Description
Zinc L-carnosine is a chelate of divalent zinc and the dipeptide L-carnosine. L-carnosine (see Carnosine) is comprised of the nonprotein amino acid beta-alanine (see Beta-alanine) and the protein amino acid L-histidine.
Zinc L-carnosine was synthesized by the Japanese in the late 1980s. It was first known as Z-103 and later on as polaprezinc. The idea for the synthesis of zinc L-carnosine came from the knowledge that L-carnosine was reported to increase granulation tissue and accelerate gastric healing in rats, and that zinc had been reported to have protective action against various experimental gastric lesions and also had been reported to possess antiulcer action in clinical studies. The thinking was that the combination of the beneficial effects of zinc and L-carnosine under the chemical roof of one molecule would make for a novel and potent antiulcer agent. Japanese researchers found that the zinc L-carnosine complex did exhibit marked antiulcer activity against various experimental models of gastric ulcers and duodenal ulcers by acting directly on the gastric and intestinal mucosa. However, even during the early days of zinc L-carnosine research, it was already demonstrated to have other activities, such as inhibition of bone resorption in experimental animals. Recently, zinc L-carnosine entered the dietary supplement marketplace in the United States.
Zinc L-carnosine is described chemically as 2-[(3-azanidyl-1-oxidopropylidene)amino]-3-(3H-imidazol-4-yl)propanoate. It is also known as polaprezinc, zinc carnosine, β-alanyl-L-histidinato zinc, N-(3-aminopropionyl)-L-histidinato zinc, [N-β-alanyl-L-histidinato(2-)-N,NN, Oα] zinc, and catena-(S)-[_lm-[Nα-(3-aminopropionyl)-L-histidinato (2-)-N1,N2,O:Nτ]-zinc]. Originally known as Z-103, zinc L-carnosine was demonstrated to be much more active against gastric ulceration in rats than various other Zn(II) complexes. Zinc D-carnosine was found to have little or no activity. Spectroscopic data indicated that the zinc ions coordinate with L-carnosine to form a quadridentate 1:1 complex of polymeric nature in order to maintain low strain of the chelate rings. Small amounts of zinc L-carnosine may be found in muscle and nervous tissue. (Carnosine in muscle and nervous tissue may form chelates with zinc, copper and iron.)
Zinc L-carnosine's empirical formula is (C9H12N4O3Zn)n, its molecular weight is 288.62, and its CAS Registry Number is 107667-60-7. It is insoluble in water and common organic solvents, but does dissolve in acid, including stomach acid.
Zinc L-carnosine is represented by the following chemical structure.
Chemical Structure
Zinc L-carnosine
Actions & Pharmacology
Actions
Zinc L-carnosine has antiulcer, antigastritis and mucosal protective activities. It may also have bone-protective and hepatoprotective activities.
Mechanism of Action
Antiulcer activity: In an early study of zinc L-carnosine and peptic ulcer disease, it was found that the agent prevented ethanol-induced gastric mucosal damage in rats through increases in the activities of the gastric mucosal antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). Zinc L-carnosine also inhibited the increase in thiobarbituric acid reactive substances (TBARS) in gastric mucosa injured by the ethanol. (TBARS is a measure of oxidative stress.) The study authors concluded that the protective mechanism of zinc L-carnosine against gastric ulceration was due, at least in part, to the scavenging of oxygen-derived free radicals via increases in the synthesis of SOD and GSH-px in the gastric mucosa, induced by zinc L-carnosine.
The antiulcer pharmacological effects of zinc L-carnosine on indomethacin-induced gastric lesions and acetic acid-induced gastric ulcers, were found to be significantly greater than those of either of its components, L-carnosine and divalent zinc, or than a mixture of the two. In a study with rats, it was determined that zinc L-carnosine, which acts directly in mucosal lesions, was retained in the stomach much longer and adhered to the ulcerous sites more strongly than did divalent zinc or L-carnosine. The characteristics of the compound were thought to arise from its much lower solubility when compared to the high solubility of divalent zinc forms, such as zinc sulfate or L-carnosine.
