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Factors Affecting Separation and Detection of Bile Acids by Liquid Chromatography Coupled with Mass Spectrometry in Negative Mode

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Factors Affecting Separation and Detection of Bile Acids by Liquid Chromatography Coupled with Mass Spectrometry in Negative Mode Anal Bioanal Chem DOI 10.1007/s00216-017-0489-1 RESEARCH PAPER Factors affecting separation and detection of bile acids by liquid chromatography coupled with mass spectrometry in negative mode Shanshan Yin1 & Mingming Su2,3 & Guoxiang Xie3 & Xuejing Li4 & Runmin Wei3 & Changxiao Liu5 & Ke Lan1,3 & Wei Jia 3 Received: 10 April 2017 /Revised: 13 June 2017 /Accepted: 22 June 2017 # Springer-Verlag GmbH Germany 2017 Abstract Bile acids (BAs) are cholesterol metabolites with hydroxylation. It was also found that the retention of taurine important biological functions. They undergo extensive host- conjugates on the BEH C18 column was sensitive to the gut microbial co-metabolisms during the enterohepatic circu- strength of formic acid and ammonium in mobile phases. By lation, creating a vast structural diversity and resulting in great using the volatile buffers with an equivalent ammonium level challenges to separate and detect them. Based on the as mobile phases, we comprehensively demonstrated the ef- bioanalytical reports in the past decade, this work developed fects of the elution pH value on the retention behaviors of BAs three chromatographic gradient methods to separate a total of on both the BEH C18 column and HSS T3 column. Based on 48 BA standards on an ethylene-bridged hybrid (BEH) C18 the retention data acquired on a C18 column, we presented the column and high-strength silica (HSS) T3 column and accord- ionization constants (pKa) of various BAs with the widest ingly unraveled the factors affecting the separation and detec- coverage beyond those of previous reports. When we made tion of them by liquid chromatography coupled with mass attempts to establish the structure-retention relationships spectrometry (LC-MS). It was shown that both the acidity (SRRs) of BAs, the lack of discriminative structural descrip- and ammonium levels in mobile phases reduced the tors for BA stereoisomers emerged as the bottleneck problem. electrospray ionization (ESI) of BAs as anions of [M−H]−, The methods and results presented in this work are especially especially for those unconjugated ones without 12- useful for the development of reliable, sensitive, high- throughput, and robust LC-MS bioanalytical protocols for Electronic supplementary material The online version of this article the quantitative metabolomic studies. (doi:10.1007/s00216-017-0489-1) contains supplementary material, which is available to authorized users. Keywords High-performance liquid chromatography . Mass spectrometry . Bile acid . Electrospray ionization . Ionization * Ke Lan constant . Structure-retention relationship [email protected] * Wei Jia [email protected] Introduction 1 Key laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan Human bile acids (BAs) are C24 molecules comprised of a University, Chengdu 610041, China C19 cyclopentanophenanthrene (steroid) nucleus and a car- 2 Metabo-Profile Biotechnology Co., Ltd, Shanghai, China boxylate side chain. They are cholesterol metabolites under- 3 Metabolomics Shared Resource, University of Hawaii Cancer going extensive enterohepatic circulation driven by a series of Center, Honolulu, HI, USA host-gut microbial metabolism and transport mechanisms – 4 Chengdu Health-Balance Pharmaceutical and Biomedical Tech. Co. [1 3]. During exchanges between the host and gut microbiota, Ltd, Chengdu, China BAs act on both of them and play multiple biological roles – 5 State key Laboratory of Drug Delivery Technology and [4 10]. The metabolomic profile of BAs therefore manifests a Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, footprint of host-gut microbial interactions that are closely Tianjin, China associated with health and diseases. However, the highly Yin S. et al. interactive disposition of BAs by the host and gut microbiota produces a vast structural diversity (Fig. 1,Electronic Supplementary Material (ESM), Table S1) associated with (1) A/B ring fusion stereochemistry (trans/5α-H or cis/5β- H); (2) sites of hydroxylation at C3, C6, C7, and/or C12; (3) dehydrogenation and epimerization of the hydroxyl groups; and (4) conjugation of glycine or taurine at the C24-carboxyl group and/or conjugation of glucuronide or sulfate at hydroxyl/C24-carboxyl groups [11]. It is challenging to sepa- rate and detect such a great deal of BAs in biological samples with such a small structural difference but disparate physico- chemical properties. Liquid chromatography coupled with mass spectrometry (LC-MS) is currently prevailing in BA analysis [12]. In a Fig. 1 Chemical structure of C24 bile acids. The mostly known typical LC-MS