Discovery of neurosteroid glucuronides in mouse brain

Kallonen, Sirkku; Tammimäki, Anne; Piepponen, Petteri; Raattamaa, Helena; Ketola, Raimo A.; Kostiainen, Risto

doi:10.1016/j.aca.2009.07.059

Cited by 10 publications

(19 citation statements)

References 28 publications

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“…Determination of tissue steroid hormone in adult male rat high concentrations, and the conjugate forms were also found in higher levels in the adrenal gland (Tables II and III), suggesting that each steroid was glucuronidated after the synthesis in the adrenal gland, as demonstrated in the brain (34). The glucuronide forms of the adrenal steroids CCS and 11-DCC were detected in the blood and whole organs at high concentrations (Table III), suggesting that these glucuronides were delivered to the target cells that express a glucuronide transporter and that the steroid can perform its respective function after deconjugation.…”

Section: Discussionmentioning

confidence: 99%

Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat

Maeda

Tanaka

Suzuki

et al. 2012

The Journal of Biochemistry

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The actual levels of steroid hormones in organs are vital for endocrine, reproductive and neuronal health and disorders. We developed an accurate method to determine the levels of steroid hormones and steroid conjugates in various organs by an efficient preparation using a solid-phase-extraction cartridge. Each steroid was identified by the precursor ion spectra using liquid chromatographyelectrospray ionization timeof-flight mass spectrometry, and the respective steroids were quantitatively analysed in the selected reaction monitoring mode by liquid chromatograph-mass spectrometry/mass spectrometry (LC-MS/MS). The data showed that significant levels of testosterone, corticosterone and precursors of both hormones were detected in all organs except liver. The glucuronide conjugates of steroid hormones and the precursors were detected in all organs except liver, but sulfate conjugates of these steroids were observed only in the target organs of the hormones and kidney. Interestingly, these steroids and the conjugates were not observed in the liver except pregnenolone. In conclusion, an accurate determination of tissue steroids was developed using LC-MS analysis. Biosynthesis of steroid hormones from the precursors was estimated even in the target organs, and the delivery of these steroid conjugates was also suggested via the circulation without any significant hepatic participation.

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Section: Discussionmentioning

confidence: 99%

Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat

Maeda

Tanaka

Suzuki

et al. 2012

The Journal of Biochemistry

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“…To circumvent these problems, column-switching has been added to the analysis of glucuronide conjugates (or in general to drug analysis). One example is the analysis of neurosteroids and their phase I and II metabolites from brain samples [36]. The brain samples contain a large amount of phospholipids, which can interfere with the determination of steroids and their metabolites, even when an SPE technique was utilized to purify the organic extracts of brain samples.…”

Section: Separation In Lc-msmentioning

confidence: 99%

“…Bile, small intestine content Nabumetone Centrifugation + LLE [67] Body fluids (blood, CSF, vitreous humor, urine) Morphine Centrifugation + SPE [140,150] Body fluids (plasma, urine, bile, fecal) Rofecoxib Centrifugation + LLE [200] Brain tissue Neurosteroids SLE (ethanol/acetone), centrifugation, SPE [36] Fingerprint Lorazepam Extraction with dichloromethane/methanol, reconstitution [37] Food samples Chloramphenicol SLE (ethyl acetate) or SPE (C18) [35] Hepatocyte cultures Leukotriene B4 Ethanol wash, precipitation, centrifugation, reconstitution [200] Hepatocyte cultures Amlodipine Dilution, centrifugation, SPE (C18) [64] Hepatocyte cultures BVT.2938 Precipitation, centrifugation [200] Herbal Flavonoids Extraction with hot water + freeze-drying [106] Meconium Morphine SLE (methanol) + SPE (C2) [21] Meconium Buprenorphine SLE (buffer) + SPE (mixed mode) [23] Microsomal incubation Steroids Protein precipitation + LPME [32] Microsomal incubation BVT.2938 Precipitation, centrifugation [202] Microsomal incubation Dopamine Centrifugation + SPE (mixed mode SAX) [44] Microsomal incubation Etoposide Precipitation, centrifugation + reconstitution [18] Microdialysis sample 1 , Plasma 2 Morphine Protein precipitation (2), column switching [142] Placenta Buprenorphine Norbuprenorphine Dilution + protein precipitation + SPE [161] Plasma Mycophenolic acid Dilution + SPE (C2) [39] Plasma Mycophenolic acid Dilution, centrifugation + SPE (Oasis HLB) [40] Plasma ILT-threo Extraction with acetonitrile, centrifugation + reconstitution [200] Plasma Cannabinoids Dilution + SPE (C18) [42] Plasma Morphine SPE (MCX) [25] Plasma Morphine pH adjustment + SPE (C18) [166] Plasma Naveglitazar Protein precipitation + centrifugation [109] Serum Morphine SPE [50] Serum Ethanol Centrifugation, protein precipitation [188] Serum Psilocin Dilution + centrifugation [13] Urine Steroids LPME …”

