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Based Quantification of Hydrolyzed Urinary Steroids Published OnlineFirst January 19, 2010; DOI: 10.1158/1055-9965.EPI-09-0581 Cancer Research Article Epidemiology, Biomarkers & Prevention Systematic Error in Gas Chromatography-Mass Spectrometry– Based Quantification of Hydrolyzed Urinary Steroids Ju-Yeon Moon1,2, Young Wan Ha1, Myeong Hee Moon2, Bong Chul Chung1, and Man Ho Choi1 Abstract Gas chromatography-mass spectrometry–based metabolite profiling can lead to an understanding of vari- ous disease mechanisms as well as to identifying new diagnostic biomarkers by comparing the metabolites related in quantification. However, the unexpected transformation of urinary steroids during enzymatic hy- drolysis with Helix pomatia could result in an underestimation or overestimation of their concentrations. A comparison of β-glucurondase extracted from Escherichia coli revealed 18 conversions of 84 steroids tested as an unexpected transformation under hydrolysis with β-glucuronidase/arylsulfatase extracted from Helix pomatia. In addition to the conversion of 3β-hydroxy-5-ene steroids into 3-oxo-4-ene steroids, which has been reported, the transformation of 3β-hydroxy-5α–reduced and 3β-hydroxy-5β–reduced steroids to 3-oxo- 5α–reduced and 3-oxo-5β–reduced steroids, respectively, was newly observed. The formation of by-products was in proportion to the concentration of substrates becoming saturated against the enzyme. The substances belonging to these three steroid groups were undetectable at low concentrations, whereas the corresponding by-products were overestimated. These results indicate that the systematic error in the quantification of uri- nary steroids hydrolyzed with Helix pomatia can lead to a misreading of the clinical implications. All these hydrolysis procedures are suitable for study purposes, and the information can help prevent false evaluations of urinary steroids in clinical studies. Cancer Epidemiol Biomarkers Prev; 19(2); 388–97. ©2010 AACR. Introduction duce deconjugated steroids because sulfate conjugates are not hydrolyzed by E. coli (12-16). There are many naturally occurring steroids that are However, unexpected transformations of steroids excreted mainly through the urine by their water-soluble during hydrolysis could obstruct the analysis. The con- conjugates formed by the substitution of 3- or 17-hydrox- version of 3β-hydroxy-5-ene steroids leads to both 3- yl groups with either sulfate or β-glucuronide (1), and oxo-4-enes as the major products and 6-oxy metabolites their direct measurements have been introduced to clini- as the minor ones with Helix pomatia (14, 16-21). These cal studies (2-5). Gas chromatography-mass spectrometry two actions suggest that they are caused by the presence – β Δ (GC-MS) based profiling is a proven technique in steroid of 3 -hydroxysteroid dehydrogenase/ 5-4-ene steroid analysis, whereas immunoassays have limited applicabil- isomerase and 6-hydroxylase as additional enzymes (17, ity due to cross-reactions (6, 7). However, GC-MS–based 18, 20) in the Helix pomatia extracts. The generation of techniques mainly require the hydrolysis of steroid con- 3-oxo-4-ene steroids might be converted by cholesterol jugates due to their low volatility before instrumental oxidase because 3β-hydroxysteroid dehydrogenase does analysis (8-11), and the need to treat samples with one not require oxygen (16, 17, 21-24), but this has not been of two enzyme solutions, β-glucuronidase and a mixture proven. The variability of the selectivity and reactivity of β-glucuronidase/arylsulfatase, which are extracted of Helix pomatia is also affected by the reaction tempera- from Escherichia coli and Helix pomatia, respectively. The ture, incubation time pH, and amount of enzyme added enzyme solution of Helix pomatia is used widely to pro- (14, 25-27). Metabolite profiling in biological fluids can help un- derstand the metabolic perturbation of biological systems with comprehensive insight by comparing many metabo- Authors' Affiliations: 1Life/Health Division, Korea Institute of Science lites of individual or populations simultaneously (28-31). and Technology and 2Department of Chemistry, Yonsei University, However, the unwanted transformation of steroids dur- Seoul, Korea ing hydrolysis can result in an underestimation or over- Note: Supplementary data for this article are available at Cancer Epide- estimation of their concentrations. Because most of the miology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). cancer