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Characterization of Nuciferine Metabolism by P450 Enzymes and Uridine Diphosphate Glucuronosyltransferases in Liver Microsomes from Humans and Animals

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Characterization of Nuciferine Metabolism by P450 Enzymes and Uridine Diphosphate Glucuronosyltransferases in Liver Microsomes from Humans and Animals Acta Pharmacologica Sinica (2010) 31: 1635–1642 npg © 2010 CPS and SIMM All rights reserved 1671-4083/10 $32.00 www.nature.com/aps Original Article Characterization of nuciferine metabolism by P450 enzymes and uridine diphosphate glucuronosyltransferases in liver microsomes from humans and animals Yan-liu LU1, Yu-qi HE2, Miao WANG1, Li ZHANG1, Li YANG2, Zheng-tao WANG2, Guang JI1, * 1Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; 2Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Shanghai 201203, China Aim: To characterize the metabolism of nuciferine by P450 enzymes and uridine diphosphate glucuronosyltransferase (UGT) in liver microsomes from humans and several other animals including rats, mice, dogs, rabbits and monkeys. Methods: Nuciferine was incubated with both human and animal liver microsomal fractions containing P450 or UGT reaction compo- nents. Ultra performance liquid chromatography coupled with mass spectrometry was used to separate and identify nuciferine meta- bolites. Chemical inhibition was used to identify the involved isozymes. Species difference of nuciferine metabolism in human and various animals were investigated in the liver microsomal incubation system. Results: Among the nuciferine metabolites detected and identified, seven were catalyzed by P450 and one by UGT. Ketoconazole inhi- bited the formation of M292, M294 and M312. Furafylline, 8-methoxypsoralen and quercetin inhibited the formation of M282. Heco- genin showed a significant inhibitory effect on nuciferine glucuronidation. While the P450-catalyzed metabolites showed no species differences, the glucuronidation product was only detected in microsomes from humans and rabbits. Conclusion: The isozymes UGT 1A4, CYP 3A4, 1A2, 2A6 and 2C8 participated in the hepatic metabolism of nuciferine. Based on the observed species-specific hepatic metabolism of nuciferine, rats, mice, dogs and even monkeys are not suitable models for the phar- macokinetics of nuciferine in humans. Keywords: nuciferine; metabolism; cytochrome P450; UGT; species differences; rats; mice; rabbits; monkeys; human Acta Pharmacologica Sinica (2010) 31: 1635–1642; doi: 10.1038/aps.2010.172 Introduction of the known phase I metabolism of drugs[5] and, as such, are Lotus is a common plant that grows worldwide. This plant among the most important drug-metabolizing enzymes. In has long been used as an herb in traditional Chinese medi- recent years, there has been increased interest in in vitro metab- cine[1]. In recent years, significant pharmacological activities olism studies involving P450 enzymes during preclinical drug have been observed for lotus, which displays beneficial effects development[6–8] in order to identify drugs with undesirable on hyperlipidemia[2], obesity[3], arrhythmia[4] and atherosclero- metabolites and to prevent failure in clinical trials. In addi- sis [2]. Most of the beneficial effects have been attributed to the tion to CYP enzymes, UDP-glucuronosyltransferases (UGTs) main constituent of lotus, the aporphine alkaloid nuciferine[4]. participate in nearly half of the known phase II metabolism of Given its salutary effects, nuciferine is a promising drug the top 200 prescribed drugs in the United States[9]. Thus, like candidate. However, the metabolism and in vivo kinetics of CYPs, UGTs are important drug-metabolizing enzymes. nuciferine have not been investigated until now. In the present study, both P450- and UGT-mediated metabo- Cytochrome P450 (CYP) enzymes participate in 70%–80% lism of nuciferine were investigated in order to learn the general structure of the metabolites, to identify the isozymes * To whom correspondence should be addressed. involved in nuciferine metabolism and to examine the spe- E-mail [email protected] cies differences in nuciferine metabolism in humans and other Received 2010-03-04 Accepted 2010-09-13 commonly used experimental animals. npg www.nature.com/aps Lu YL et al 1636 Materials and methods lows: 296 to 235 for nuciferine; 294 to 248 and 294 to 279 for Chemicals and materials M294-1 and M294-2, respectively; 292 to 246 for M292; 282 to Nuciferine, glucose-6-phosphate (G-6-P), G-6-P dehydro- 191 and 282 to 250 for M282-1 and M282-2, respectively; 312 to genase, alamethicin, uridine diphosphate glucuronic acid, 250 and 312 to 248 for M312-1 and M312-2, respectively; 472 to β-nicotinamide-adenine dinucleotide phosphate (NADP), 265 for M472. sulfaphenazole, quinidine, clomethiazole, furafylline, 8-meth- Another alkaloid, senecionine, was used as the internal