Influence of androgens upon tryptophan metabolism in man

Vol. 8, Part II, pp . 1193-1199, 1989 . Life Sciences Printed in Great Britain

Pergamon Press

IID?I+II~iCB Qr 11PDROG8113 IIP~i TRYPTOPHAIi YE4~BOLISY IN Y~lf F. YoGiaty and D. P. Rose Departaent aß Chsdoal Pathology, Royal Infirmary, Sheßßiald S6 3DA. (Received 4 July 1969 ; in final form 21 August 1989) TRYPTOPHAN is oo~erted to aiootinio aoid iibomiolsotide ~ a series aß metabolio reaotione, the ßirat aß which involves rupture aß the indole audeus to yield fossylhynurenine sad is catalysed by tryptophsn au~gemau (EC 1 . 13 " 1 . 12) .

An inoreaae in the activity oß thin easyms is husau liver

is brought about b9 hormonal induction ßollosing treatment with cartiaol, and results in as elevated e~xorstioa aß lgnuraaiaé , awl other intermediate me~bolltsa aß the tryptophaa-nicotinic aoid ribonucleotide pathway in urine collected aßter a tryptophan load2. The esoretioa oß tryptophan metabolites ~ women is aignifioaat~y higher than by man ßollowiag as oral dose aR' aaino acid3'~, and ~roaely elevated levels occur is the urine of osatrogsn-treated subjects and wo~ea who are ûeing ooatraoeptive steroid preparations5'6.

Thsrs do not appear to have bsea

arp atndies published aß the effect d aadroge~as on tryptophan mstaboliaw . "e have a:amined thereßase, the influence that androgens sight have upon tryptophsn aetabolism is son, and, is addition, ws have observed their effect oa the urinary e~oretioa oß ttyptophan metabolites follaeiag the administration of oortisol. Yateriala and Yethoda The aubjeota for atu~ were healti~y adult melee aged 21 to 31F years . IIri~ wan collected far 24 h after the administration aß a 5 g oral done oß lrtryptophsn .

1(ynurenine (R), 3-i~dro~]q+nureaiae (Iig), and 3-hydrc~+anthraa

ilio aoid (HA) were determined by the method aß Hsele~r~, and zauthurenio 1193

AI~ROGEN3 AND TRYPTOPHAN METABOLLSM Vol. S, No.22

1194

aoid (L) and ~anraio soil (E") sooordina to the prooedare of Satoh sad Prioi.

?he wins war aot ~drollred before aaal~sir . 1(etlpltutortsrons war

sine rnb~+~~+-~= is a dosa of 24 ~ twine daims, and llesterol+oae (id-setipl5et-androstesons-l7~-01-;-oae, Baharina Ltd. ) war ahan oral],T is a does of 20 sa three Haas s d4" " control tr~ptophan load test war carried ont fini fos ahioh the rabjeot raosind 5 a L-tgptophan at 1400 h. lour dgrs Ltar oortiral X50 a6, was ad~inistered b! intram.oular injection at 0900 h. "a oral dors of trlptaphaa was aiwu 5 h later, and all nriae war oolLoted for the rob.egneat 2~ h period.

"daiairtratioa of dther asttpltatutsraw ar

lluteralama wu oaaa»med on the folloriaa d+V and a third tryptophaa load tent was perfca~ed after 14 dolt traataeat.

The sapsriasat war ooapleted

after a fmrthsr j dqr d aadroaan adsiairtratioa

io

oars7laa ont amther

tgrptophsn load tent 5 h after the injaotiaa of ?,50 ~6 oortisol .

The reraltr are prorated is Tabler i (nei~ltatutsa~ene) cad i (1(utez~

.Sea).

ANDROGENS AND TRYPTOPHAN METABOLISM

Vol . 8, No . 22

1195

TABLE 1 Effsat af IIst2~yltestostsroae oa Tryptophan Ystabolite Bzarstions ~ solsa/2yh) aad on ths $eeponss to Cartiaol Adiinistratioa Snbjeat No . 1

2

3

4

5

~cpt .