progression is correlated with either the inhibition Corresponding Author: Man Ho Choi, Life/Health Division, Korea Institute of Science and Technology, 39-1 Hawolkok-dong, Seoul or promotion of targets in specific molecular pathways, 136-791, Korea. Phone: 82-2-958-5081; Fax: 82-2-958-5059. E-mail: the tests of multiple biomarkers would be focused on [email protected] metabolic pathways and not on a single molecule (32). doi: 10.1158/1055-9965.EPI-09-0581 Although the analytic conditions for this particular study ©2010 American Association for Cancer Research. were optimized, the relative amounts of biomarkers are 388 Cancer Epidemiol Biomarkers Prev; 19(2) February 2010 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst January 19, 2010; DOI: 10.1158/1055-9965.EPI-09-0581 Systematic Error in Hydrolysis of Urinary Steroids Table 1. GC-MS information for quantitative analysis of the steroids studied Compounds Abbreviation Exact Molecular TMS-derivitized Ion Retention (trivial name) mass ion ions* selected† time (min) Androgens 5β-Androstan-3α,17α-diol βαα-diol 292.24 436.32 256, 241, 346, 331, 436, 421 256 11.68 5β-Androstan-3β,17α-diol ββα-diol 292.24 436.32 256, 241, 346, 331, 436, 421 256 12.41 5α-Androstan-3α,17α-diol ααα-diol 292.24 436.32 241, 256, 331, 346, 436, 421 241 12.54 5β-Dihydrotestosterone 5β-DHT 290.22 434.30 434, 405, 419 434 12.98 Androsterone An 290.22 434.30 419, 434, 329 434 14.78 Etiocholanolone Etio 290.22 434.30 419, 434, 329 434 14.96 5β-Androstan-3β,17β-diol βββ-diol 292.24 436.32 256, 241, 346, 331, 421, 436 256 15.15 5α-Androstan-3α,17β-diol ααβ-diol 292.24 436.32 241, 256, 331, 346, 436, 421 241 15.52 5β-Androstan-3α,17β-diol βαβ-diol 292.24 436.32 256, 241, 346, 421, 331, 436 256 15.61 5α-Androstan-3β,17α-diol αβα-diol 292.24 436.32 421, 241, 346, 256, 331, 436 241 16.52 Epidihydrotestosterone Epi-DHT 290.22 434.30 434, 405, 419 434 16.95 11-Keto-androsterone 11-keto-An 304.20 520.32 415, 520, 505 520 17.05 11-Keto-etiocholanolone 11-keto-Etio 304.20 520.32 415, 505, 520 520 17.15 Dehydroepiandrosterone DHEA 288.21 432.29 432, 417, 327 432 17.34 Epiandrosterone Epi-An 290.22 434.30 419, 434, 329 419 17.59 Androstenediol A-diol 290.22 434.30 239, 344, 254, 329, 434, 419 434 18.08 Androstanedione 5α-dione 288.21 432.29 275, 432, 417, 290 432 18.10 Epitestosterone Epi-T 288.21 432.29 432, 417, 327 432 18.27 5α-Androstan-3β,17β-diol αββ-diol 292.24 436.32 241, 421, 346, 256, 331, 436 241 18.35 5αDihydrotestosterone 5αDHT 290.22 434.30 434, 405, 419 434 18.83 Androstenedione A-dione 286.19 430.27 430, 415, 325 430 19.28 Testosterone T 288.21 432.29 432, 417, 301 432 20.02 11β-Hydroxyandrosterone 11β-OH-An 306.22 522.34 522, 327, 507, 417 522 20.23 11β-Hydroxyetiocholanolone 11β-OH-Etio 306.22 522.34 522, 417, 507, 327 522 20.55 16α-Hydroxy-DHEA 16α-OH-DHEA 304.20 520.32 505, 520, 415 505 28.05 16α-Hydroxy- 16α-OH-A- 302.19 518.32 503, 518, 430 503 30.43 androstenedione‡ dione Estrogens 17α-Estradiol 17α-E2 272.18 416.26 416, 285, 401 416 18.12 Estrone E1 270.16 414.24 414, 399, 309 414 18.63 17β-Estradiol 17β-E2 272.18 416.26 416, 285, 401 416 19.48 4-Methoxyestrone 4-MeO-E1 300.17 444.25 444, 429, 414 444 22.24 4-Methoxy-17β-estradiol 4-MeO-E2 302.19 446.27 446, 315, 325, 416 446 23.22 2-Methoxyestrone 2-MeO-E1 300.17 444.25 444, 429, 414 444 24.06 2-Methoxy-17β-estradiol 2-MeO-E2 302.19 446.27 446, 315, 416, 431 446 25.05 2-Hydroxyestrone 2-OH-E1 286.16 502.28 502, 487, 397 502 25.42 2-Hydroxy-17β-estradiol 2-OH-E2 288.17 504.29 504, 489, 373 504 26.26 4-Hydroxyestrone 4-OH-E1 286.16 502.28 502, 487, 397 502 26.87 4-Hydroxy-17β-estradiol 4-OH-E2 288.17 504.29 504, 373, 489 504 27.97 17-Epiestriol 17-epi-E3 288.17 504.29 504, 345, 311, 386, 297, 489 504 28.72 Estriol E3 288.17 504.29 504, 345, 311, 386, 297, 489 504 29.40 16-Keto-17β-estradiol 16-keto-E2 286.16 502.28 487, 502, 399 487 29.70 16α-Hydroxyestrone 16α-OH-E1 286.16 502.28 487, 502, 399 487 29.70 16-Epiestriol 16-epi-E3 288.17 504.29 504, 345, 311, 386, 297, 489 504 30.76 2-Hydroxyestriol 2-OH-E3 304.17 592.33 592, 433, 385 592 36.97 Progestins 5β-Dihydroprogesterone 5β-DHP 316.20 388.24 445, 460, 355 445 19.49 Epipregnanolone Epi-P-one 318.26 462.33 447, 462, 357 447 22.81 Pregnanolone P-one 318.26 462.33 447, 462, 357 447 23.12 (Continued on the following page) www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 19(2) February 2010 389 Downloaded from cebp.aacrjournals.org on September 23, 2021. © 2010 American Association for Cancer Research.
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