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MINI REVIEW ARTICLE Effects of dietary components on testosterone metabolism via UDP-glucuronosyltransferase

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MINI REVIEW ARTICLE Effects of dietary components on testosterone metabolism via UDP-glucuronosyltransferase
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    MINI REVIEWARTICLE published: 08 July 2013doi: 10.3389/fendo.2013.00080 Effects of dietary components on testosterone metabolismvia UDP-glucuronosyltransferase Carl Jenkinson,Andrea Petroczi and Declan P. Naughton*  School of Life Sciences, Kingston University, Kingston uponThames, UK  Edited by:  Lena Ekström, Karolinska Institutet,Sweden Reviewed by:  Cheryl A. Frye, University of Alaska Fairbanks, USALena Ekström, Karolinska Institutet,Sweden *Correspondence:  Declan P. Naughton, School of Life Sciences, Kingston University,Penrhyn Road, Kingston uponThames, Surrey KT1 2EE, UK e-mail: d.naughton@kingston.ac.uk  The potential interference in testosterone metabolism through ingested substances hasramifications for: (i) a range of pathologies such as prostate cancer, (ii) medication contra-indications, (iii) disruption to the endocrine system, and (iv) potential confounding effectson doping tests. Conjugation of anabolic steroids during phase II metabolism, mainly dri-ven by UDP-glucuronosyltransferase (UGT) 2B7, 2B15, and 2B17, has been shown to beimpaired  in vitro   by a range of compounds including xenobiotics and pharmaceuticals. Fol-lowing early reports on the effects of a range of xenobiotics on UGT activity  in vitro  , thework was extended to reveal similar effects with common non-steroidal anti-inflammatorydrugs. Notably, recent studies have evidenced inhibitory effects of the common foodstuffsgreen tea and red wine, along with their constituent flavonoids and catechins.This reviewamalgamates the existing evidence for the inhibitory effects of various pharmaceutical anddietary substances on the rate of UGT glucuronidation of testosterone; and evaluates thepotential consequences for health linked to steroid levels, interaction with treatment drugsmetabolized by the UGT enzyme and steroid abuse in sport. Keywords: UGT2B17, inhibition, testosterone, glucuronidation, green tea, red wine, catechins, flavonoids INTRODUCTION As a major route for excretion of exogenous and endogenouscompounds, there is considerable interest in the roles of theUDP-glucuronosyltransferase (UGT) family, which has led towidespread investigations of their potential effects in health anddisease (1–4). In particular, genetic and chemical modification of UGT activity relating to steroid metabolism has ramificationsfor a range of pathologies such as prostate cancer, medicationcontra-indications,disruptiontotheendocrinesystem,andpoten-tial confounding effects on doping tests in sport. Therefore, it istimelytoreviewlifestylefactorsthataffectUGTactivity.Variationsin the activity of UGT isozymes occur as a result of gender andethnic srcins giving different levels of expression of UGT formsandalteredratiosof testosterone/epitestosteroneexcretedinurine(5). In addition to genetic variations, from a steroid metabolismviewpoint, one current focus of investigation is on the regulationof specific UGT activity via induction or inhibition by exogenouscompounds such as pharmaceuticals and dietary components.Several reports show induction of UGT activity by a range of compoundsincludingphytochemicalsandpharmaceuticals(6–8). Early studies reported the effects of drugs and dietary compoundsonUGTactivityinisolatedmicrosomesorinratswithoutdetailingthe specific UGT isozymes involved (9,10). Liver microsomal glu- curonidation of estradiol and estrone was inhibited by green andblack teas, along with a constituent catechin [(-)-epigallocatechingallate] and several flavonoids (kaempferol, quercetin, rutin,flavone, naringenin, hesperetin) (11). Green tea polyphenols hadastronginhibitory effectof glucuronidation  in vitro   and