mentioning

confidence: 99%

“…Another example of SLE is a recent study in which neurosteroid glucuronides were for the first time demonstrated to exist in rat brain samples. The multistage extraction procedure consisted of ethanol/acetone extraction, centrifugation, SPE, and dilution [36]. SLE was recently applied to extraction of fingerprints, and in this way drug glucuronides were detected for the first time in deposited fingerprints [37].…”

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confidence: 99%

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Direct Analysis of Glucuronides with Liquid Chromatography-Mass Spectrometric Techniques and Methods

Ketola¹,

Hakala

2010

CDM

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Glucuronidation is one of the main phase II metabolic reactions in humans and animals. A variety of analytical techniques and methods have been used for the detection and quantification of glucuronides of both endogenous and xenobiotic compounds from different biological samples of humans and animals. Drug metabolism has been extensively studied with both in vitro and in vivo experiments under various conditions. The purpose of this review is to explore in detail the benefits and drawbacks of different liquid chromatography-mass spectrometric (LC/MS) methods and techniques in detection and identification of all forms of glucuronide conjugates from in vitro, biological, and environmental samples. The entire analytical procedure is covered, from sample treatment, separation, and ionization to qualitative and quantitative analyses. The aim of this review is not to cover every published paper where glucuronides are identified and/or quantified, but rather to focus on special cases where a new analytical approach or technical development has led to a better, more specific, or more comprehensive detection, identification, or quantitation of glucuronide conjugates.

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“…16) β-Estradiol 3-glucuronide is formed by UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2A1, and UGT2A2 in humans. 17) Considering that β-estradiol 3-glucuronide has been found in the mouse brain, 18) β-estradiol could be metabolized by UGTs in the brain, as glucuronide, with its high water solubility, generally does not easily penetrating the blood-brain barrier. However, the kinetics of β-estradiol 3-glucuronidation in the brain remain to be elucidated.…”

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confidence: 99%

Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

Asai

Sakakibara

Onouchi

et al. 2017

Biological & Pharmaceutical Bulletin

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β-Estradiol is conjugated by uridine 5′-diphosphate-glucuronosyltransferase (UGT) 1A to 3-glucuronide in the human liver. UGT1A has been found in the brain; therefore, UGT1A may be involved in β-estradiol 3-glucuronidation in the brain. In the present study, we aimed to characterize the β-estradiol 3-glucuronidation reaction in the rat brain. β-Estradiol 3-glucuronidation was detected in eight rat brain regions (cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, striatum, and thalamus). β-Estradiol 3-glucuronidation in the cerebellum was fitted to the Hill equation (S 50 8.0 µM, n 1.1). In inhibition experiments, β-estradiol 3-glucuronidation was inhibited to 73.6% in the cerebellum by 50 µM bilirubin, whereas it was reduced to 20.5% with 5 µM bilirubin in the liver. Unlike in the liver, Ugt1a1 may not be the main isoform catalyzing this glucuronidation in the brain. Serotonin and acetaminophen at 10 mM inhibited glucuronidation to 1.17 and 25.5%, respectively, in the cerebellum. In induction experiments, the administration of β-naphthoflavone, carbamazepine, and phenobarbital did not increase β-estradiol 3-glucuronidation in the brain except for phenobarbital in the striatum. In addition, β-estradiol 3-glucuronidation was not correlated with serotonin or acetaminophen glucuronidation in the brain, suggesting that Ugt1a6 and Ugt1a7 are not major isoforms of β-estradiol 3-glucuronidation in the rat brain. In the present study, although we were unable to identify the isoform responsible for β-estradiol 3-glucuronidation, we confirmed that β-estradiol could be metabolized to glucuronide in the brain under a different metabolic profile from that in the liver.

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Discovery of neurosteroid glucuronides in mouse brain

Cited by 10 publications

References 28 publications

Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat

Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat

Direct Analysis of Glucuronides with Liquid Chromatography-Mass Spectrometric Techniques and Methods

Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

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