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  Year: 2012 | Volume: 3 | Issue: 3 | Page No.: 61-74
DOI: 10.17311/pharmacologia.2012.61.74
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Pharmacological and Toxicological Considerations of Homogentisic Acid in Alkaptonuria

D.P. Williams, Amy Lawrence and Xiaoli Meng

Background: Patients with alkaptonuria are exposed to a high body-burden of homogentisic acid, due to a genetic deficiency of the enzyme homogentisate 1,2-dioxygenase. Younger patients appear to be more robust at withstanding or adapting to this chemical stress. As the patients age, the deposition of ochronotic pigments appears in connective tissues. This is thought to lead to the weakening of tissues and development of osteoarthritis. Currently, there is no marketed drug to treat alkaptonuria and the disease is managed through non-steroidal anti-inflammatory agents. Results: This review considers potential pharmacological strategies for increasing the excretion of homogentisic acid, with the goal of reducing the exposure of patient tissues to this acid. In order to define these strategies, we need to understand the processes by which low molecular weight compounds are handled by the body and enzymatically manipulated into forms which are more easily excreted. These processes are more commonly referred to as drug metabolism and are well understood within the pharmaceutical industry, who are required to design drugs that can reach pharmacological targets at a concentration required to achieve efficacy. Drug metabolism consists of phase I and phase II reactions. Phase I reactions (oxidation, reduction or hydrolysis) are required to increase the chemical reactivity of a molecule by adding or uncovering a more reactive chemical group. Phase II reactions add a polar, hydrophilic conjugate molecule (glucuronide, sulphate, GSH), increasing the renal excretion. In certain cases, drug metabolism can produce reactive and potentially toxic metabolites which can bind to DNA leading to carcinogenesis, or bind to protein leading to either direct organ toxicity (e.g., paracetamol) or immune-mediated toxicity (e.g., halothane). Conclusion: A better understanding of these processes within a disease such as alkaptonuria will help design rational patient management strategies through increasing the excretion and reducing the overall body burden of homogentisic acid.
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How to cite this article:

D.P. Williams, Amy Lawrence and Xiaoli Meng, 2012. Pharmacological and Toxicological Considerations of Homogentisic Acid in Alkaptonuria. Pharmacologia, 3: 61-74.

DOI: 10.17311/pharmacologia.2012.61.74






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