柑橘类果汁对大鼠细胞色素P450 3A的抑制与果汁中呋喃香豆素组成的相关性

中国临床药理学与治疗学 ›› 2004, Vol. 9 ›› Issue (9): 970-977.

柑橘类果汁对大鼠细胞色素P450 3A的抑制与果汁中呋喃香豆素组成的相关性

郭联庆, 鲍浩, 杨娟, 陈巧云¹, 刘玉秀², 李金恒, 山添康³

金陵医院南京大学医学院临床医院临床药理科,¹药品科,²科研科, 南京210002, 江苏;
³东北大学大学院药学研究科药物动态分野, 仙台980-8578, 日本

收稿日期:2004-06-21 接受日期:2004-07-30 出版日期:2004-09-26 发布日期:2020-11-23

Correlation of furanocoumarin composition and rat cytochrome P450 3A inhibition among citrus fruit juices

GUO Lian-Qing, BAO Hao, YANG Juan, CHEN Qiao-Yun¹, LIU Yu-Xiu², LI Jin-Heng, YAMAZOE Yasushi³

Department of Clinical Pharmacology,¹Department of Pharmacy,²Department of Science Research, Jinling Hospital &Clinical School of Medical College of Nanjing University, Nanjing 210002, Jiangsu, China;
³Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan

Received:2004-06-21 Accepted:2004-07-30 Online:2004-09-26 Published:2020-11-23
Contact: GUO Lian-Qing, male, doctor of pharmacy, associate professor, tutor of master, engaged in drug metabolism. Tel:025-80860196 E-mail:guokaku @hotmail.com
Supported by:
Project partly supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (№0214H010)

摘要/Abstract

摘要： 目的: 呋喃香豆素类(补骨脂素类) 是导致葡萄柚汁与药物相互作用的重要成分。本研究拟调查该类化合物在其它柑橘类果汁中的存在, 并比较这些果汁对细胞色素P450 (CYP) 3A 活性的抑制强度。方法: 用梯度高压液相色谱法测定柑橘类的鲜榨果汁中6 种呋喃香豆素化合物的组成与含量。以雄性Sprague-Dawley 大鼠肝微粒体的睾酮6β-羟化活性测试每种果汁对CYP3A 的抑制作用。结果: 与葡萄柚汁比较, Jaffa sweetie 果汁中呋喃香豆素的组成与含量基本相同, 对CYP3A 的抑制强度也相当;日本红柚、溪蜜柚和金柚的果汁中呋喃香豆素组成相似但含量较低, 对CYP3A 的抑制强度也较弱;常山胡柚、甜橙与宽皮橘果汁中呋喃香豆素种类少且含量极低, 且多数对CYP3A 无抑制作用。结论: 根据呋喃香豆素组成可以预测柑橘类果汁因为抑制CYP3A 引起的药物相互作用;王官溪蜜柚及近缘品种的果汁可能导致类似于葡萄柚汁的药物相互作用, 有必要在临床上加以验证。

关键词: 补骨脂素类, 柑橘类果汁, 高压液相色谱, 细胞色素P450 3A, 酶抑制

Abstract: AIM: To investigate the existence of these compounds in other citrus fruit juices, and check their inhibitory intensities on activity of cytochrome P450 (CYP) 3A.METHODS: Freshly squeezed citrus fruit juices were determined separately for their composition and levels of six furanocoumarins with a gradient highpressure liquid chromatographic (HPLC) method. Inhibition of CYP3A by each juice sample was tested with the activity of testosterone 6β-hydroxylation in liver microsoms of male Sprague-Dawley rats.RESULTS: Comparing with grapefruit juices, the Jaffa sweetie showed almost the same composition and levels of furanocoumarins, and a comparable inhibitory intensity of CYP3A; the Japanese red pommelo, `Guanxi Miyou' and `Jinyou' pommelos showed similar compositions but lower levels of furanocoumarins, and weaker inhibiting intensities of CYP3A; While `Changshan Huyou' pummelos, sweet oranges and mandarins showed less varieties and much lower levels of furanocoumarins, and most of them showed no inhibition of CYP3A.CONCLUSION: Furanocoumarin composition can be an index to predict citrus fruit juice-drug interaction based on CYP3A inhibition; Clinical validations should be conducted on `Guanxi Miyou' pummelo and closely related accessions for their possible drug interactions similar to grapefruit juice.