In a study with primary monolayer cultures of rat gastric fundic mucosa, it was demonstrated that zinc L-carnosine protected gastric cells from oxidative stress caused by hydrogen peroxide and ethanol in vitro, that ethanol-induced cytotoxicity was linked with superoxide anion radical production from cells, and that zinc L-carnosine-induced protection against ethanol seemed to be due, at least in part, to the scavenging of reactive oxygen species (ROS). The authors of the study concluded that zinc L-carnosine worked via an antioxidant mechanism and directly protected gastric mucosal cells from noxious agents via its antioxidant properties in vitro, independently of microcirculatory and neural or hormonal factors.
The antiulcer and mucocytoprotective effects of zinc L-carnosine may be explained, in part, by its antioxidant properties, as well as its stimulative effect on mucus secretion and its membrane-stabilizing effect. However, this does not completely explain the mechanism of action of its antiulcer activity. In a study using gastric epithelial cells (MKN28, a cell line derived from moderately differentiated gastric carcinoma), it was reported that zinc L-carnosine suppressed interleukin-8 (IL-8) secretion induced by tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta) dose-dependently. IL-8 messenger RNA expression was also inhibited by zinc L-carnosine. Proinflammatory cytokine nuclear factor-kappaB (NF-kappaB) activation in response to TNF-alpha, IL-1beta, phorbol ester, and hydrogen peroxide, was downregulated by zinc L-carnosine. Further, Western blot analysis revealed inhibition of TNF-alpha-induced IkappaB-alpha phosphorylation in the presence of zinc L-carnosine.
Thus, an anti-inflammatory action, specifically the downregulation of proinflammatory cytokine-induced NF-kappaB activation and IL-8 expression in gastric epithelial cells, can be added to the list of zinc L-carnosine's antiulcer mechanisms of action.
To add yet another mechanistic possibility, zinc L-carnosine was shown to inhibit indomethacin-induced apoptosis in the rat gastric epithelial cell line RGM1, a diploid and non-transformed epithelial cell line isolated from normal Wistar rat gastric mucosa. Pretreatment of the cells with zinc L-carnosine suppressed caspase-3 activation and subsequent apoptosis in the cells exposed to indomethacin, dose-dependently. Treatment of the cells with indomethacin did produce ROS, but zinc L-carnosine did not scavenge ROS in the indomethacin-treated cells, ruling out an antioxidant mechanism of action. Thus, in this case, zinc L-carnosine inhibited apoptosis via inhibition of caspase-3 activation, not by antioxidant activity.
Zinc L-carnosine was reported to help in the healing of acute gastric lesions in diabetic rats. In this case, enhancement of mucosal insulin-like growth factor-1 (IGF-1) messenger RNA expression was thought to contribute to the effect.
The effect of zinc L-carnosine on cellular proliferation was studied in human umbilical vein endothelial cells (HUVEC), human foreskin fibroblasts and guinea pig gastric mucosal cells. Zinc L-carnosine stimulated cellular proliferation in the HUVEC and the human foreskin fibroblasts, but did not stimulate proliferation in the guinea pig gastric mucosal cells. Stimulation of cellular proliferation was accompanied by increased IGF-1 messenger RNA levels. The authors of the study concluded that their results suggested that the promotion of wound healing by zinc L-carnosine was related to a proliferative effect on nonparenchymal cells, with zinc and IGF-1 being important for the action. Although divalent zinc in the form of zinc sulfate also demonstrated a proliferative effect, its action was much weaker than that of zinc L-carnosine.
The effects of the roles of inflammatory cytokines, neutrophil accumulation and lipid peroxidation in the protective effect of zinc L-carnosine against aspirin-induced gastric mucosal injury was examined in rats. Zinc L-carnosine dose-dependently inhibited the total gastric erosive area following aspirin administration, inhibited increases in thiobarbituric acid-reactive substances (TBARS), an index of lipid peroxidation, and inhibited tissue-associated myeloperoxidase activity. TBARS and myeloperoxidase activity are both markers of oxidative stress. In addition, zinc L-carnosine dose-dependently inhibited the aspirin-induced rise in the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). This study suggested that the protective effects of zinc L-carnosine on aspirin-induced gastric mucosal injury may be attributed to its antioxidative and anti-inflammatory activities.
