问题：大黄的毒副作用是什么?
请描述大黄的毒副作用
回答：大黄为常用中药，具有泻热通肠、凉血解毒，逐瘀通经的功效。用于实热便秘，积滞腹痛，泻痢不爽，湿热黄疸，血热吐衄，目赤，咽肿，肠痈腹痛，痈肿疔疮，瘀血经闭，跌扑损伤，外治水火烫伤；上消化道出血。酒大黄善清上焦血分热毒。用于目赤咽肿，齿龈肿痛。熟大黄泻下力缓，泻炎解毒。用于火毒疮疡。大黄炭凉血化瘀止血。用于血热有瘀出血症。现代医学证明，本品具有导泻、利胆、保肝、抗溃疡、抗菌、抗病毒等作用。目前对于大黄国内文献尚未见有明显的毒性报导，但是近年来国外学术刊物较多地报道了大黄素及其蒽醌类化合物的肾毒性和致癌性。如何正确、全面、深刻认识和评价大黄素及其蒽醌类成分的安全性，是新药研究和评价双方都无法回避的现实问题。审评一部对此十分重视，本人在近期查阅了大量国外文献，其中包括美国国立卫生研究院对大黄素和大黄蒽醌进行长达两年多的实验研究文献报道资料，现将这两篇文献的实验结果加以整理汇总，供同行参考。1 大黄素（emodin） 在进行二年的口饲大黄素实验研究中，大黄素在280, 830, 2500 ppm食物含量中，对F344/N雄性大鼠无致癌性，对F344/N雌性大鼠有可能诱发Zymmbal腺癌的发生，对B6C3F1雄性小鼠，有可能发生少见的肾小管赘生物（renal tuble neoplasms），但发生率较低；大黄素在312， 625，1250 ppm食物含量下，B6C3F1雌性小鼠未发现有致癌性的证据。 大黄素可导致雄性大鼠肾小管透明滴(renal tuble hyaline droplets)和染色(pigmentation) 的发生率增加，可导致雌性大鼠肾小管透明滴的发生率增加，可导致雌雄大鼠肾小管染色的严重性增大，可导致雌雄小鼠肾小管染色的发生率增加，导致雌性小鼠肾病的发生率增加。2 蒽醌 (Anthraquinone) 通过两年给药研究表明，基于肾小管腺瘤（renal tubule adenoma）、肾脏和膀胱迁移性上皮细胞乳头瘤（transitional epithelial papillomas）的发生率增加，表明蒽醌对雄性F344/N大鼠具有致癌性。肝细胞瘤的发生与给予蒽醌有关。基于肾小管腺瘤的发生率增加，表明蒽醌对雌性F344/N大鼠具有致癌性。膀胱移行性上皮细胞乳头瘤或/和癌的发生率以及在雌性大鼠出现的肝细胞腺瘤均与使用蒽醌有关。有明显的证据表明蒽醌可增加雄性和雌性B6C3F1小鼠肝癌的发生率。在雄性和雌性小鼠上的甲状腺滤泡细胞瘤（Thyroid gland follicular cell neoplasms）的产生可能与蒽醌的使用有关。使用蒽醌两年，可引起雄性和雌性大鼠肾、肝、脾、骨髓非肿瘤性损害增加，可引起雄性和雌性小鼠肝、膀胱和脾非肿瘤性损害增加，也可导致雄性小鼠甲状腺和肾脏的非肿瘤性损害。使用蒽醌可使雄性和雌性大鼠单核细胞性白血病的发生率减少。表1. 口饲蒽醌和大黄素在大鼠试验使用剂量与病变程度分析用药时间蒽醌（Anthraquinone）大黄素（Emodin）文献使用量 (mg/kg) 折算成人的临床等效剂量(mg/kg)文献使用量 (mg/kg)折算成人的临床等效剂量(mg/kg) 16-day 508.30 17028.22 48079.67 1400肾232.37 3700肾614.12 14-week 135肾、肝 22.41203.32 275肾、肝 44.82406.64 555肾、肝 89.64 80肾13.28 1130肾、肝 179.28 170肾28.22 2350肾、肝 358.56300肾49.79 2-year 33.77肾、瘤 5.61110肾18.26 67.54肾、瘤 11.22320肾53.11 135肾、瘤 22.441000肾、癌165.98注：表 1文献资料大鼠使用量折算成临床人使用量，按体表面积折算，人按60公斤，大鼠按200克。肾：肾病变，包括肾小管透明小滴生成，堆积，肾矿化；肝：肝肥大；瘤：肿瘤。表2. 口饲蒽醌和大黄素在小鼠试验使用剂量与病变程度分析用药时间蒽醌（Anthraquinone）大黄素（Emodin）文献使用量 (mg/kg) 折算成人的临床等效剂量(mg/kg)文献使用量 (mg/kg)折算成人的临床等效剂量(mg/kg) 16-day 120 14.10 40047.01 1200肾、膀141.03 3800肾、膀446.58 14-week 250膀、肝、瘤 29.38505.88 500膀、肝、瘤 58.76100肾11.75 1050膀、肝、瘤 117.52190肾22.33 2150膀、肝、瘤 235.04400肾47.01 4300膀、肝、瘤 470.09800肾94.02 2-year 90肾、肝、膀、瘤 10.5815肾1.76 265肾、肝、膀、瘤 31.1435肾、瘤4.11 825肾、肝、膀、瘤 96.9570肾、瘤8.23注：表 2文献资料小鼠使用量折算成临床人使用量，按体表面积折算，人按60公斤，大鼠按20克。肾：肾病变，包括肾小管透明小滴生成，堆积，肾矿化；肝：肝肥大；瘤：肿瘤。膀：细胞浆改变。从以上提供的材料，可以看出大黄素和蒽醌，在一定的给药剂量和用药时间下，对大鼠和小鼠可能出现一定的肾毒性和致癌性。据文献资料，目前西方一些国家的用药人群，因长期服用含有芦荟、大黄、番泻叶等制成的泻剂，而出现“黑便”，经检查显示癌症的病人时有出现，经流行病学调查，这些病人可能与长期服用泻剂有关，故西方一些国家如德国、加大拿、西班牙、美国等对这些药用植物有着明确的使用规定。我国是这些药用植物的用药大国，尽管国内尚未见有这方面的毒性报道，我们能否从国外这些文献资料中得到一些启发，引起一些警觉呢?我们在开发含有这些药材的新药时，是否应切实考虑大黄素、蒽醌的用药量、用药时间和适应症的选择呢? 国外学术刊物发表了大量的文章对大黄、芦荟、番泻叶等中所含大黄素、芦荟大黄素等成分进行了较深入的报道，由于文章太多，以下仅随机列出几篇，供参考：1. Mai LP, Gueritte F, Dumontet V, Tri MV, Hill B, Thoison O, Guenard D, Sevenet T. Cytotoxicity of Rhamnosylanthraquinones and Rhamnosylanthrones from Rhamnus nepalensis. J Nat Prod 2001 Sep;64(9):1162-8。Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette Cedex, France.2. Mueller SO, Schmitt M, Dekant W, Stopper H, Schlatter J, Schreier P, Lutz WK. Occurrence of emodin, chrysophanol and physcion in vegetables, herbs and liquors. Genotoxicity and anti-genotoxicity of the anthraquinones and of the whole plants. Food Chem Toxicol 1999 May; 37(5): 481-91 Department of Toxicology, University of Wurzburg, Germany.3. Chung JG, Wang HH, Wu LT, Chang SS, Chang WC.Inhibitory actions of emodin on arylamine N-acetyltransferase activity in strains of Helicobacter pylori from peptic ulcer patients. Food Chem Toxicol 1997 Oct-Nov;35(10-11):1001-7。 Department of Medicine, China Medical College, Taichung, Taiwan, Republic of China.4. Avila H, Rivero J, Herrera F, Fraile G. Cytotoxicity of a low molecular weight fraction from Aloe vera (Aloe barbadensis Miller) gel. Toxicon 1997 Sep;35(9):1423-30。Centro de Investigaciones Biomedicas (BIOMED), Facultad de Ciencias de la Salud, Universidad de Carabobo, Maracay, Venezuela.5. Brusick D, Mengs U. Assessment of the genotoxic risk from laxative senna products. Environ Mol Mutagen 1997;29(1):1-9 。Corning Hazleton Inc., Vienna, Virginia 22182, USA.6. Muller SO, Eckert I, Lutz WK, Stopper H. Genotoxicity of the laxative drug components emodin, aloe-emodin and danthron in mammalian cells: topoisomerase II mediated? Mutat Res 1996 Dec 20;371(3-4):165-73 。Department of Toxicology, University of Wurzburg, Germany.7. Zhang L, Chang CJ, Bacus SS, Hung MC. Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by emodin. Cancer Res 1995 Sep 1;55(17):3890-6 。Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.8. Muller L, Kasper P. OTC pharmaceuticals and genotoxicity testing: the paracetamol, anthraquinone, and griseofulvin cases. Arch Toxicol Suppl 1995;17:312-25。Federal Institute for Drugs and Medical Devices, Berlin, Germany.9. Perkins SL, Livesey JF. A rapid high-performance thin-layer chromatographic urine screen for laxative abuse. Clin Biochem 1993 Jun;26(3):179-81。Division of Biochemistry, Ottawa Civic Hospital, Ont, Canada.10. Wolff FA, Edelbroek PM, de Haas EJ, Vermeij P. Experience with a screening method for laxative abuse. Hum Toxicol 1983 Apr;2(2):385-911. Faber P; Strenge-Hesse A. Senna-containing laxatives: excretion in the breast milk? Geburtshilfe Frauenheilkd 1989 Nov; 49(11):958-612. Lyd’en-Sokolowski A; Nilsson A; Sioberrg P. Two-year carcinogenicity study with sennosides in the rat: emphasis on gastro-intestinal alterations. Pharmacology; VOL 47 Suppl 1, 1993, P209-1513. Villand J. Acute hemorrhagic colitis following administration of sennosides A and B (letter), Presse Med, 14(2):104-5 1985 Jan 1914. Van Gorkom BA; Karrenbeld A; van Der Sluis T; Koudstaal J; de Vries EG; Kleibeuker JH, influence of a highly purified senna extract on colonic epithelium. Digestion, 61(2):113-20 200015. Grimminger W; Witthohn K. Analytics of senna drugs with regard to the toxicological discussion of anthranoids, Pharmacology, 47 Suppl 1(-HD-):98-109 1993 Oct16. Mukhopadhyay MJ; Saha A; Dutta A; De B;Mukherjee A. Genotoxicity of sennosides on the bone