showedasmallincreaseinliverglucuronidationactivityagainstestroneandestradiol was observed  in vitro   in rats with green tea as the solefluid source (11). Consequent alterations in steroid metabolismhave been debated to have a range of putative effects includingvarying responses to doping tests, inter-medication interactions,and susceptibility to developing cancer (2, 12). From a treatment perspective, the roles of common com-pounds, including dietary components have been investigated asUGT inhibitors with a view to enhancing bioavailability of drugs.This approach to impairing metabolism and thus increasing thehalf-lives of drugs has been the subject of patent protection for awide range of drugs (raloxifene, 2-methoxyestradiol, irinotecan,estradiol, labetalol, dilevalol, zidovudine, and morphine) usingnumerous inhibitors from plant srcin (epicatechin gallate, epi-gallocatechin gallate,octyl gallate,propyl gallate,quercetin,tannicacid,benzoin gum,capsaicin,dihydrocapsaicin,eugenol,gallocat-echin gallate, geraniol, menthol, menthyl acetate, naringenin, all-spice berry oil,  N  -vanillylnonanamide, clovebud oil, peppermintoil, silibinin, and silymarin) (13). Regulation of UGTs by phyto-chemicalshasbeenreviewedwithafocusoncancerprevention(3).The aim of this review is to present a critical evaluation of thecurrent literature on dietary effects on steroid clearance. To date,the reports have focused on  in vitro   studies using supersomes,microsomes, and enzymes model systems, with reports of   in vivo  studieswithafocusonUGT2B17arelacking.Thus,itisappositetogenerate a fuller understanding of the role of dietary componentsbefore  in vivo   studies are undertaken. PHARMACEUTICALINHIBITORSOFUGTSTEROIDGLUCURONIDATION Earlyreportsdemonstratedthatanumberof compoundsinterferewith the activity of UGT2B17 which is the major isozyme forclearance of anabolic steroids, having greater than double theactivity of the next most active form UGT2A1. Sten et al. www.frontiersin.org  July 2013 |Volume 4 | Article 80 |  1    Jenkinson et al. Dietary inhibition of UGT2B17 FIGURE 1 | Structures of testosterone (1) and selected inhibitors: epicatechin (2), quercetin (3), and epigallocatechin gallate (4) . (14, 15) reported that epitestosterone and two non-steroidal anti- inflammatorydrugs(NSAID)actascompetitiveinhibitorsagainstUGT2B17. Using human microsomes and recombinant enzymesthey demonstrated that diclofenac and ibuprofen inhibited testos-terone glucuronidation without having significant effects onepitestosterone glucuronidation. Similar inhibitory effects ontestosterone glucuronidation were reported for both UGT2B15and UGT2B17 isozymes in  in vitro   studies. The authors measuredIC 50  values for diclofenac inhibition of testosterone glucuronida-tion by UGT2B15 and UGT2B17 of 25 µ M and 65 µ M respec-tively,attestosteroneconcentrationsof10 µ M.ThecorrespondingIC 50  values for ibuprofen were 121 µ M and 1340 µ M againstUGT2B15 and UGT2B17 respectively. Kinetic experiments usingDixon plots revealed that the diclofenac acts through competitiveinhibition.To date, no commensurate studies have been reported demon-strating an effect of pharmaceuticals on testosterone glucuronida-tion  in vivo  . A recent report showed only a slight modificationbut no significant effects of concomitant use of maximum recom-mended doses of ibuprofen or diclofenac with testosterone on theurinary ratios of testosterone/epitestosterone in individuals witheither two, one, or no allele of the UGT2B17, and no effect whenibuprofen/diclofenac was administered prior to single dose of testosterone (16). Given the competitive nature of the inhibition,at least for diclofenac,the experiment was limited by restriction tomaximum doses of the NSAID. Thus, doses of 50mg × 3 per day of the single competitive inhibitor, although well reasoned, may not elicit an inhibitory effect given that ibuprofen can also elevateUGTenzymeactivity  in vivo   (8).Althoughreportsof   in vivo   stud-ies are lacking to date, the potential effects of inhibiting majortestosterone-metabolizing