Helicobacter pylori is a common cause of chronic gastritis and peptic ulcer disease. In H. pylori-colonized gastric mucosa, activated neutrophils generate superoxide anion radicals and hydrogen peroxide. Myeloperoxidase in neutrophils catalyzes the oxidation of chloride by hydrogen peroxide to produce hypochlorous acid. The hypochlorous acid reacts with ammonia generated by H. pylori to produce monochloramine, which is reactive, toxic and causes gastric mucosal cell injury via damage to DNA. Zinc L-carnosine has been reported to inhibit H. pylori-induced gastritis and DNA damage in Mongolian gerbils through its scavenging action against monochloramine.
The treatment of H. pylori is a course of triple therapy, usually with the two antibiotics—amoxicillin and clarithromycin—and a proton pump inhibitor. In a clinical study, a seven-day course of triple therapy with amoxicillin, clarithromycin and lansoprazole was found to be effective in H. pylori eradication, but the regimen was significantly improved by the addition of zinc L-carnosine.
Zinc L-carnosine has also been found to protect against colonic mucosal injury. A study investigated the effects of zinc L-carnosine on acetic acid-induced colonic mucosal injury in rats in vivo. Zinc L-carnosine inhibited visible damage in the rat colonic mucosa and this was accompanied by a significant increase in the expression of heat shock protein 72 (HSP72) and suppression of nuclear factor-kappaB (NF-kappaB) activation in the colonic mucosa. Heat shock proteins protect cells against heat stress as well as other stressors. The authors of the study suggested that, based on the findings, zinc L-carnosine may be a novel treatment for inflammatory bowel disease. The mechanism of action of this effect is not completely understood, but continued research in this area is needed and warranted.
Bone-protective activity: Zinc L-carnosine has been reported to have possible antiosteoporosis and bone-sparing activities. However, the mechanism of action of these effects is unclear. In one study, prolonged administration of zinc L-carnosine to ovariectomized rats was found to prevent bone loss. In another study, using mouse marrow cultures, an inhibitory effect of zinc L-carnosine on parathyroid hormone (PTH)-stimulated osteoclast-like cell formation was reported. It was speculated that the zinc L-carnosine inhibition of the PTH-stimulated osteoclast-like cell formation was mediated via calcium-dependent activation of protein kinase C.
A small clinical pilot study of postmenopausal women with rheumatoid arthritis reported that zinc L-carnosine improved periarticular osteoporosis, probably through an increase in bone formation.
Zinc L-carnosine has been found to promote the differentiation of osteoblasts, to suppress the formation of osteoclasts and to prevent the progression of osteoporosis. These findings, if they can be verified, could have powerful applications to promote new bone formation, including periodontal bone regeneration. High quality randomized, double-blind, placebo-controlled clinical trials are very much needed and warranted in order to learn if zinc L-carnosine has any role to play in bone regeneration.
Hepatoprotective activity: Non-alcoholic steatohepatitis (NASH) is an increasingly common disorder, which may have serious consequences. This has only recently been recognized. In some cases, it may lead to liver fibrosis, cirrhosis and even hepatocellular carcinoma. The pathogenesis of NASH is unclear. Although a similar condition can occur in people who abuse alcohol, NASH occurs in those who drink little or no alcohol.
The effects of zinc L-carnosine on the development of NASH was investigated in a mouse model of the disease. Zinc L-carnosine was demonstrated to reduce lipid peroxidation, to suppress messenger RNA expression of proinflammatory cytokines and to suppress the activation of hepatic stellate cells. (Stellate cell activation is the central event in hepatic fibrosis.) The results suggested that zinc L-carnosine attenuated fibrosis in NASH by reducing lipid peroxidation and inflammation, and, during a later phase, promoting fibrinolysis by inhibiting tissue inhibitors of metalloproteinase expression.
In a small clinical trial of patients with early liver cirrhosis, it was reported that those patients who received zinc L-carnosine demonstrated reduction in the activity of tissue inhibitors of metalloproteinase-1 as well as decreased levels of type IV collagen, a marker of fibrosis.
Further research in this area is needed and warranted.