method, BAs are separated by reverse chro- structural diversity appears at (1) A/B ring fusion stereochemistry matography, ionized by the negative electrospray ionization (trans/5α-H or cis/5β-H); (2) sites of hydroxylation at C3, C6, C7, and/ (ESI−), and detected by multiple reaction monitoring (MRM). or C12; (3) dehydrogenation and epimerization of the hydroxyl groups; and (4) conjugation of glycine or taurine at the C24-carboxyl group and/ Owing to the occurrence of a lot of isomers and stereoisomers, or conjugation of glucuronide or sulfate at hydroxyl/C24-carboxyl groups it is difficult to differentiate them with current tandem mass spectrometric techniques. A pseudo-MRM method, which stationary phases, the reverse C18 columns were utilized in employs the same product ion as the parent ion under an the majority of reports. The high-strength silica (HSS) T3 optimized collision energy, has to be employed for the uncon- columns were employed in several reports and only two re- jugated isomers and stereoisomers, such as m/z 375 > 375 for ports utilized a reverse C8 column. The situation became LCA/isoLCA, m/z 391 > 391 for chenodeoxycholic acid much more complicated at the side of mobile phases. Some β (CDCA)/ursodeoxycholic acid (UDCA)/ -ursodeoxycholic reports only used formic acid (HCOOH) in aqueous phase β β acid ( UDCA)/hyodeoxycholic acid (HDCA)/ HDCA/ and/or organic phase. A few others used ammonium acetate murocholic acid (muroCA), and m/z 407 > 407 for hyocholic (CH COONH ), but the pH value of mobile phases varied α α β 3 4 acid (HCA)/ -muricholic acid ( MCA)/ -muricholic acid from 4.0 to 9.0. It is not completely clear how the additives β ω ω ( MCA)/ -muricholic acid ( MCA). All these unconjugat- and pH value of mobile phases affect the separation and de- ed BAs have no 12-hydroxyl group. They fragmented merely tection of BAs on a specific stationary phase. Therefore, the via dehydration and dehydrogenation and exhibited none dis- first aim of this study was to disclose the factors that have criminative fragments regardless of sites and epimerization of potential impacts on the separation and detection of BAs by the hydroxyl groups on the skeleton [13]. We have character- LC-MS. By using the collected data, the second aim of this ized a distinctive fragmentation mechanism for the 12- work was to highlight the challenges for understanding the hydroxylated unconjugated ones, such as deoxycholic acid fundamental relationship between the structure and physico- (DCA) and cholic acid (CA). The 12-hydroxyl group induces chemical property of BAs, which will play a pivotal role in the the rotation of the carboxylate side chain and the proton trans- characterization and identification of the unknown BAs de- fer between the 12-hydroxyl group and 24-carboxyl group. tected in human and animals. The subsequent dissociation routes enable the discrimination of 12-hydroxylated ones from the others with a MRM method [13]. For the conjugated BAs, such as glycine conjugates and taurine conjugates, the dissociations of the steroid nucleus Material and methods have been obscured by the signals derived from a cleavage of the amide side chain [13]. As a result, isomers and stereo- Chemicals and reagents isomers of conjugated BAs may also not be discriminated by a MRM method. In summary, the discrimination of the un- Forty-eight BA reference standards were purchased from known BAs from the known ones relies heavily on the sepa- Steraloids (Newport, RI, USA), TRC (Toronto, Canada), or ration power and the robustness of chromatography. It is cru- Sigma-Aldrich (St. Louis, MO, USA). The authentic standard cial to disclose the fundamental factors affecting the separa- of 3β-ursocholic acid (βUCA) was kindly gifted from Prof. tion and detection of them and accordingly establish structure- Dr. Takashi Iida (Nihon University). The name, chromato- retention relationships (SRRs). graphic peak label, CAS, m/z of [M−H]−, and retention data ESM, Table S2 summarizes the published chromatographic of them were summarized in Table 1. The LC-MS grade meth- methods for BA separation in the past decade. At the side of anol (MeOH), acetonitrile (ACN), isopropanol alcohol (IPA), Factors affecting separation and detection of bile acids by LC-MS Table 1 The peak no., name, abbreviated name, CAS, m/z of [M−H]−, retention time, and corresponding percentage of organic phase at its eluted time of bile acids included in this study No. Name Abbr. CAS [M−H]− Retention time (min)/percentage of organic phase (%) Gradient Ia Gradient IIb Gradient IIIc 1 Lithocholic acid LCA 434-13-9 375.3 17.17/71.0 11.75/85.0 23.16/95.5 2 Isolithocholic acid IsoLCA 1534-35-6 375.3 15.95/61.1 10.91/67.2 22.49/86.5 3 Allolithocholic acid AlloLCA 2276-93-9 375.3 15.65/59.9 11.11/65.8 22.60/88.0 4 Isodeoxycholic acid IsoDCA 566-17-6 391.3 16.23/62.1 11.16/67.6 22.69/89.2 5 Deoxycholic acid DCA
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