enzymes warrants further exploration,especially if common substances are considered where maximumdosage effects do not limit intake. From one standpoint, thiseffect could alter the results of a doping test which is based onthe ratio of the glucuronidated testosterone and epitestosterone.Following these advances, researchers have recently explored theeffects of dietary components on steroid metabolism. The chemi-cal structures of testosterone and selected inhibitors are shown in Figure 1 . DIETARYINHIBITORSOFUGTSTEROIDGLUCURONIDATION Given the growing body of literature regarding: (i) key roles forUGT enzymes in the metabolism a wide range of endogenousand exogenous compounds, (ii) the increasing understanding of the specificity UGT isozymes for varying substrates, and (iii)the roles of many common substances in elevating UGT activ-ity   in vivo   and reducing UGT activity   in vitro  ; studies on the rolesof dietary components on testosterone glucuronidation  in vitro  were warranted.Jenkinson et al. (17) first reported the effects of dietary greenand white teas on the activity of UGT2B17 toward testosteroneglucuronidation. Using an high performance liquid chromatogra-phy (HPLC) assay, testosterone glucuronidation was monitoredin the presence of tea extracts using human UGT2B17 super-somes. Under the conditions studied, green and white tea prepa-rations inhibited the reaction by circa 20% with a white tea Frontiers in Endocrinology  | Experimental Endocrinology  July 2013 |Volume 4 | Article 80 |  2    Jenkinson et al. Dietary inhibition of UGT2B17 Table 1 | Inhibitory profiles for intact foods and catechins.Foods Testosterone glucuronidation rate(ng/mL/min/mg protein) Testosterone control (12 µ g/mL) 682.09 ± 30.73Cacao beans 666.22 ± 23.55Cacao block 572.89 ± 20.14White tea beard 249.83 ± 18.87White tea leaf 246.22 ± 16.61Green tea 179.56 ± 22.64White tea powder 69.57 ± 11.04 Catechin (250 µ M) Testosterone glucuronidation rate(ng/mL/min/mg protein) Testosterone control (10 µ g/mL) 453.77 ± 10.24Gallocatechin 446.25 ± 37.92Caffeine 441.25 ± 23.75Epigallo catechin 420.42 ± 27.08( − ) Epicatechin 352.08 ± 20.42( + ) Epicatechin 264.17 ± 15.83Epicatechin gallate 143.75 ± 13.75Epigallocatechin gallate 99.17 ± 19.17Catechin gallate 70.42 ± 7.92 powder inhibiting glucuronidation by 30%. HPLC analysis of the teas revealed key constituents such as epicatechin (EC) andepigallocatechingallate(EGCG).AnalysisviaaDixonplotrevealedthatEGCGwasactingasacompetitiveinhibitorwithanIC 50  valueof 64 µ Mwhichequaledthatfoundpreviouslyfordiclofenac(15).At a concentration of 1mM,EC inhibited testosterone (at 10 µ M)glucuronidation by some 55% (17).Furtherstudiesbytheauthors,usingadifferentHPLCmethod,revealed that cacao also inhibits UGT2B17 but to a lesser extent(ca. 15%) as shown in  Table 1  (18). Under these conditions,at testosterone concentrations of 12 µ g/mL, white and green teapreparationsinhibitedover70%ofactivitywithawhiteteapowderform showing inhibition of some 90% ( Table 1 ). For the individ-ual phenolics, inhibition was insignificant for gallocatechin andcaffeine but ranged up to 22 and 42% for ( − ) epicatechin and ( + )epicatechin respectively ( Table 1 ). As shown in  Table 1 , extensiveinhibition of testosterone glucuronidation was observed for epi-catechin gallate (ca. 70%), epigallocatechin gallate (ca. 78%), andcatechin gallate (ca. 90%) (17).Analysisof theteaandcacaosamplesbyHPLC(17,18)revealed the catechins displayed in  Table 1  were present in these samplesat lower levels in comparison to the tea samples. The cacao sam-ples, whilst inhibiting testosterone glucuronidation, did so at amuch lesser rate than the tea samples which could be linked withhaving lower levels of inhibiting catechin compounds at the sameconcentrations of the tea samples.In addition, red wine and its constituents were shown toinhibit testosterone glucuronidation by human UGT2B17 super-somes (19). Under the conditions studied, red wine inhibitedglucuronidation by up to 70% over a 2-h period, with littleeffect