A few studies on the effects of zinc L-carnosine have also been performed in patients with chronic hepatitis C infection. In one study, it was reported that zinc L-carnosine administration resulted in reduced hepatocyte injury as measured by the increase in serum transaminase enzyme levels in patients with hepatitis C who were on therapy with pegylated interferon alpha-2b and ribavirin. The mechanism of this effect was not clear. However, the authors of the study speculated that the effect of zinc L-carnosine had to do with its possible antioxidant activity.
In another study of patients with chronic hepatitis C infection, it was reported that those patients receiving zinc L-carnosine had reduced iron overload as determined by serum ferritin levels. Again, the mechanism of this effect was unclear.
Pharmacokinetics
There is very little on the pharmacokinetics (PK) of zinc L-carnosine in humans. Studies of the PK of zinc L-carnosine in rats show that, following ingestion, zinc L-carnosine slowly dissociates into its components, L-carnosine and divalent zinc. Zinc L-carnosine, which acts directly in mucosal lesions, is retained in the stomach much longer than other forms of divalent zinc and adheres to the mucosal lesions and ulcerous sites much more than do divalent zinc and L-carnosine themselves. The characteristics of the compound may arise from its much lower solubility when compared to the high solubility of divalent zinc, for example, in the form of zinc sulfate, and L-carnosine. One can think of zinc L-carnosine in this regard as a slow-release form of divalent zinc and L-carnosine.
In the rat studies, zinc was found to be efficiently absorbed from the small intestine. However, it is unclear how much zinc L-carnosine, if any, is transported into the body. It is known that following absorption, zinc is mainly bound to albumin and transported from the intestine to the liver via the portal system. Zinc was found mainly excreted in the feces; a small amount was found excreted in the urine. (See Zinc and L-carnosine for further information on the PK of zinc and of L-carnosine.)
Indications & Usage
Zinc L-carnosine is a one-to-one complex of a synthetic derivative of carnosine and zinc. It is marketed as a zinc supplement with claimed benefits for gastric health. It may help protect the liver against hepatitis C infection and other stressors. It could have some radioprotective effects.
Overdosage
There are no reports of overdosage from use of zinc L-carnosine supplements.
Dosage
Zinc L-carnosine supplements are available in strengths of 37.5 milligrams and 75 milligrams. Amounts used in most gastric ulcer studies were 75 milligrams twice daily. Doses higher than those recommended on the supplement label should not be exceeded.
Literature
Fuji Y, Matsura T, Kai M, et al. Protection by polaprezinc, an anti-ulcer drug, against indomethacin-induced apoptosis in rat gastric mucosal cells. Jpn J Pharmacol. 2000;84(1):63-70.Furuta S, Toyama S, Miwa M, et al. Residence time of polaprezinc (zinc L-carnosine complex) in the rat stomach and adhesiveness to ulcerous sites. Jpn J Pharmacol. 1995;67(4):271-278.Hamano H, Yoshinaga K, Eta R, et al. Effect of polaprezinc on taste disorders in zinc-deficient rats. Biofactors. 2006;28(3-4):185-193.Handa O, Yoshida N, Tanaka Y, et al. Inhibitory effect of polaprezinc on the inflammatory response to Helicobacter pylori. Can J Gastroenterol. 2002;16(11):785-789.Hiraishi H, Sasai T, Oinuma T, et al. Polaprezinc protects gastric mucosal cells from noxious agents through antioxidant properties in vitro. Aliment Pharmacol Ther. 1999;13(2):261-269.Ishihara R, Iishi H, Sakai N, et al. Polaprezinc attenuates Helicobacter pylori-associated gastritis in Mongolian gerbils. Helicobacter. 2002;7(6):384-389.Ito M, Shii D, Segami T, et al. Preventive actions of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) through increases in the activities of oxygen-derived free radical scavenging enzymes in the gastric mucosa on ethanol-induced gastric mucosal damage in rats. Jpn J Pharmacol. 