Etpt .

E

HE

L

E"

HA

Total

(s)

119

88

108

106

66

487

(b)

576

142

161

209

105

1193

(o)

142

126

118

138

101

625

(d)

221

184

180

190

109

884

(a)

41

47

134

156

29

407

(b)

734

342

238

398

126

1838

(o)

108

77

113

106

113

517

(d)

134

86

122

125

85

552

(a)

85

50

132

172

52

491

(b)

1920

284

250

731

338

3523

(a)

360

139

180

281

88

1048

(d)

912

271

302

551

410

2446

(a)

156

72

127

162

88

605

(b)

1166

437

586

514

202

2905

(a)

90

46

141

122

69

468

(d)

595

302

295

323

167

1682

(s)

662

306

226

742

159

2095

(b)

3168

549

288

875

211

5091

(a)

1430

459

245

954

231

3319

(d)

1872

45a

288

1060

163

3833

(a)

Bkoretioa of netabolitee of ter 5 g L-tryptophaa alone.

(b)

Ezaretion after oortisol injeatlon.

(a)

Ezaretion after 14 days of androgen .

(d)

Szoretion after 17 dava oP androgen and aortiaol injeatiaa.

1198

ANDROGENS AND TRYPTOPHAN METABOLISM

Vol. 8, No. 22

TABLS 2 Sffsot d lleeterolone on Tt7ptophan llstsbolite Ezoretions (~unoles/2bh) aad oua their ~eepoaee to Cortisol Aàainistratian

Snbjeot lfo .

6

7

8

9 10

B:pt .

a

~

L

L

H~

?otal

(a)

132

90

218

280

103

823

(b)

629

510

580

380

168

2263

(o)

108

56

156

204

68

592

(d)

288

235

310

315

137

1~5

(a)

430

229

140

156

198

t149

(b)

1225

610

235

250

3~

2640

(o)

4A8

225

86

103

182

1001~

(d)

1080

560

1~

152

272

219~

(a)

418

235

120

116

198

1087

(b)

1060

470

263

203

265

2261

(e)

300

154

86

114

137

791

(d)

720

311

200

195

190

1616

(a)

216

135

108

233

101

793

(o)

127

97

93

154

64

535

(a)

850

378

302

4?1r

101

2u55

(e)

1~13

248

192

292

107

1252

Bit. (a) to (d) as Table 1 . lostr of the

5

aide snbjsots aoreted a greater total aaouat ad aetabolites is

nriae after 14 dqs treatawat with asti~ltestoaterone üan thq~ did daring the ooatrol tryptophan load test. in

3

lC, Ba and Ht were affeotsd predoainant~Y, althoagh

subjeob there were inorsaees also in the rmoretions

as

L and St .

Yestex"-

olone produced as owesall rednation in the uriaary eroretioas of ssiabolitea in all of the 5 eubjeots, cad again S, ~ and Hl were affeoted to a greater degree than L cad L .

Both aethJltutoetes+one cad ltseteiwloa . oaused s fall in the

Vol . 8, No . 22

ANDROGENS AND TRYPTOPHAN METAHOLLSM

1197

elevatid ezaretian of tsyptophan astsbolites which aaraal~y followed tare 3aduotion of tryptophan aurygaaaee bY oortisol, although the esoretion levels wave still higher than those obtained for the control stadiea . Disonesiea The increased azorstioa of 1C sad other tryptaphaa aetabolites which ooamred is ~ of the 5 subjects folloeiag the adainistratioa of aetlavlteatosteroae wu uaezpeated .

Tsstoateraae oar be converted to oestrogane is vivo became it

poaseassa the O ~-j-ozo group which ie required fca~ tre aroaatisatiaa of rlng ~ is the steroid aolsanls .

The oheaioal structure of Yesterolone does not include

such a group and it is act aetsbolised to osetroganio steroids .

lIe do act lmaw

if the ooaversion of aeth~ltestoateraae to oestrogena wsa responsible for the difference in the response of tryptophaa rtsbolisa to this androgen, sa ooapsrsd to the effect of Yeataa~olone .

