6 : CSH,, CSH 27%, 18.33% (CS), C 2 H 7 NS, 77.15,, ,,,,, C 2 H 7 NS HCl, , 3 5 : 0 (D1) 400 (D2) 1200 (D3) 2400 (D4) 120

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1 34 6 Vol. 34, No ACTA HYDROBIOLOGICA SINICA Nov., DOI: /SP.J 葛红云 2 丁建华张 1 伟薛 1 敏 1,3 郑银桦 1 吴秀峰 3 赵维香 3 王秋艳 1,3 郭利亚 (1.,, ; 2., ; 3., ) :, (Cysteamine Hydrochloride, CSH, 27%) (Micropterus salmoides),, CSH : CSH 648 mg/kg (P<0.05), (P>0.05), mg/kg, (P<0.05) ( CSH27%) 56d (NOAEL) 24 mg/kg w d, CSH 56dNOAEL 6.5 mg/kg w d : ; ; ; (NOAEL) 中图分类号 : X 文献标识码 : A 文章编号 : (2010) (Cysteamine, CS) β-,,, A,, CS, CS (somatostatin, SS), SS, (Growth hormone, GH) SS -I(Insulin-like growth factor-i, IGF-I) (Cholecystokinin, CCK) (T3 T4) [1 3] CS, [1,2], mg/kg, [1 3], 800 mg/kg, [3], ( ),, [4] 1998, (European Medicines Agency, EMEA) (Cysteamine Hydrochloride, CSH) (cystinosis), [5], FDA/USDA [6,7], (, 1126 ), 27%, (no observed adverse effect level, NOAEL), 收稿日期 : ; 修订日期 : 基金项目 : ; (2006BAD12B06)(2006BAD12B08); 作者简介 : (1982 ),, ; ; gehongyun623@163.com 通讯作者 :, xuemin@caas.net.cn

2 6 : CSH,, CSH 27%, 18.33% (CS), C 2 H 7 NS, 77.15,, ,,,,, C 2 H 7 NS HCl, , 3 5 : 0 (D1) 400 (D2) 1200 (D3) 2400 (D4) mg/kg(d5), (CSH) mg/kg, 100, [1 3] GB/T [8] (European Food Safety Authority, EFSA) [9] 5 ( 1) Φ2.0 mm,, (Micropterus salmoides),, ( ),, 24h, [ (14.25±0.1) g], 0.25 m 3, 22,, 2, 9: 00 16: 00, DO>6mg/L, NH 4 -N< Ingredient Tab. 1 表 1 实验饲料配方及营养成分 Experimental diet formulation and nutrition composition Content (%) D1 D2 D3 D4 D5 Peru fishmeal Wheat flour Soybean meal Fish oil Squid liver meal Spray blood meal Wheat gluten meal Lecithin (93%) Calcium phosphate monobasic Vitamins 1 and minerals 2 premix CSH (27%) Analysed chemical composition (in wet basis %) Moisture Crude protein Crude lipid Crude ash Gross energy (MJ/kg) : 1. (mg/kg diet): VB 1 15, VB 2 15, Niacin 100, VB 6 60, VB 12 (1%)4, Ca-pantothenate 50, Biotin 1, Inositol 200, Folic acid 5, Choline chloride 2500, VC 240, VA 20, VD 3 8, VE 300, VK 3 10, α- cellulose162, BHT400; 2. (mg/kg diet): MgSO , NaHCO , FeSO 4 600, ZnSO 4 350, 180, KI 10, Na 2 Se 2 O 3 10, COCl 2 50, CuSO 4 10

