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TITLE PAGE Identification of Epoxide-Derived Metabolite(S) Of DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 TITLE PAGE Identification of Epoxide-Derived Metabolite(s) of Benzbromarone Kai Wang, Hui Wang, Ying Peng, and Jiang Zheng School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Downloaded from Therapeutics, Seattle Children’s Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.) dmd.aspetjournals.org at ASPET Journals on September 24, 2021 1 DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 RUNNING TITLE PAGE Running title: Epoxidation of Benzbromarone Corresponding Authors: Jiang Zheng, PhD Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington, Seattle, WA 98101 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, P. R. Downloaded from China Email: [email protected] Tel: 206-884-7651; Fax: 206-987-7660 dmd.aspetjournals.org Ying Peng, PhD School of Pharmacy, Shenyang Pharmaceutical University, PO Box 21, 103 Wenhua Rode, Shenyang, 110016, P. R. China Email: [email protected] Tel: +86-24-23986361; Fax: +86-24-23986510 at ASPET Journals on September 24, 2021 The number of text pages: 22 The number of figures: 9 The number of schemes: 2 The number of references: 33 The number of words in the Abstract: 154 The number of words in the Introduction: 464 The number of words in the Discussion: 927 Abbreviations: BBR, benzbromarone; ACN, acetonitrile; NAC, N-acetylcysteine; DEX, dexamethasone; NADPH, β-nicotinamide adenine dinucleotide 2′-phosphate reduced tetrasodium salt; MLMs, mouse liver microsomes; DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, cell exit potential; EPI, enhanced product ion; SIM, selected ion monitoring; MRM, multiple-reaction monitoring; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; and MS/MS, tandem mass spectrometry. 2 DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 Abstract Benzbromarone (BBR) is a benzofuran derivative that has been a quite useful drug for the treatment of gout. However, it was withdrawn from European markets in 2003, due to reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. Downloaded from An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated dmd.aspetjournals.org with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). at ASPET Journals on September 24, 2021 The present study provided new information on metabolic activation of BBR. 3 DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 Introduction Gout is a form of inflammatory arthritis caused by elevation of blood urate levels (a condition known as hyperuricemia) which crystallize and deposit into joints and/or surrounding tissues (Kenneth and Hyon, 2006; Azevedo et al., 2014). Benzbromarone (BBR) is a benzofuran derivative (as shown in Figure 1) acting as a uricosuric agent by inhibiting urate reabsorption (Shin et al., 2011). Both BBR and Downloaded from 6-hydroxy BBR (a metabolite of BBR) have been reported to show potent human uric acid transporter 1 (hURAT1) inhibition property (Wempe et al., 2011), which made dmd.aspetjournals.org BBR a quite useful anti-gout agent for approximately 30 years in many countries. But recently, clinical cases of acute liver damage including some fatalities related to BBR (Wagayama et al., 2000; Arai et al., 2002; Reinders et al., 2007) draw our at ASPET Journals on September 24, 2021 attention to the metabolism profiles of BBR. Hepatotoxicity is often associated with metabolic activation mediated by cytochromes P450 (He et al., 2015). Debromination was initially considered to be a main bioactivation of BBR in vivo (Broekhuysen et al., 1972; Ferber et al., 1981). It was clarified in 1988 that hydroxylation rather than debromination was the predominant metabolic pathway of BBR (Walter-Sack et al., 1988). Early metabolic studies revealed two major hydroxylated metabolites identified as 1′-hydroxy BBR and 6-hydroxy BBR (De Vries et al., 1993; Walter-Sack et al., 1998). It was also reported that P450s 2C9 (major) and 2C19 (minor) were involved in the formation of the 6-hydroxy BBR metabolite (De Vries et al., 1993) characterized by comparison with synthetic standard (McDonald and Rettie, 2007). Initially, BBR was found to be 4 DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 