Electrospray and atmospheric pressure chemical ionization tandem mass spectrometric behavior of eight anabolic steroid glucuronides

Kuuranne, Tiia; Vahermo, Mikko; Leinonen, Antti; Kostiainen, Risto

doi:10.1016/s1044-0305(00)00135-5

Cited by 99 publications

(81 citation statements)

References 31 publications

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“…Collision gas and lens offset voltages were optimized using either [M ϩ NH 4 ] ϩ or [M ϩ H] ϩ as precursor ions to yield maximum intensity of two characteristic product ions (dwell time 350 ms) per analyte. Formation of characteristic ions, mainly those resulting from the cleavage of glucuronide moiety with further losses of one or two water molecule(s), was in good agreement with the steroid glucuronides discussed earlier (Kuuranne et al, 2000). The data were collected and processed with Analyst 1.1 software (Applied Biosystems/MDS Sciex).…”

Section: Kuuranne Et Alsupporting

confidence: 74%

Glucuronidation of Anabolic Androgenic Steroids by Recombinant Human Udp-Glucuronosyltransferases

Kuuranne¹,

Kurkela²,

Thevis³

et al. 2003

Drug Metab Dispos

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ABSTRACT:A multidimensional study on the glucuronidation of anabolic androgenic steroids and their phase I metabolites by 11 recombinant human UDP-glucuronosyltransferases (UGTs) was carried out using liquid chromatographic-tandem mass spectrometric analyses. Large differences between the enzymes with respect to the conjugation profiles of the 11 tested aglycones were detected. Two UGTs, 1A6 and 1A7, did not exhibit measurable activity toward any of the aglycones that were examined in this study. Regioselectivity was demonstrated by UGTs 1A8, 1A9, and 2B15 that preferentially catalyzed hydroxyl glucuronidation at the 17␤-position. Most of the other enzymes glucuronidated hydroxyl groups at both the 3␣-and the 17␤-positions. Clear stereoselectivity was observed in glucuronidation of diastereomeric nandrolone metabolites (5␣-estran-3␣-ol-17-one and 5␤-estran-3␣-ol-17-one), whereas such specificity was not seen when analogous methyltestosterone metabolites were assayed. UGTs 1A1, 1A3, 1A4, 1A8, 1A9, 1A10, 2B4, 2B7, and 2B15 readily glucuronidated 5␣-androstane-3␣,17␤-diol, but none of them exhibited methyltestosterone glucuronidation activity. In agreement with the latter observations, we found that the methyltestosterone glucuronidation activity of human liver microsomes is extremely low, whereas in induced rat liver microsomes it was significantly higher. The homology among UGTs 1A7 to 1A10 at the level of amino acid sequence is very high, and it was thus surprising to find large differences in their activity toward this set of aglycones. Furthermore, the high activity of UGT1A8 and 1A10 toward some of the substrates indicates that extrahepatic enzymes might play a role in the metabolism of anabolic androgenic steroids.

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Section: Kuuranne Et Alsupporting

confidence: 74%

Glucuronidation of Anabolic Androgenic Steroids by Recombinant Human Udp-Glucuronosyltransferases

Kuuranne¹,

Kurkela²,

Thevis³

et al. 2003

Drug Metab Dispos

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“…The product ion spectrum of this metabolite produced the same m/z 241 fragment ion corresponding to the sulfated glucose, which we have observed in the product ion spectrum of the glucosylsulfate conjugate of ARQ 501. Hence, this fragment appears to be a marker for glucosylsulfate conjugation just as the 175 m/z and 113 m/z fragment ions are specific markers for glucuronide conjugation (Kuuranne et al, 2000;Kostiainen et al, 2003). This is an important observation given that we have been unable to obtain any NMR data for this metabolite, primarily due to the synthetic difficulties in preparing an authentic The only other report of glucosylsulfate metabolites in plants involves the metabolism of phenmedipham in sugar beets to 2-O-sulfate glucosides (Lamoureux, 1989).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Glucosylsulfate Conjugate as a Metabolite of 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, β-Lapachone) in Mammals