arising from the alcohol content. Phenolic componentswere selected following HPLC analysis of the selected red wineand quercetin, caffeic acid, and gallic acid inhibited UGT2B17testosterone glucuronidation by 72, 22, and 9% respectively, withconcentrations of phenolic:testosterone of 100 µ M:250 µ M. Forthe most active phenolic, reducing the quercetin concentration to2 µ M, maintained inhibition of 20% in spite of the 10-fold excessof testosterone. DISCUSSIONANDFUTUREDIRECTIONS Based on the observed effect  in vitro  , the presence of flavonoidsand catechins in a wide range of foodstuffs points to the poten-tial for interaction  in vivo   with UGT2B17 activity. However, toour knowledge this has yet to be investigated in a clinical set-ting. Studies have shown oral administration of green tea extractcatechins in rats lead to increased plasma testosterone as well aselevatingotherhormonesover8weeks(20).Theshorttermeffectsof iP administration EGCG in rats over 7days found a number of hormonesinserumdroppedincludingtestosterone,howeverhor-mone levels remained the same when EC,epigallocatechin (EGC),and epicatechin-3-gallate (ECG) were administered (21).Dietary components inhibiting UGT2B17 could have clini-cal significance in altering the risk for prostate cancer. A recentreview (2) highlights a number of studies that demonstrate anincrease risk of prostate cancer with altered UGT2B17 function,althoughinthemidstofconflictingevidence,determiningthecon-sequence of UGT2B17 polymorphism in prostate cancer risk hasremained inconclusive. In a clinical setting catechins have beenanalyzed more for their apoptotic activities on prostate cancercells rather than the links between endocrine levels and prostatecancer (22).Clearly, the confounding issue of the contrasting effects of ele-vating enzyme activity, perhaps by induction, and concomitantchemical inhibition of the enzyme, will require rigorous inves-tigation. We need to considerably further our knowledge of theeffectsof dietonthekeyUGTisozymesinvolvedinsteroidmetab-olism. This includes effects and mechanisms leading to elevationof enzyme activity but also gaining a full profile of inhibitors.Given the potential for varied responses in different tissues, theroles of UGT2B17 inhibitors as endocrine disrupters (23), devel-oping androgen related pathologies, and in contra-indications tomedicines still warrants full investigation. REFERENCES 1. Angstadt AY, Berg A, Zhu J, MillerP, Hartman TJ, Lesko SM, etal. 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Chung LY, Cheung TC, Kong SK,Fung KP, Choy YM, Chan ZY, etal.Inductionofapoptosisbygreentea catechins in human prostatecancerDU145cells. LifeSci   (2001) 68 :1207–14. doi:10.1016/S0024-3205(00)01020-123. Turgeon D, Carrier JS, ChouinardS, Bélanger A. Glucuronida-tion activity of the UGT2B17enzyme toward xenobiotics.  Drug Metab Dispos   (2003)  31 :670–6.doi:10.1124/dmd.31.5.670 Conflict of Interest Statement:  Theauthors declare that the research wasconducted in the absence of any com-mercial or financial relationships thatcould be construed as a potential con-flict of interest. Received: 30 April 2013; paper pending  published: 19 May 2013; accepted: 20  June2013;publishedonline:08July2013.Citation: Jenkinson C, Petroczi A and Naughton DP (2013) Effects of dietary components on testosterone metabolismvia UDP-glucuronosyltransferase.Front. Endocrinol.  4  :80. doi:10.3389/fendo.2013.00080 This article was submitted to Frontiers in Experimental Endocrinology, a specialty of Frontiers in Endocrinology.Copyright © 2013 Jenkinson, Petroczi and Naughton. This is an open-access article distributed under the terms of the Creative Commons Attribution License,which permits use, distribution and reproduction in other forums, provided the srcinal authors and source are cred-ited and subject to any copyright notices concerning any third-party graphics etc. Frontiers in Endocrinology  | Experimental Endocrinology  July 2013 |Volume 4 | Article 80 |  4
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