Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.617373
Title: Inhibitory actions of dietary and pharmaceutical components on steroid glucuronidation
Author: Jenkinson, Carl
ISNI:       0000 0004 5350 4202
Awarding Body: Kingston University
Current Institution: Kingston University
Date of Award: 2014
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Abstract:
Anabolic steroid abuse remains the most potent and frequent form of doping in elite sports, originally utilising synthetic potent anabolic steroids. However, advances in highly sensitive mass spectrometry-based urine drug screens for synthetic anabolic steroids has led to exploits in the illicit use of the natural anabolic steroid testosterone, which is difficult to distinguish between the endogenous form of testosterone. Glucuronidation, performed by UDP glucuronosyltransferases (UGTs), is a key process for inactivation of anabolic steroids before excretion. The key enzyme involved in testosterone glucuronidation is UGT2B17, in contrast to epitestosterone which is mainly glucuronidated by UGT2B7. Changes in the regulation of these enzymes could alter excreted concentrations of these steroids and affect urinalysis, performed to determine testosterone doping in sport. Literature reports reveal alterations to testosterone glucuronidation through inhibition and pharmacogentic variations of UGT2B17, along with the interaction of epitestosterone on testosterone glucuronidation. This study aims to investigate the role of compounds commonly found in dietary substances such as teas and red wine samples, along with pharmaceuticals on UGT mediated testosterone and epitestosterone glucuronidation. The interaction of epitestosterone and stanozolol on testosterone glucuronidation was also investigated. HPLC and LC-MS/MS analysis were used to monitor levels of testosterone and epitestosterone glucuronidation following UGT supersome and microsome based assays in vitro. A rat model was used to investigate the role of diclofenac and stanozolol on excreted testosterone and epitestosterone. An LC-MS/MS method capable of measuring 0.125 ng/mL testosterone and 0.250 ng/mL epitestosterone (deconjugated) in rat blood and urine was optimised and validated. Dietary green and white teas along with red wine inhibit UGT2B17 testosterone glucuronidation and UGT2B7 epitestosterone glucuronidation. The inhibitory activities of constituent catechin and phenolic compounds against these enzymes have been determined. In an in vivo study, stanozolol reduced the long term excretion levels of testosterone, coupled to increased epitestosterone excretion and reduced T/E ratios. On the other hand diclofenac did not appear to alter excreted testosterone and epitestosterone levels, apart from having a short term effect on T/E levels. This study demonstrates the role of dietary, pharmaceutical and steroid interactions on UGT testosterone and epitestosterone glucuronidation, along with an evaluation of the consequences linked with enhanced anabolic steroid levels and anti-doping regulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.617373  DOI: Not available
Keywords: Biological sciences
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