1992;59(3):267-274.Kishi S, Segawa Y, Yamaguchi M. Histomorphological confirmation of the preventive effect of beta-alanyl-L-histidinato zinc on bone loss in ovariectomized rats. Biol Pharm Bull. 1994;17(6):862-865.Korolkiewicz RP, Fujita A, Seto K, et al. Polaprezinc exerts a salutary effect on impaired healing of acute gastric lesions in diabetic rats. Dig Dis Sci. 2000;45(6):1200-1209.Maeno M, Ito-Kato E, Suzuki N, et al. Effect of beta-alanyl-L-histidinato zinc on the differentiation pathway of human periodontal ligament cells. Life Sci. 2004;74(20):2493-2504.Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilizes small bowel integrity and stimulates gut repair processes. Gut. 2007;56(2):168-175.Matsukura T, Tanaka H. Applicability of zinc complex of L-carnosine for medical use. Biochemistry (Mosc). 2000;65(7):817-823.Matsuu-Matsuyama M, Shichijo K, Okaichi K, et al. Protection by Polaprezinc Against Radiation-Induced Apoptosis in Rat Jejunal Crypt Cells. J Radiat Res (Tokyo). 2008; 49:341-347.Miller DJ, O'Dowd A. Vascular smooth muscle actions of carnosine as its zinc complex are mediated by histamine H(1) and H(2) receptors. Biochemistry (Mosc). 2000;65(7):798-806.Naito Y, Yoshikawa T, Yagi N, et al. Effects of polaprezinc on lipid peroxidation, neutrophil accumulation, and TNF-alpha expression in rats with aspirin-induced gastric mucosal injury. Dig Dis Sci. 2001;46(4):845-851.Odashima M, Otaka M, Jin M, et al. Zinc L-carnosine protects colonic mucosal injury through induction of heat shock protein 72 and suppression of NF-kappaB activation. Life Sci. 2006;79(24):2245-2250.Odashima M, Otaka M, Jin M, et al. Induction of a 72-kDa heat-shock protein in cultured rat gastric mucosal cells and rat gastric mucosa by zinc L-carnosine. Dig Dis Sci. 2002;47(12):2799-2804.Ohkawara T, Nishihira J, Nagashima R, et al. Polaprezinc protects human colon cells from oxidative injury induced by hydrogen peroxide: relevant to cytoprotective heat shock proteins. World J Gastroenterol. 2006;12(38):6178-6181.Segawa Y, Tsuzuike N, Itokazu Y, et al. Effect of beta-alanyl-L-histidinato zinc on bone metabolism in rats with adjuvant arthritis. Biol Pharm Bull. 1993;16(7):656-659.Sugino H, Kumagai N, Watanabe S, et al. Polaprezinc attenuates liver fibrosis in a mouse model of non-alcoholic steatohepatitis. J Gastroenterol Hepatol. pub: 2008 Apr 19. Epub: 2008 Apr 19.Suzuki H, Mori M, Seto K, et al. Polaprezinc attenuates the Helicobacter pylori-induced gastric mucosal leucocyte activation in Mongolian gerbils–a study using intravital videomicroscopy. Aliment Pharmacol Ther. 2001;15(5):715-725.Takada T, Suzuki N, Ito-Kato E, Noguchi Y, Ito M, Maeno M, Otsuka K. Effect of beta-alanyl-L-histidinato zinc on the differentiation of C2C12 cells. Life Sci. 2004;76(5):509-520.Tameyasu T, Yamada M, Tanaka M, et al. Effect of zinc-carnosine chelate compound on muscle function in mdx mouse. Jpn J Physiol. 2002;52(1):111-120.Yamaguchi M, Hashizume M. Effect of beta-alanyl-L-histidinato zinc on protein components in osteoblastic MC3T3-El cells: increase in osteocalcin, insulin-like growth factor-I and transforming growth factor-beta. Mol Cell Biochem. 1994;136(2):163-169.Yamaguchi M, Kishi S. Effect of zinc-chelating dipeptide on bone metabolism in weanling rats: comparison with beta-alanyl-L-histidinato zinc-related compounds. Peptides. 1994;15(4):671-673.Yamaguchi M, Kishi S. Prolonged administration of beta-alanyl-L-histidinato zinc prevents bone loss in ovariectomized rats. Jpn J Pharmacol. 1993;63(2):203-207.Yoshikawa T, Naito Y, Tanigawa T, et al. The antioxidant properties of a novel zinc-carnosine chelate compound, N-(3-aminopropionyl)-L-histidinato zinc. Biochim Biophys Acta. 1991;1115(1):15-22.Research & Summary
