Hyaluronidase inhibitors

Flavonoids are well known as inhibitors of hyaluronidase. Li 1950 Rodney et al, reported the effect of several flavonoids on hyaluronidase using in vitro and in vivo methods [79], Knppusamy et al. investigated the structure-activity relationship of die flavonoids as inhibitors of testicular hyaluronidase [80] and hyaluronidase from snake, scorpion, and bee venom [81]. They showed that flavones. flavanols. and chalcones possess the general ability to inhibit hyaluronidase Kinetic investigations showed that these compounds acted as competitive inhibitors [80]. Several hyaluronidase inhibitors were shown to be able to delay the action of snake venom when injected into mice [8ll One caimnt rule out the possible interaction of the flavonoids with other components of the venom, as the inhibitory effects of flavonoids are not specific to hyaluronidase... 

As hyaluronidase plays an important role in fertilization, several investigations dealt with the possible use of hyaluronidase inhibitors as contraceptive... 

Y. Macda, M. Yamamoto, T. Masut, K. Sugfyama, M, Yokota, N. Okada, K. Sugjyama, H. Katayama, and K. NakngomL Hyaluronidase inhibitor in ihe fruit... 

C. Joyce, M Freund, and R. N. Peterson. Contraceptive effects of intravaginal application of aciosui and hyaluronidase inhibitors in rabbit. Contraception isw5 (1979). 

Tissues that contain high molecular weight HA are unusually resistant to invasion and penetration.49 Blood vessels are unable to penetrate joint synovium, cartilage, and the vitreous of the eye. It is also unusual for tumor metastases to develop in these structures. It may be the large size of the HA polymer that also protects such structures from invasion by parasites. The mechanism by which such high molecular weight structures resist hyaluronidase degradation, and avoid the rapid HA turnover characteristic of the rest of the body is not known. Potent hyaluronidase inhibitors may be involved, a class of molecules about which little is known. 

If inhibition of HA degradation by hyaluronidase occurs, then a class of molecules that have not been explored, the hyaluronidase inhibitors, are very important. It can be postulated that with extreme stress, hyaluronidase inhibitors would be found in the circulation as acute phase proteins, the stress response products synthesized by the liver. These would prevent the ever-present rapid destruction and allow levels of HA to quickly increase. 

Circulating hyaluronidase inhibitor activity has been identified in human semm over half a century ago.202 203 Modifications in levels of inhibitor activity have been observed in the serum of patients with cancer,204-205 liver disease,206 and with certain dermatological disorders.207 This area of biology is unexplored, and though some early attempts were made,208-210 and even though a review appeared,211 these hyaluronidase inhibitors have never been isolated nor characterized at a molecular level. 

Inhibitors of mammalian origin, such as the serum inhibitor or heparin, are far more potent than the relatively weak inhibitors of plant origin. Hyaluronidase inhibitors of animal origin would provide a means for enhancing levels of HA in skin, and represent an important research area in attempting to enhance skin moisture. 

The hyaluronasome, because of its ability to respond to extracellular events as well as to the intracellular metabolic state of the cell may contain HA receptors such as RHAMM and CD44, HA synthase enzymes, the hyaluronidases, hyaluronidase inhibitors,247,248 the /i-cxoglycosidascs, and HA-binding proteins such as HABP1.249... 

As aforementioned, derivatives of Vitamin C and their analogs can function as hyaluronidase inhibitors. In particular L-ascorbic acid-6-hexadecanoate is a potent inhibitor (A. Botski, et al., pers. commun.). Vitamin C itself, D-isoascorbic acid, and dehydroascorbic acid are also inhibitors 262 Thus, some of the ability of Vitamin C to enhance HA deposition may be attributed to its inhibiton of hyaluronidase. 

Fiszer-Szafarz, B., Demonstration of a new hyaluronidase inhibitor in serum of cancer patients, Proc. Soc. Exp. Biol. Med., 129, 300, 1968. 

Snively, G.G. and Glick, D., Mucolytic enzyme systems. X. Serum hyaluronidase inhibitor in liver disease, J. Clin. Invest., 29, 1087, 1950. 

Moore, D.H. and Harris, T.N., Occurrence of hyaluronidase inhibitors in fractions of electrophoretically separated serum, J. Biol. Chem., 179, 377, 1949. 

Mathews, M.B. et al., Effect of metals on the hyaluronidase inhibitor of human serum. Arch. Biochem. Biophys., 35, 93,1952. 

P. J. Burck and R. E. Zimmerman. An intravaginal contraceptive device for the delivery of an acrosin and hyaluronidase inhibitor. Fert. Ster. 47 314 (1984). 

The partially reduced compound 139 is mentioned in a paper on piperazines as a tranquilizer/ The compound showed moderate activity in several animal tests. The oxo compound 140 is claimed in a patent for heart stimulants, hyaluronidase inhibitors, CNS depressants, and fungicides. ... 

Vitamin C/hyaluronidase Hyaluronidase inhibitor Intercellular ground substance... 

There is strong evidence to indicate that ascorbic acid is involved in some way in the synthesis of physiological hyaluronidase inhibitor. A strong suggestion to this effect is provided by the manifestations of scurvy, resulting... 

Possible Uses of Hyaluronidase Inhibitor and Ascorbic Acid... 

Click, D. Hyaluronidase inhibitor of human blood serum in health and disease. J. Mt Sinai Hosp. 17 207-228 (1950). 

A recent brief report by Shapiro ef a/. (295) indicating that prescorbutic guinea pigs have increased rather than decreased PHI levels is difficult to reconcile with the general pattern. A possible explanation for this apparent contradiction may lie in the finding by Fiszer-Szafarz (117) that serum contains a number of different hyaluronidase inhibitor fractions distinguishable by the use of different laboratory techniques. 

Glick, D., and Sylven, B. Evidence for the heparin nature of the nonspecific hyaluronidase inhibitor in tissue extracts and blood serum. 

Kiriluk. L. B.. Kremen, A. J.. and Glick, D. Mucolytic enzyme sterns. XII. Hyaluronidase in human and animal tumors, and further studies on the serum hyaluronidase inhibitor in human cancer. J. Natl. Cancer Inst.. 10 993-1000,1950. 

A hyaluronidase inhibitor in human blood has been isolated and purified 81). This glycoprotein contains 4% hexosamine and 2% uronic acid and has a molecular weight of about 100,000. 

Isoyama, T., Thwaites, D., Selzer, M. G., Carrey, R. I., Barbucci, R., and Lokeshwar, V. B. (2006). Differential selectivity of hyaluronidase inhibitors towards acidic and basic hyaluronidases. Gfycobiology 16, 11-21. 

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