Potentially harmful advantage to athletes: a putative connection between UGT2B17 gene deletion polymorphism and renal disorders with prolonged use of anabolic androgenic steroids

Abstract

Background and objectiveWith prolonged use of anabolic androgenic steroids (AAS), occasional incidents of renal disorders have been observed. Independently, it has also been established that there are considerable inter-individual and inter-ethnic differences, in particular with reference to the uridine diphosphate-glucuronosyltransferase 2B17 (UGT2B17) gene, in metabolising these compounds. This report postulates the association of deletion polymorphism in the UGT2B17 gene with the occurrence of renal disorders on chronic exposure to AAS.Presentation of the hypothesisThe major deactivation and elimination pathway of AASs is through glucuronide conjugation, chiefly catalyzed by the UGT2B17 enzyme, followed by excretion in urine. Excretion of steroids is affected in individuals with a deletion mutation in the UGT2B17 gene. We hypothesize that UGT2B17 deficient individuals are more vulnerable to developing renal disorders with prolonged use of AAS owing to increases in body mass index and possible direct toxic effects of steroids on the kidneys. Elevated serum levels of biologically active steroids due to inadequate elimination can lead to prolonged muscle build up. An increase in body mass index may cause renal injuries due to sustained elevated glomerular pressure and flow rate.Testing the hypothesisIn the absence of controlled clinical trials in humans, observational studies can be carried out. Real time PCR with allelic discrimination should be employed to examine the prevalence of different UGT2B17 genotypes in patients with impaired renal function and AAS abuse. In individuals with the UGT2B17 deletion polymorphism, blood tests, biofluid analyses, urinalysis, and hair analyses following the administration of an anabolic steroid can be used to determine the fate of the substance once in the body.Implications of the hypothesisIf the hypothesis is upheld, anabolic steroid users with a deletion mutation in the UGT2B17 gene may be exposed to an increased risk of developing renal disorders. In the current detecting - sanctioning anti-doping system, athletes motivated by the potential to evade detection owing to their unique genetic make-up could subject themselves to a serious health consequence. More research on AAS metabolism in the presence of UGT2B17 gene deletion is required. Benefit - harm evaluations in therapeutic use of anabolic steroids should also consider this potential link between UGT2B17 gene deletion polymorphism and renal disorders.

Inhibitory Effects of Diclofenac on Steroid Glucuronidation in Vivo Do not Affect Hair-Based Doping Tests for Stanozolol

“…Similarly, in another study carried out by Shen et al stanozolol was detectable in guinea pig hair after administering stanozolol at a single high dose of 60 mg/kg, whereas, 3'-hydroxystanozolol was not detectable [20]. However, the method developed for the current study is capable of detecting stanozolol and 3'-hydroxystanozolol in rat hair after administering stanozolol for 6 days at a dose of 5.0 mg/kg/day that is considered equivalent to those levels abused by athletes [6].…”

Genome-wide discovery of chromosomal copy number variants in human amniotic cell using array-based comparative genomic hybridization

“…Additional consistent report has represented that in chromosome 2 PPM1B gene, which is recognized as one of the genes with high frequency in the homozygous deletion of 179 kb, leading to 2p21 deletion syndrome 15 . Also, on chromosome 4 the homozygous loss and loss at identified region of UGT2B17 (uridine diphosphate-glucuronosyltransferase 2B17) gene encoding an enzyme participating in steroid hormones catabolism 16 . A potential link between deletion polymorphism in UGT2B17 gene and renal disorders has been observed in athletes with prolonged use of anabolic androgenic steroids 16 .…”

“…Also, on chromosome 4 the homozygous loss and loss at identified region of UGT2B17 (uridine diphosphate-glucuronosyltransferase 2B17) gene encoding an enzyme participating in steroid hormones catabolism 16 . A potential link between deletion polymorphism in UGT2B17 gene and renal disorders has been observed in athletes with prolonged use of anabolic androgenic steroids 16 . Other study has revealed involvement of deletion variant UGT2B17 in CNV 4q13.2 for osteoporotic pathogenesis 17 .…”

LC-MS/MS-Based Assay for Free and Deconjugated Testosterone and Epitestosterone in Rat Urine and Serum

“…This report of a straightforward novel method of rapid analyses of testosterone and epitestosterone in both rat urine and sera benefits from a new rapid liquid-liquid extraction procedure, suitable for both biofluids. Unlike the predecessors, the proposed method streamlines experimental in vivo designs where simultaneous monitoring of testosterone and epitestosterone in both urine and blood is required, such as investigating the effect and consequences of altered metabolic function in testosterone and epitestosterone glucuronidation [7][8][9][10]. The new method also eliminates potential confounding effects from applying multiple methods to cater for multiple sample matrices.…”

“…Variations in enzyme preference are observed with UGT 2B17 predominating for testosterone glucuronidation, whilst UGT2B7 is the most active UGT for epitestosterone glucuronidation [5]. A variety of effectors of steroid UGT glucuronidation have been identified, including pharmacogenetic variations resulting in different UGT2B17 expression which affects the urinary T/E ratios [6][7][8]. A number of in vitro studies have identified small molecule inhibitors of UGT2B17 and other UGTs toward testosterone metabolism.…”