo-controlled RCT evidence remains lacking.
Pepsin is now recognized as a primary pathogenic agent in gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR), not merely a bystander. Refluxed pepsin damages esophageal and extraesophageal epithelium by degrading tight junction proteins and triggering reactive oxygen species, directly causing heartburn symptoms. Unlike acid, pepsin retains activity at pH levels up to 6.5 and is not fully denatured until above pH 8, meaning acid suppression with PPIs does not fully neutralize its damaging effects. Salivary pepsin concentration is a validated biomarker correlated with GERD symptom severity in clinical studies.
Pepsin is the primary gastric protease, activated by hydrochloric acid, that initiates protein digestion in the stomach. It is produced as pepsinogen by chief cells of the gastric mucosa and is included in animal-source digestive enzyme supplements. It is a recognized component of gastric digestive physiology and oral enzyme preparations.
Pepsinogen (the inactive precursor of pepsin) levels — particularly pepsinogen II (PgII) — are well-established clinical biomarkers of gastric mucosal inflammation and H. pylori-associated gastritis. Elevated serum PgII correlates significantly with active H. pylori infection and the degree of histologic gastritis. Pepsin itself, through its mucolytic activity and ability to degrade the mucus-bicarbonate barrier, contributes directly to gastric mucosal injury in the setting of inflammatory gastritis.
Pepsin is a well-established co-factor in peptic ulcer disease alongside gastric acid. Studies demonstrate that the gastroduodenal mucosal barrier is damaged by pepsin under conditions where it is resistant to acid alone, and that pepsin type 1 activity in gastric juice is elevated four- to five-fold in peptic ulcer patients. The classic formulation 'no acid, no pepsin, no ulcer' reflects the scientific consensus that both agents are required for mucosal breakdown leading to ulceration.
Sistemas corporales que pepsina puede ayudar a apoyar.
Volver