The reported variation is the urinary

ezorstioa of trarptophsn astabolites with the stage of the aenatrual oyole~' 9 indicates the effeoti~ensss of relatively sash changes in oestrogen levsL, and ao perhaps the aadrogemio ioflueaoe of asthyltsetoateroae was outweighed ~ the effect of oeatrogans derived lrca it . ltesterolone adainiatratioa caused s radnotion in the eaaretioa of tryptaphaa astabolites, sad both aetl~lteetoatarons and Yeaterolone diminished the elevation of aetsbolite asaretions which noraal]y follows treataent with cortisol .

Ia our view these changes are beat explained ~ as inhibitory cation

of a~lrogeaa on tryptophea oryge~naes aotivitJ such that a reduced propartien of the ammo said load eaters the trJptophaa-~niootiaio said ribomroleotide patkw~ . IPs suggest that in the case of aet~yltsetosterone, perhaps because oestrogsna derived Pros it are proaoting as increase is the asaretion of aetabolitea, this partial inhibition of t:yptophan orygensse is not apparent aiap]y Pros the deteraiaation of astabolitee after s trfptophan load .

However, it beooaea

evident Pros s stud of the levels at uri~ry aeiabolitea when there are detaraired in urine collected after oortisol as-+w+~ tratioa, sad the outputs ooa~ared

AI~ROGENS AND TRYPTOPHAN METABOLISM

1198

Vol . 8, No. 22

with those attained when the easyae is induosd ~ oartisol is the absemoe of aaàrogsa . asgardlsas of the aeohaaio by which androgens rodity the urinar9 ezoretlon of tryptophaa netabolitea is ass the results reported here han reletanoe to the nae of loading teats far the iateatigatiaa of sbnorral trJptophaa aetaboliaa. Diatarbanoea at the t~gptophaa-nicotinic acid riboauoleotide pathway hate basa described is a tarisiy at diseaaesi0 , sad. it has been anggested that a factor which is ooaoa to shy at these is a haraoae-iadnosd rise is tr:ptaphan o~"geaaae sotitity dau to as iaorwsed oortisol secretion rats is rsspamee to the noon-specific stns at illaesai.

The elteota of oeatmgena, oontraoaptite ste-

roids, adreaoocrtiaoateroids and aurasxy an tryptophaa astaboliaa hats bees repasted prstioua],~' 6' 2, sad the present rssnlts show the aeoesaity of eaoluding also patients reoeiting eadrogems fraw clinical studies at tryptaphaa aatabolisw in sisa . ao)morledgeaent The Yestesolane need in thin inreatigstion wan a gift Iron Dr . Y.ß . Briggs at sohariag CheaioaL Ltd.

Thin wori wan supported is part by the British

E.pire Cancer Caapaign tar Beaeeroh . R,aterenoss

o.

1.

a. eL7,7Id11 sad

2.

D. P. BCBE a~ ! . YoGZNi't, Clia

BBD, J. Clic. latest . ~, 1527 (1966)

so . ~, 1 (1968) .

3. a, r. rl~, a. u. n~o~ecaem, D. DoanBK, J. e. aaDEBSaK a~ a. ~. cooD, J. Clia In
D. P. ß0B8, Clin . Chia . iota ~, 221 (1967) .

5.

D. P. soBE, C]in . Soi. ~, 265 (1966) .

6.

J. lI . PRICE, lI . J. 7SOR11TQP sad L. Y. WELLER, aces. J. Clic . Iiutrit. ~0,

452 (i%7) .

a. P . B~LEi, Clin . sol,. ~, 465 (1965) " 8. a. sar~ and J. r. PRICE, J. Biol . che.. ~, 781 (1958) . 7.

Vol . 8, No. 22

ANDZOGEN3 AND TRYPTOPIiAN METABOLISM

9. _. a. naa; a. a. ars~ aaa a. Y. ~cs, a. citu.

~. r., xus~.~o ana c. ~. aouesi, ~a..no ..

1199

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