Effect of Aristolochic Acid I on Liver Metabolic Enzymes of Mice

doi:10.19803/j.1672-8629.2020.07.05

Abstract

Abstract: Objective To determine the effect of aristolochic acid I (AAI) on the liver metabolic enzymes of mice and the associated mechanism using metabolic kinetics and related techniques. Methods Male 6-week-old C57BL/6 mice were assigned to four treatment groups and one control group. Established doses of AAI (0.2, 2, 10, and 20 mg/kg) were administered intragastrically 5 days per week for 4 weeks. The effects of AAI on liver metabolic enzymes were determined using metabolic kinetics and molecular biology techniques. Results AAI induced enzyme activities and mRNA expressions of liver cyp1a2 and cyp3a11, and increased the content of indoxylsulfuric acid by inducing sulfotransferase (SULT1B1). However, renal toxicity induced by AAI was the main cause of the accumulation of indoxylsulfuric acid in the plasma, liver, and kidney, which in turn aggravated the renal toxicity caused by AAI. Conclusion AAI has multiple effects on liver metabolic enzymes in mice.

Key words: aristolochic acid I, CYP450 enzyme, bile acid synthetase, sulfotransferase, molecular docking

CLC Number:

R994.11

JI Hainan, LI Haishan, SONG Naining, LI Bin, SUI Feng, LI Yingfei, GUO Jiabin, JIA Qiang, LI Hua, GAO Yue, SHEN Guolin. Effect of Aristolochic Acid I on Liver Metabolic Enzymes of Mice[J]. Chinese Journal of Pharmacovigilance, 2020, 17(7): 403-407.

References

[1] Chen, YP.Renal damage associated with Chinese Herbal Medicine[J]. Journal of Clinical Internal Medicine,2003,20(4):174-175.
[2] 梁爱华,高月,张伯礼. 含马兜铃酸中药的安全性问题及对策[J].中国食品药品监管,2017(11):17-20.
[3] Jadot I, Dedeves AE, Nortier J, et al., An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature[J]. Int J Mol Sci, 2017,18(2):297.
[4] Lemy A, Wissing KM, Nortier J, et al.Late on set of bladder urothelial carcinoma after kidney transplantation for end-stage aristolochic acid nephropathy:a case series with 15-year follow-up[J].Am J Kidney Dis,2008,51(3):471-477.
[5] Chan W, Luo H B, Zheng Y, et al.Investigation of the metabolism and reductive activation of carcinogenic aristolochic acids in rats[J].Drug Metab Dispos, 2007,35(6): 866-874.
[6] Stiborova M, Frei E, Arlt V M, et al.Metabolic activation of carcinogenic aristolochic acid, a risk factor for Balkan endemic nephropathy[J]. Mutat Res, 2008, 658(1-2): 55-67.
[7] Schmeiser HH, Stiborova M, Arlt VM.Chemical and molecular basis of the carcinogenicity of Aristolochia plants[J]. Curr Opin Drug Discov Devel, 2009, 12(1):141-148.
[8] Xiao Y, Ge M, Xue X, et al.Hepatic cytochrome P450s metabolize aristolochic acid and reduce its kidney toxicity[J]. Kidney Int,2008, 73(11): 1231-1239.
[9] Xue X, Xiao Y, Zhu H, et al.Induction of P450 1A by 3-methyl-cholanthrene protects mice from aristolochic acid-I-induced acute renal injury[J]. Nephrol Dial Transplant, 2008, 23(10):3074-3081.
[10] Krumbiegel G, Hallensleben J, Mennicke WH, et al.Studies on the metabolism of aristolochic acids I and II[J]. Xenobiotica,1987, 17(8): 981-991.
[11] Schmeiser HH, Pool BL, Wiessler M.Identification and mutagenicity of metabolites of aristolochic acid formed by rat liver[J]. Carcino-genesis, 1986, 7(1): 59-63.
[12] Williams JA, Hyland R, Jones BC, et al.Drug-drug interactions for UDP-glucuronosyltransferase substrates: A pharmacokinetic explanation for typically observed low exposure(AUCI/AUC)ratios[J].
Drug Metab Dispos, 2004, 32(11):1201-1208.
[13] 艾国民, 王庆敏, 邹东云, 等. 高效液相色谱法测定家蝇细胞色素P450O-脱甲基活性[J]. 分析化学, 2009, 37(8):1157-1160.
[14] Benz RJ, Granneman GR.Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions[J].Clin Pharmacokinet, 1997, 32(3):210-258.
[15] Stiborova M, Frei E, Wiessler M, et al.Human enzymes involved in the metabolic activation of carcinogenic aristolochic acids:evidence for reductive activation by cytochromes P450 1A1 and 1A2[J]. Chem Res Toxicol,2001, 14(8): 1128-1137.
[16] Stiborova M, Frei E, Hodek P, et al.Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH: cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid-DNA adducts found in patients with urothelial cancer[J]. Int J Cancer, 2005, 113(2): 189-197.
[17] Shi Z, Chen Y, Dong H, et al.Generation of a 'humanized' hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr d mouse line harboring the poor-affinity aryl hydrocarbon receptor[J]. Biochem Biophys Res Commun,2008, 376(4):775-780.
[18] De Loor H, Meijers BK, Meyer TW, et al.Sodium octanoate to reverse indoxyl sulfate and p-cresyl sulfate albumin binding in uremic and normal serum during sample preparation followed by fluorescence liquid chromatography[J]. Chromatogr A,2009,1216(22):4684-4688.
[19] 崔媛,李海山,宋乃宁等. 马兜铃酸I影响小鼠肝脏脂肪酸β氧化和糖代谢以及TCA 循环的代谢组学研究[J]. 中国药物警戒,2019,16(8):449-466.
[20] Deguchi T, Ohtsuki S, Otagiri M, et al.Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney[J].Kidney Int,2002,61(5):1760-1768.
[21] Muniz Martinez MC, Nortier J, Vereerstraeten P, et al.Progression rate of chinese herb nephropathy: impact of aristolo-chiafangchi in gested dose[J]. Nephrol Dial Transplant,2002,17(3):408-412.
[22] Cosyns JP.Aristolochic acid and 'Chinese herbs nephropathy': a review of the evidence to date[J]. Drug Safe.2003,26(1):33-48.
[23] 中国人民解放军肾脏病专业协作组. 2001例血液透析患者病因分析及高血压和贫血治疗状况[J].中国血液净化,2005,4(5):235-238.
[24] Pahl MV, Vaziri ND.The chronic kidney disease-colonic axis[J].Sermin Dial,2015,28(5):459-463.