Polaprezinc (zinc L-carnosine), an anti-ulcer drug which is a chelate compound consisting of zinc and L-carnosine, has been used in a number of studies in which it demonstrates an ability to protect against gastric mucosal injury. It inhibited indomethacin-induced apoptosis in a rat gastric mucosal cell line in a dose-dependent manner, apparently by suppressing activation of caspase-3, which plays a role in cell death by cleaving cellular protein substrates. An antioxidant mode of action was not observed in this study, and the zinc, rather than the L-carnosine, was thought to be responsible for the caspase-3 inhibition. In another study, polaprezinc was shown to inhibit Helicobacter pylori-associated gastritis in gerbils. The authors believe the agent scavenged monochloramine, which has been associated with H. pylori-associated gastric mucosal injury. Rats administered zinc L-carnosine were protected against acetic-acid induced colonic mucosal injury in another study. The effect was attributed to induction of heat shock protein 72 and suppression of nuclear factor kappa B (NF-kB). The heat shock proteins are thought to have cytoprotective functions in the presence of various stressors. NF-kB is involved in inflammation. These authors concluded that zinc L-carnosine may have significant potential as a new therapeutic drug for inflammatory bowel disease.
More recently, a number of studies have suggested a possible role for zinc L-carnosine in the treatment of chronic hepatitis C infection. Human subjects with this disease were randomly administered 150 mg of polaprezinc daily for 48 weeks in combination with the drugs interferon and ribavirin and 300 mg of vitamin E and 600 mg of vitamin C daily or, in the case of the controls, the same regimen devoid of the zinc L-carnosine supplement. Increase in transaminase was significantly prevented in those receiving the zinc L-carnosine, compared with controls. The authors of this study concluded that the zinc L-carnosine supplementation thus reduced hepatocyte injury during the treatment period and attributed this favorable effect to an antioxidative action.
In another recent study of 14 patients with hepatitis C-related chronic liver disease, subjects were given polaprezinc 225 mg/day for six months along with other medications. The zinc L-carnosine supplement was credited in this study with a significant decrease in iron overload, thought to have resulted from the supplement's anti-inflammatory activity in the liver. The authors recommend zinc L-carnosine as a complementary therapy for hepatitis C-related chronic liver disease.
Also recently, another group of researchers has shown that polaprezinc attenuates liver fibrosis in a mouse model of non-alcoholic steatohepatitis. An inhibition of inflammation and lipid peroxidation was reported. Oral supplementation with polaprezinc for 24 weeks resulted in benefit to patients with early cirrhosis, again primarily due to hepatitis C infection, compared with controls.
The extent to which zinc L-carnosine supplementation can be liver-protective in healthy individuals is unknown. More research is needed and warranted.
Noting that polaprezinc has exhibited various antiapoptotic effects in the gut, researchers have recently examined the effects of this substance on radiation-induced apoptosis in rat jejunal crypt cells. Pretreatment with the agent significantly reduced the number of apoptotic cells. Whether this could be of benefit in ameliorating damage related, for example, to radiotherapy for pelvic malignancies demands further study.
Contraindications, Precautions & Adverse Reactions
Contraindications
Zinc L-carnosine dietary supplements are contraindicated in those who are hypersensitive to any component of a zinc L-carnosine-containing supplement.
Precautions
Those who wish to try a zinc L-carnosine supplement for a health condition should first discuss its use with his or her physician.
Because of the lack of long-term safety studies on zinc L-carnosine dietary supplements, pregnant women and nursing mothers should avoid their use.
Adverse Reactions
No reports.
Interactions
Drugs
H2 blockers (cimetidine, ranitidine, famotidine): The combination of an H2 blocker and zinc L-carnosine may be more effective than when each agent is used alone.
Sucralfate: The combination of the cytoprotectant sucralfate and zinc L-carnosine may be more effective than when each agent is used alone.
Nutritional Supplements
No known interactions.
Food
No known interactions.
Herbs
No known interactions.