a P450 2C9 inhibitor (Marques-Soare et al., 2003; Locuson et al., 2004). Subsequently, BBR and four of its analogues were discovered to exhibit extraordinary inhibitory potency for P450 2C19 (Locuson et al., 2004). Idiosyncratic hepatotoxicity of BBR has primarily been suggested to be associated with metabolite 6-hydroxy BBR proposed by McDonald and Rettie (McDonald and Rettie, 2007). They suggested that sequential oxidation of 6-hydroxy BBR results in a catechol Downloaded from structure, 5,6-dihydroxy BBR, which can be further oxidized to a reactive quinone intermediate capable of adducting protein. However, we believe that the initial dmd.aspetjournals.org epoxidation of BBR may be more important for metabolic activation of BBR. Epoxide-derived metabolites of many pro-toxicants, such as bromobenzene (Slaughter et al., 1991; Zheng and Hanzlik, 1992a), naphthalene (Zheng et al., 1997; Morisseau at ASPET Journals on September 24, 2021 et al., 2008), styrene (Carlson et al., 2011), and coumarin (Born et al., 2000) are suggested to play important roles in the development of toxicities. The objectives of this study included (1) characterization of epoxide-derived metabolite(s) of BBR in vitro and in vivo; and (2) identification of cytochromes P450 enzymes responsible for the formation of the metabolite(s). We anticipate that the study would allow us to better understand the mechanisms of idiosyncratic hepatotoxicity of BBR. 5 DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 Materials and methods Chemicals and Materials. Benzbromarone (BBR, purity ＞ 98%) was obtained from Aladdin Industrial Technology Co., Ltd. (Shanghai, China). N-Acetylcysteine (NAC), ketoconazole, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were purchased from Sigma-Aldrich Co. (St. Louis, MO). Recombinant human P450 enzymes were purchased from BD Gentest (Woburn, MA). Downloaded from Dexamethasone (DEX), sodium nitrite, and tin chloride were purchased from the National Institute for the Control of Pharmaceutical and Biological Products dmd.aspetjournals.org (Shenyang, China). All organic solvents were from Fisher Scientific (Springfield, NJ). All reagents and solvents were of either analytical or HPLC grade. Animal Experiments. Male Kunming mice (20 ± 2 g) were obtained from the at ASPET Journals on September 24, 2021 Animal Center of Shenyang Pharmaceutical University. The animals were maintained on standard mouse chow and tap water ad libitum in a 25 °C room with a 12 h dark/light cycle. Mice were individually placed in metabolism cages. After fasting for 12 h with free access to water prior to the experiment, mice were intraperitoneally treated with BBR dissolved in corn oil (10 mL/kg) at 65 mg/kg. Urine samples were collected from 0 to 24 h after dosing. The control animals treated with corn oil were included. During the experiment, the animals were allowed to free access to food and water. Individual groups (BBR-treated and control) contained four mice. The collected urine samples were stored at -20 °C until analysis. 6 DMD Fast Forward. Published on January 20, 2016 as DOI: 10.1124/dmd.115.066803 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 66803 Sample Preparation. The collected urine samples were pooled and mixed with triple volumes of acetonitrile (ACN). All samples were vortexed for 3 min and then centrifuged at 16,000 rpm for 10 min at 4 °C. The supernatants were harvested and the ACN was evaporated under a stream of nitrogen gas at 40 °C. The resulting urine samples were extracted with ethyl acetate (Wu et al., 2012). The organic layer was collected and evaporated to dryness under a stream of nitrogen gas at 40 °C. Downloaded from The residues were reconstituted with 100 μL of 50% ACN in water. After centrifugation, the supernatants (5 μL) were injected onto LC-MS/MS for analysis. dmd.aspetjournals.org Microsomal Incubations. Mouse liver microsomes (MLMs) were prepared in our laboratory according to previous published method (Lin et al., 2007). Dexamethasone-induced mouse liver microsomes (DEX-induced MLMs) were at ASPET Journals on September 24, 2021 prepared from mice pretreated with DEX (an inducer of CYP3A4) for five consecutive days, using the same procedure above.
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