| L. Kacugin |
SSAO INHIBITOR SEMICARBAZIDE AS A POTENTIAL DRUG
FOR HUMANS |
| GlobalTrials, Clinical Trial Management, email: Kacugin@gmx.de
|
Semicarbazide-sensitive amine oxidase (SSAO) denotes a family of copper-dependant
glycoproteins. Significant levels of the enzyme are present in human
plasma. The main site for SSAO is within the vascular wall. The properties
of Plasma semicarbazide-sensitive amine oxidase (SSAO) have not been well
defined . The enzyme may be involved in the deamination of circulating
biogenic amines. The enzyme activity was found significantly increased
in blood and tissues in some pathological conditions. The enzyme activity
has been reported to be elevated in diabetes mellitus in accordance with the
severity of the disease. The mean specific activity of SSAO was significantly
elevated in the group of patients having prostate cancer with skeletal metastases.
SSAO activity correlates with serum VEGF levels in lung cancer patients. SSAO
is also known to be up-regulated in inflammation. SSAO is involved in
the formation of formaldehyde, which results from deamination of methylamine.
Increased SSAO-mediated deamination may initiate endothelial injury. Vascular
endothelial injury also is a major contributing factor to burn damages (secondary
necrosis), atherosclerosis, diabetic damages in eyes and the kidneys, peripheral
nerves, as well as other cardiovascular disorders. SSAO is involved in cellular
damage through the formation of reactive aldehydes, hydrogen peroxide and
ammonia from endogenous substrates. Formaldehyde can be generated endogenously.
Formaldehyde, an extremely reactive compound. Both formaldehyde and hydrogen
peroxide are known to be toxic. Hydrogen peroxide is involved in various oxidative
reactions, and can itself be transformed into a hydroxyl free radical. Formaldehyde,
however is more toxic than hydrogen peroxide. The subsequent generation of
formaldehyde and hydrogen peroxide may be responsible for the acute and chronic
cellular damage. It also can cause pain. Free radicals are capable to modify
chemical structures of proteins and nucleic acids, and change their functions.
These highly reactive aldehydes may cause DNA injury. Conventional drugs and
vitamins (without SSAO activities) have been unable to prevent the development
of all complications caused by oxidative stress. However SSAO inhibitors have
been shown to prevent such toxicity.
The enzyme inhibitor Semicarbazide is known to interact easily with compounds
that contain an aldehyde group. Many essential pyridoxal-containing enzymes
are thus inactivated by semicarbazide. All SSAO enzymes are inhibited irreversibly
by semicarbazide. The first experimental study in humans were conducted
in 19571962 in Russia as open pilot trials (cancer semicarbazide-cadmium therapy
and experimental burn treatment). Blocking the SSAO activity by semicarbazide
reduces the development of an inflammatory reaction). It also can reduce
pain. The SSAO-inhibitors also appears able to protect endothelial cells against
toxic effects of free radicals. Semicarbazide can protect against the progressive
vascular complications caused by oxidative stress. Clinical use of semicarbazide
gives the evidence that an inflammatory reaction can be reduced by blocking
the enzymatic activity of the SSAO. Semicarbazide can reduce inflammatory
response in acute burn wounds. The formation of secondary necrosis can be
prevented with semicarbazide. This “proof of principle” identifies
semicarbazide as a potential drug for humans.