marrow cells of mice. Food Chem Toxicol 36(11):937-40 1998 Nov17. Staumont G; Frexinos J; Fioramonti J; Bu’eno L. Sennosides and human colonic motility. Pharmacology, 36 Suppl 1 (-HD-):49-56 198818. Dufour P; Gendre P. Long-term mucosal alterations by sennosides and related compounds. Pharmacology 36 Suppl 1(-HD-):194-202 198819. Hietala P; Marvola M; Parviainen T; Laininen H. Laxative potency and acute toxicity of some anthraquinone derivatives, senna extracts and fractions of senna extracts. Pharmacol Toxicol, 61(2):153-6 1987 Aug20. Mengs U. Toxic effects of sennosides in laboratory animals and in vitro. Pharmacology, 36 Suppl 1(-HD-):180-7 198821. Van Gorkom BA; de Vries EG; Karrenbeld A; Kleibeuker JH. Review article: anthranoid laxatives and their potential carcinogenic effects. Aliment Pharmacol Ther, 13(4):443-52 1999 Apr22. Emeriau JP; Manciet G; Borde C; Raynal F; Galley P. Measurement of the intestinal clearance of alpha 1-antitrypsin and the exchangeable potassium pool in elderly patients treated with anthraquinone glycosides. Gastroenterol Clin Biol; VOL 7, ISS 10, 1983, P799-80123. Lyd ochen-Sokolowski A; Nilsson A; Sjochoberg P. Two-year carcinogenicity study with sennosides in the rat: emphasis on gastro-intestinal alterations. Pharmacology, 47 Suppl 1(-HD-)?:209-15 1993 Oct24. Dufour P; Gendre P. Ultrastructure of mouse intestinal mucosa and changes observed after long term anthraquinone administration. Gut; VOL 25, ISS 12, 1984, P1358-6325. Heidemann A; Miltenburger HG; Mengs U. The genotoxicity status of senna. Pharmacology, 47 Suppl 1(-HD-):178-86 1993 Oct26. Geboes K; Nijs G; Mengs U; Geboes KP; Van Damme A; de Witte P. Effects of ‘contact laxatives’ on intestinal and colonic epithelial cell proliferation. Pharmacology, 47 Suppl 1(-HD-):187-95 1993 Oct27. Leng-Peschlow E. Effect of sennosides and related compounds on intestinal transit in the rat. Pharmacology, 36 Suppl 1(-HD-):40-8 198828. Mengs U. Reproductive toxicological investigations with sennosides. Arzneimittelforschung, 36(9):1355-8 1986 Sep29. Fioramonti J; Staumont G; Garcia-Villar R; Bu ocheno L. Effect of sennosides on colon motility in dogs. Pharmacology, 36 Suppl 1(-HD-):23-30 198830. Frexinos J; Staumont G; Fioramonti J; Bueno L. Effects of sennosides on colonic myoelectrical activity in man. Dig Dis Sci, 34(2):214-9 1989 Feb31. Odenthal KP; Leng-Peschlow E; Voderholzer W; Mochuller-Lissner S. Effects of long-term sennoside treatment on in vitro motility of rat colon. Pharmacology, 47 Suppl 1(-HD-):146-54 1993 Oct32. Leng-Peschlow E; Odenthal KP; Voderholzer W; Mochuller-Lissner S. Chronic sennoside treatment does not cause habituation and secondary hyperaldosteronism in rats. Pharmacology, 47 Suppl 1(-HD-):162-71 1993 Oct33. Mereto E; Ghia M; Brambilla G. Evaluation of the potential carcinogenic activity of Senna and Cascara glycosides for the rat colon. Cancer Lett, 101(1):79-83 1996 Mar 19