Savage¹,

Tyler²,

Miao³

et al. 2008

Drug Metab Dispos

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ARQ 501 (Fig. 1) is an investigational anticancer agent that consists of a fully synthetic small molecule (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione, ␤-lapachone, molecular mass 242 Da) in a stable HP␤CD formulation suitable for intravenous administration. In preclinical studies in vitro (Docampo et al., 1979; SchaffnerSabba et al., 1984;Chau et al., 1998;Li et al., 2000) and in vivo (Li et al., 1999;Ough et al., 2005), ARQ 501 showed activity against a variety of cancers. In a phase Ib clinical study, ARQ 501 showed promising anticancer activity against pancreatic cancer when administered in combination with gemcitabine. ARQ-501 is currently in several phase II cancer trials.Most pharmaceutical products (ϳ80%) that undergo biotransformation are cleared by the phase I cytochrome P450 enzymes (Coughtrie and Fisher, 2003). However, it is widely known that a second class of enzymes, the phase II enzymes, also plays a significant role in drug metabolism. Among the most common phase II enzymes are the UDPglucuronosyltransferases (UGTs), the sulfotransferases (SULTs), and the glutathione transferases (GSTs). Phase II metabolites are easily identified by mass spectrometry, as these biotransformation pathways are well characterized and the metabolites easily predicted by looking for mass differences when comparing the parent drug with its metabolite. For example, glucuronide, sulfate, and glutathione metabolites are easily predicted by an increase in mass of 176, 80, and 305 Da, respectively, to the mass of the parent drug (Kostiainen et al., 2003;Levsen et al., 2005). Over the last decade, highly sensitive and specific analytical techniques such as LC/MS/MS, high resolution quadrupole-time-of-flight (Q-Tof) mass spectrometry, and LC/NMR have been widely applied to the study of drug metabolism. Not surprisingly, this has led to the recent discovery of a number of novel metabolites (Jaggi et al., 2002;Miao et al., 2005;Chang et al., 2006;Endo et al., 2007) and, in some cases, to the discovery of novel metabolic pathways (Tang et al., 2003;Yin et al., 2003;Zhen et al., 2006). Although many studies have been conducted on ␤-lapachone (ARQ 501), there have been no previous reports on its metabolism either in animals or in humans. Preliminary metabolism studies for this compound were conducted with plasma from mice dosed intraperitoneally and rats dosed intravenously at 40 mg/kg with ARQ 501 formulated with HP␤CD. Later analyses were performed with human plasma samples obtained from a clinical study. In all species, the majority of conjugated product corresponds to glucuronidation or sulfation, but one metabolite representing a minor proportion of conjugate does not correspond to any commonly expected phase II metabolic process. The present study was conducted to characterize this rare metabolite, which has been identified as a novel glucosylsulfate conjugate. There are several accounts of a similar metabolic process occurring in cotton plants that were exposed to pesticides including profenofos (Capps et al.,...

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“…The analysis of steroids has been carried out by gas chromatography-mass spectrometry (GC-MS) [10][11][12][13][14][15][16], liquid chromatography-mass spectrometry (LC-MS) [17][18][19], electrospray mass spectrometry (ESI-MS) [20][21][22][23][24], atmospheric pressure chemical ionization mass spectrometry (APCI-MS) [25], matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) [26][27][28], and immunoassay [29]. Although GC-MS approaches are highly sensitive, they have some limitations due to the need for multistep derivatization procedures for these thermally-labile compounds, especially those that contain large numbers of hydroxyl groups [9,30,31]. In recent years, ESI-MS has been widely used for steroid analysis [32][33][34].…”

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confidence: 99%

Novel Fragmentation Pathways of Anionic Adducts of Steroids Formed by Electrospray Anion Attachment Involving Regioselective Attachment, Regiospecific Decompositions, Charge-Induced Pathways, and Ion–Dipole Complex Intermediates

Rannulu

Cole

2012

J. Am. Soc. Mass Spectrom.

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Electrospray and atmospheric pressure chemical ionization tandem mass spectrometric behavior of eight anabolic steroid glucuronides

Cited by 99 publications

References 31 publications

Glucuronidation of Anabolic Androgenic Steroids by Recombinant Human Udp-Glucuronosyltransferases

Glucuronidation of Anabolic Androgenic Steroids by Recombinant Human Udp-Glucuronosyltransferases

Identification of a Novel Glucosylsulfate Conjugate as a Metabolite of 3,4-Dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (ARQ 501, β-Lapachone) in Mammals

Novel Fragmentation Pathways of Anionic Adducts of Steroids Formed by Electrospray Anion Attachment Involving Regioselective Attachment, Regiospecific Decompositions, Charge-Induced Pathways, and Ion–Dipole Complex Intermediates

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