oxypsoralen, hecogenin, fluconazole, androsterone and phe- standard, which was also detected in MRM mode with ion nylbutazone were purchased from Sigma-Aldrich (St Louis, transition of 336 to 138. The accuracy for determination of MO, USA). Ketoconazole and S-mephenytoin were obtained nuciferine was more than 90% and less than 105%. The preci- from ICN Biomedicals Inc (Aurora, OH, USA) and Toronto sion for determination of nuciferine and metabolites was mea- Research Chemicals Inc (North York, Canada), respectively. sured, and the residual standard deviation (RSD) values were Pooled human liver microsomes (HLM) were prepared using less than 15%. tissue from 13 Chinese donors and stored in phosphate buffer (100 mmol/L, pH 7.4). Except the pooled HLM, 6 HLM sam- Microsomal incubation system for P450-mediated metabolism ples (male) and male cynomolgus monkey liver microsomes A standard incubation system for P450-mediated metabo- were purchased from Rild Research Institute for Liver Dis- lism (System P450) included HLM (0.5 g/L, 10 µL), G-6-P eases (Shanghai, China). Experiments involving human sub- (1 mmol/L, 20 µL), G-6-P dehydrogenase (1 unit/mL, 20 jects were approved by the local governmental ethics authori- µL), phosphate buffer (100 mmol/L, pH 7.4, 108 µL), MgCl2 ties and were pursuant to the Helsinki Declaration. All other (4 mmol/L, 20 µL), and nuciferine (200 μmol/L, 2 µL). reagents were of HPLC grade or the highest grade commer- Nuciferine was dissolved in methanol; all other reagents were cially available. dissolved in phosphate buffer. The total volume of the incuba- tion system was 200 μL, and the total organic volume was less Preparation of liver microsomes than 1% of the system. The reaction was initiated by adding Livers from rats (Sprague-Dawley, male, n=6), mice (Swiss, NADP (1 mmol/L, 20 µL). After incubation for 60 min, 200 male, n=6), rabbits (New Zealand white, male, n=6) and dogs μL of acetonitrile was added to stop the reaction. The stopped (Beagle, male, n=6) were obtained from healthy animals at the incubation system was centrifuged for 10 min at 20 000 g Experimental Animal Center of Shanghai University of Tradi- (4 °C) and a 2-µL aliquot of the supernatant was analyzed as tional Chinese Medicine (SUTCM, Shanghai, China). The use described above. of livers in the present study was approved by the ethics com- mittee of SUTCM. Liver samples were pooled by species and Microsomal incubation system for UGT-mediated metabolism stored in liquid nitrogen immediately after being harvested. A standard incubation system for UGT-mediated metabo- Microsomes were prepared from pooled frozen liver tissue lism (system UGT) with a total volume of 200 µL contained by differential ultracentrifugation as described previously[10]. HLM (0.5 g/L, 10 µL), alamethicin (25 µg/mg protein, 10 µL), Protein concentration was determined using bovine serum UDPGA (5 mmol/L, 20 µL), MgCl2 (4 mmol/L, 20 µL), Tris- albumin as reference[11]. Liver microsomes were diluted to 10 HCl buffer (50 mmol/L, pH 7.4) and nuciferine (200 μmol/L, mg/mL and stored at -80 °C. 2 µL). Reactions were started by adding UDPGA at 37 °C and stopped after 60 min by adding ice-cold 10% trichloroacetic Parameters for chromatography and mass spectrometry acid (200 µL). After stopping the reaction, the incubation mix- An ultra performance liquid chromatography (UPLC) system ture was centrifuged for 10 min at 20 000 g (4 oC). Aliquots of coupled with triple quadrupole mass spectrometry (Acquity- the supernatant were subsequently analyzed. Premier, Waters, Milford, MA) and an electrospray ionization (ESI) source was used in the present study. A Waters bridged Identification of metabolites ethyl hybrid (BEH) C18 (50×2.1 mm, 1.7 μm) column was used Three experimental groups were used in the present study for separation. Acetonitrile and formic acid solution (0.1% to identify P450-catalyzed nuciferine metabolites: a reaction in water) were used as mobile phase components A and B, group, which included nuciferine, HLM, NADP and the other respectively. The mobile phase elution gradient was as fol- components described above; a negative control group, which lows: 0 to 0.5 min, 5% A; 0.5 to 1.5 min, 5% to 50% A; 1.5 to 3 included nuciferine and the other reaction components except min, 50% to 80% A; 3 to 4 min, 80% to 95% of A. The mobile- NADP (which was replaced by phosphate buffer); and a phase flow rate was 0.3 mL/min. blank group, which included all reaction components without The positive ion monitor mode was adopted, and mass nuciferine (but with the appropriate volume of methanol). parameters for UPLC-MS were set as follows: capillary volt- Similarly, three experimental groups were used in the pres- age, 3.2 kV; cone voltage, 40 V; extractor voltage, 1.59 V; ent study to identify glucuronidated nuciferine metabolites: source and desolvation temperatures, 100 and 350
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