Xanthine oxidase, inhibition

Allomaltol, methyl — see Pyran-4-one, 5-methoxy-2-methyl-Allopurinol applications, 5, 343 metabolism, 1, 237 synthesis, 5, 316, 340 tautomerism, 5, 308 xanthine oxidase inhibition by, 1, 173 Allopurinol, oxy-applications, 5, 343 synthesis, 5, 316 Alloxan... 

Clemens, J.A., Bulkley, G.B., Cameron, J.L., Milligan, F.L., Hutcheon, L., Horn, S.D. and MacGowan, S.W. (1991). Effect of xanthine oxidase inhibition with allopurinol on the incidence and severity of post-ERCP pancreatitis and hyper-amylasaemia in a prospective, randomized, double-blind, placebo-controlled clinical trial of 168 patients. Gastroenterology 100, A270. 

Deitch, E.A., Bridges, W., Baker, J., Ma, L., Grisham, M.B., Granger, D.N., Specian, R.D. and Berg, R. (1988). Haemorrhagic shock-induced bacterial translocation is reduced by xanthine oxidase inhibition or inactivation. Surgery 104, 191-198. 

Pharmacokinetics Allopurinol is approximately 90% absorbed from the Gl tract. Effective xanthine oxidase inhibition is maintained over 24 hours with single daily doses. Allopurinol is cleared essentially by glomerular filtration oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid. 

In patients with severely impaired renal function or decreased urate clearance, the plasma half-life of oxipurinol is greatly prolonged. A dose of 100 mg/day or 300 mg twice a week, or less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels. 

Kurisawa, M. et al.. Amplification of antioxidant activity and xanthine oxidase inhibition of catechin by enzymatic polymerization. Biomacromolecules, 4, 469, 2003. 

Kim, Y.J. et al.. Superoxide anion scavenging and xanthine oxidase inhibition of (-l-)-catechin-aldehyde polycondensates. Amplification of the antioxidant property of (-l-)-catechin by polycondensation with aldehydes. Biomacromolecules, 5, 547, 2004. 

Fuchs P, Haefeli WE, Ledermann, Wenk M (1999) Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase2 and CYP1A2 activities. Eur J Clin Pharmacol 54 869-876... 

In Xanthine oxidase inhibition assay, the SFE extract show almost no bioactivity as the case of the LSE. In the oxygen free radical scavenger assay, the SFE extracts of Schizandrae fructus and Moutan Cortex Radicis were more active than the case of the LSE. 

A Oxygen radical scanvenger, Xanthine oxidase inhibition assay... 

Further support for an Mo=0 group in the reduced states of xanthine oxidase was provided by Mo K-edge EXAFS studies of the Mo(V) state of xanthine oxidase inhibited with pyridine-3-carboxaldehyde and of the Mo(IV) state of alloxanthine-inhibited enzyme (102). Both of these inhibited species showed clear evidence for an Mo=0 group (1.70 A), but neither exhibited an Mo=S distance of 2.15 A, as is observed for the oxidized state of functional xanthine oxidase (8,68,100-102). Comparison of the EPR parameters for model compounds containing the [Mo =0] and [Mo =S] groups also favors the presence of an Mo=0 group in the Mo(V) states of xanthine oxidase (Section IV.C.2) (110). Section VI presents a molecular mechanism for xanthine oxidase that combines the wealth of EPR and EXAFS data available for the various forms of the enzyme (17,64,107-109) with recent developments in model molybdenum chemistry (107-109, 111-113). 

In order to study the structure-activity relationships of phenolics as regards xanthine oxidase inhibition, berberine and eleven other naturally occurring phenolics were tested. The ICJ0 of berberine chloride was 170.74 pM, while that of quercetin (the most potent compound evaluated) was 7.23 pM [216]. 

Berman, P. A., Human, L., and Freese, J. A. (1991). Xanthine oxidase inhibits growth of Plasmodium falciparum in human erythrocytes in vitro. J. Clin. Invest. 88,1848-1855. 

Allopurinol reduces the amount of uric acid in blood and urine by slowing the rate at which the liver produces uric acid. It does this by inhibiting an enzyme, xanthine oxidase. This enzyme normally catalyses the later stages of metabolism of purines to uric acid. As a result of xanthine oxidase inhibition less uric acid is produced. Intermediate metabolites xanthine and hypoxanthine are produced in larger amounts, but these are freely water soluble and eliminated by the kidneys. 

An interesting example of a DDI due to the inhibition of a non-CYP enzyme that can have serious clinical consequences is the inhibition of xanthine oxidase by allopu-rinol 6-mercaptopurine (6-MP) as an antimetabolite type of antineoplastic drug. One of its indications is in the treatment of inflammatory bowel disease. Actually, 6-MP is a prodrug whose active metabolite, 6-thiogua-nine (6-TG) is responsible for its therapeutic activity. Some nonresponders to 6-MP do not form sufficient amounts of 6-TG. A complementary pathway of 6-MP metabolism is oxidation to 6-thiouric acid (6TU), which is mediated by xanthine oxidase. Inhibition of this complementary pathway by allopurinol shunts the metabolism of 6-MP favoring increased formation of 6-TG. 

Fig. 36. Proposed mechanism of xanthine oxidase inhibition by (HSOs) (Data from Ref 178).

Masuoka, N. and Kubo, L, Characterization of xanthine oxidase inhibition by anacardic acids, Biochim. Biophys. Acta, 1688, 245-249, 2004. 

---