Key words: psoralens, citrus fruit juice, high-pressure liquid chromatography, cytochrome P450 3A, enzyme inhibition

中图分类号:

R965.2

郭联庆, 鲍浩, 杨娟, 陈巧云, 刘玉秀, 李金恒, 山添康. 柑橘类果汁对大鼠细胞色素P450 3A的抑制与果汁中呋喃香豆素组成的相关性[J]. 中国临床药理学与治疗学, 2004, 9(9): 970-977.

GUO Lian-Qing, BAO Hao, YANG Juan, CHEN Qiao-Yun, LIU Yu-Xiu, LI Jin-Heng, YAMAZOE Yasushi. Correlation of furanocoumarin composition and rat cytochrome P450 3A inhibition among citrus fruit juices[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(9): 970-977.

参考文献

1 Guo LQ.Grapefruit juice-drug interaction and individual variation (text in Chinese with an English abstract)[J]. J Med Postgrad, 2002;15(2): 184-6
2 Guo LQ, Yamazoe Y.Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines[J]. Acta Pharmacol Sin, 2004;25(2): 129-36
3 Schmiedlin-Ren P, Edwards DJ, FitzsimmonsME, He K, Lown KS, Woster PM, et al. Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents.Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins[J]. Drug Metab Dispos, 1997;25 (11): 1228-33
4 Guo LQ, Fukuda K, Ohta T, Yamazoe Y.Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity[J]. Drug Metab Dispos, 2000;28(7): 766-71
5 Fukuda K, Guo LQ, Ohashi N, Yoshikawa M, Yamazoe Y. Amounts and variation in grapefruit juice of the main components causing grapefruit-drug interaction[J]. J Chromatogr B, 2000;741(2): 195-203
6 Malhotra S, Bailey DG, Paine MF, Watkins PB.Seville orange juice-felodipine interaction:comparison with dilute grapefruit juice and involvement of furocoumarins [J]. Clin Pharmacol Ther, 2001;69(1): 14-23
7 Bailey DG, Dresser GK, Bend JR.Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3A4 activity: comparison with grapefruit juice [J]. Clin Pharmacol Ther, 2003;73(6): 529-37
8 Zhang TP, Peng SL, Wang ZF, Ling DH, Gan LS. Genetic relationships among cultivars of Citrus maxima (Burm. ) Merr. using RAPD marker technique (text in Chinese with an English abstract)[J]. J Trop Subtrop Bot, 2001; 9(4): 322-8
9 Ohta T, Maruyama T, Nagahashi M, Miyamoto Y, Hosoi S, Kiuchi F, et al. Paradisin C: a new CYP3A4 inhibitor from grapefruit juice[J]. Tetrahedron, 2002;58(33): 6631-5
10 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ.Protein measurement with the folin phenol reagent[J]. J Biol Chem, 1951;193(1): 265-75
11 Matsubara T, Koike M, Touchi A, Tochino Y, Sugeno K. Quantitative determination of cytochrome P-450 in rat liver homogenate[J]. Anal Biochem, 1976;75(2): 596-603
12 Fukuda K, Ohta T, Yamazoe Y.Grapefruit component interacting with rat and human P450 CYP3A:possible involvement of non-flavonoid components in drug interaction[J]. Biol Pharm Bull, 1997; 20(5): 560-4
13 Guo LQ, Taniguchi M, Chen QY, Baba K, Yamazoe Y.Inhibitory potential of herbal medicines on human cytochrome P450-mediated oxidation:properties of umbelliferous or citrus crude drugs and their relative prescriptions[J]. Jpn J Pharmacol, 2001; 85(4): 399-408
14 Nicolosi E, Deng ZN, Gentile A, La Malfa S, Continella G, Tribulato E. Citrus phylogeny and genetic origin of important species as investigated by molecular markers[J]. Theor Appl Genet, 2000; 100(8): 1155-66
15 Pang XM, Hu CG, Deng XX.Phylogenetic relationships among citrus and its relatives as revealed by SSR markers[J]. Acta Genet Sin, 2003; 30(1): 81-7
16 Chen LG, Hu XQ, Zhao SQ. Molecular research on Huyou origin (text in Chinese with an English abstract) [J]. Acta Hort Sin, 2002;29(3): 276-7
17 Fujita K, Hidaka M, Takamura N, Yamasaki K, Iwakiri T, Okumura M, et al. Inhibitory effects of citrus fruits on cytochrome P450 3A (CYP3A) activity in humans[J]. Biol Pharm Bull, 2003; 26(9): 1371-3

