Scientific journal
European Journal of Natural History
ISSN 2073-4972

ROLE XANTHINEOXIDASE IN PATHOGENESIS OF THE GOUT AND ARTHRITISES

Parakhonsky A.P.
Gout is a disease barely investigated at the present time. We know its cause, uric acid, we know the enzyme that converts purines to uric acid, xanthineoxidase, and we have an inhibitor, allopurinol, which acts as an effective preventative agent. However, there are a series of unanswered questions outstanding. The first is why is the relationship between the plasma uric acid and the development of gout so poor? For instance, in chronic renal failure uric acid levels are very significantly elevated, but gout a relatively uncommon problem. Secondly, why is gout a joint disease and why does uric acid not precipitate everywhere else? The solubility of uric acid in synovial fluid is no greater than that of plasma. Perhaps the clearance of uric acid from the joint is the problem, but there are other membrane systems where one might imagine there could be difficulties, but no difficulties arise. Most patients with ischaemic limbs with a degree of renal failure experience no problems. An hypothesis is that the joint itself contributes to urate production making it an environment where super saturation can occur if plasma levels are elevated. If such a mechanism existed, the most likely explanation would be that the enzyme, xanthineoxidase, was up regulated somehow within the synovial membrane.

Our understanding of this enzyme has changed dramatically in the past few years. Firstly, it is now known that the conversion of purines to uric acid is only one of the functions of this redox centres enzyme. There are two other redox centres in the enzyme, one site, which is known to reduce oxygen to superoxide and a other site - an iron sulphur centre whose function is less clear. Recent studies have shown that the enzyme can serially reduce nitrates to nitrites, nitrites to nitric oxide and nitric oxide reacts with superoxide very rapidly to produce peroxynitrite. Nitric oxide, superoxide and peroxynitrite are powerful anti-bacterial systems. This raises the question -does the joint have a powerful anti-bacterial system and is the development of gout a reflection of this process?

Our interest in this area was stimulated when we took note of the fact that the levels of xanthineoxidase were very high in breast milk of lactating mammals (Stevens C.R. et al., 2000). A series of studies have now clearly demonstrated that the function of this enzyme is antibacterial and its purpose to protect the neonatal stomach and perhaps the lactating breast.

Now we shall consider infective and reactive arthropathies. Isolating intact organisms from the joint of patients with a bacteriamia and septicaemia is very difficult and indeed, most bacteraemic and septicaemic illnesses are not associated with an infective arthritis. The synovial membrane - is a fragile structure with multiple vessels for the most part supported by fatty tissue, potentially easily traumatised and able to leak. This structure is necessary for the correct physiological function of the joint allowing cartilage, which is avascular, but metabolic active. It is therefore at risk, and the presence of an antibacterial system, especially for the joint, would minimise this.

The evidence is recently found that the synovial micro vessels have an enhanced capacity to generate reactive nitrogen species and preliminary evidence that isolated synovial endothelial cells have an enhanced capacity prepared with other micro vessels to produce xanthineoxidase. It allows to connect these observations, and suitable experiments to do conclusion. In this presentation, we use teleological centred arguments to develop this hypothesis utilizing examples from other species in the animal kingdom.

The article is admitted to the International Scientific Conference "Present-day problems of experimental and clinical medicine", Thailand (Phuket), 19-27th December, 2007, came to the editorial office on 09.11.07.