[1]	张可心, 贾文静, 崔佳文, 敖路遥, 周芳, 王广基, 刘嘉莉. 第三代EGFR酪氨酸激酶抑制剂在非小细胞肺癌临床治疗中的应用及研究进展[J]. 中国临床药理学与治疗学, 2022, 27(9): 1016-1030.
[2]	何雪茹, 付裕豪, 荀雪姣, 崔艳军, 董占军. 尿苷二磷酸葡醛酸转移酶介导的酪氨酸激酶抑制剂药物相互作用研究进展[J]. 中国临床药理学与治疗学, 2022, 27(8): 936-945.
[3]	彭娟, 范琳琳, 李然宜, 李晓宇, 吕迁洲, 邹云增. 心力衰竭药物治疗的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(4): 373-381.
[4]	李远方, 崔兆强. 高血压合并高尿酸血症的应对之策[J]. 中国临床药理学与治疗学, 2022, 27(4): 428-432.
[5]	徐建飞, 林利. 高血压药物治疗与非药物治疗研究进展[J]. 中国临床药理学与治疗学, 2022, 27(4): 433-441.
[6]	蒯铮, 张潇伊, 邹云增. 血管紧张素受体脑啡肽酶抑制剂在老年高血压中的应用[J]. 中国临床药理学与治疗学, 2022, 27(4): 442-445.
[7]	娄安琦, 余俊先, 程子昭, 苏强. 布鲁顿氏酪氨酸激酶（BTK）抑制剂与难治性套细胞淋巴瘤[J]. 中国临床药理学与治疗学, 2021, 26(6): 680-686.
[8]	马月, 范方田. 葡萄糖6磷酸脱氢酶在恶性肿瘤中的研究进展[J]. 中国临床药理学与治疗学, 2021, 26(12): 1430-1436.
[9]	李丹云, 牛培广, 史道华 . 基于谷氨酰胺代谢抗肿瘤药物的研究进展[J]. 中国临床药理学与治疗学, 2020, 25(7): 810-816.
[10]	吴茂锋, 刘畅, 戴慧晖, 麦长凤, 黄丹丽, 缪经纬, 刘丽忠, 方翼. pazopanib血药浓度个体差异与细胞色素P450 3A4基因多态性的关系初探[J]. 中国临床药理学与治疗学, 2020, 25(12): 1376-1380.
[11]	常青青，彭英，王广基，孙建国. 抗肝癌小分子酪氨酸激酶抑制剂的临床研究进展[J]. 中国临床药理学与治疗学, 2019, 24(8): 948-956.
[12]	黄馨仪，郭飞，曾祥昌，欧阳冬生. 短链脂肪酸作为信号分子在肠道炎症中的研究进展[J]. 中国临床药理学与治疗学, 2019, 24(11): 1293-1299.
[13]	王璐，郑昕，王维聪，赵洪云，马宇翔，张力，胡蓓，江骥. 艾维替尼在一组中国晚期非小细胞肺癌病人体内单多次给药代谢产物的药代动力学研究[J]. 中国临床药理学与治疗学, 2018, 23(10): 1147-1152.
[14]	袁点，余果，王大新. 酪氨酸激酶抑制剂对QT间期的影响及临床意义研究进展[J]. 中国临床药理学与治疗学, 2017, 22(7): 825-830.
[15]	何苗，范晶，王子卫，赵和照. 胃肠间质瘤临床诊治现状与进展[J]. 中国临床药理学与治疗学, 2017, 22(11): 1315-1320.