3 mg/L, ph , (25±2),, d,,, 5, (alanine transaminase, ALT) (aspartate aminotransferase, AST) (glucose, GLU) (total protein, TP) 2, 0.7%, 24h HE : AOAC(1996) [9] (Beckman coulter CX4 Pro.), UV-2102PC 1.6 (Feed intake, %body weight/d, FI)=100 R 1 (W 0 +W t )/2/days (Feed conversion rate, FCR)=R 1 /(W t + W d W 0 ) (Specific growth rate, SGR, % day)=100 [lnw t lnw 0 ]/t (Survival, %)=100 / (Protein retention ratio, PRR, %) =100 ( )/ (Condition factor, CF, g/cm 3 )=100 (g)/ (cm) 3 (Viscerasomatic index, VSI, %)=100 / (Hepaticsomatic index, HSI, %)=100 /, R 1, W 0, W t, W d, t Statistica6.0 (one-way ANOVA), Duncan s, P< mg/kg,,,,, SGR FI, 2400 mg/kg (D4), FBW SGR FI,, 表 2 饲料中 CSH 对大口黑鲈生长性能的影响 ( 平均值 ± 标准差 ) Tab. 2 Effects of dietary CSH on the growth performance of Largemouth bass (means±s.e.) Groups D1 D2 D3 D4 D5 IBW (g) 14.25± ± ± ± ±0.01 FBW (g) 46.94±0.95 b 47.06±0.70 b 48.62±0.28 bc 50.56±0.84 c 12.00±0.09 a Survival (%) 100±0.0 a 100±0.0 a 100±0.0 a 100±0.0 a 90.6±0.3 b SGR (%) 2.13±0.04 b 2.13±0.03 b 2.19±0.01 bc 2.25±0.03 c 0.31±0.01 a FCR 1.04±0.01 b 1.06±0.01 b 1.03±0.01 b 1.04±0.02 b 3.03±0.34 a FI (%wd) 1.99±0.02 b 2.02±0.01 b 2.00±0.02 b 2.09±0.02 c 0.87±0.04 a PRR (%) 42.2±0.5 a 41.9±0.5 a 43.6±0.3 a 43.6±0.4 a 14.4±1.5 b CF (%) 1.46±0.04 bc 1.40±0.00 b 1.50±0.00 c 1.41±0.04 b 1.16±0.02 a VSI (%) 8.11±0.31 b 7.74±0.17 b 8.08±0.10 b 8.09±0.42 b 4.50±0.41 a HSI (%) 3.05±0.24 b 2.70±0.21 b 2.66±0.14 b 2.56±0.23 b 0.83±0.06 a : (P<0.05); Note: Within the same row, values with different superscripts are significantly different (P<0.05); the same bellow

4 6 : 1145, 100, 2.2 ( 3),,, (ALT) (AST) (GLU) (TP) 2.3 4,,, 2.4 5, CSH ;,, D D1 D4 D5 ( - )(A B C D1 D4 D5 ) 1A,,, 1B, CSH 648 mg/kg,, 1C D5,,, ( ) 2 D1 D4 D5 ( - )(A B C D1 D4 D5 ) 2A,, ; 2B D4 ( ); 2-C, ( ) ( )- ( GH)- ( GHR IGFs) [10] 表 3 饲料中 CSH 对大口黑鲈血液学生化指标的影响 ( 平均值 ± 标准差 ) Tab. 3 Effects of dietary CSH on the haematological profiles of Largemouth bass (means±s.e.) Groups D1 D2 D3 D4 D5 ALT (U/L) ± ± ± ±19.72 AST (U/L) 18.04± ± ± ±1.15 Glu (mmol/l) 8.37± ± ± ±0.09 TP (g/l) 36.83± ± ± ±0.69 表 4 饲料中 CSH 对大口黑鲈全鱼鱼体组成的影响 (% 湿重, 平均值 ± 标准差 ) Tab. 4 Effects of dietary CSH on the whole body compositions of Largemouth bass (means±s.e.) Groups D1 D2 D3 D4 D5 (%) Moisture 71.23±0.33 a 71.17±0.39 a 70.84±0.21 a 71.13±0.07 a 75.24±0.22 b Crude ash 4.56±0.08 a 4.72±0.05 a 4.63±0.13 a 4.81±0.15 ab 5.24±0.17 b Crude protein 17.15±0.10 b 17.03±0.18 ab 17.33±0.09 b 17.47±0.25 b 16.64±0.15 a 表 5 饲料中 CSH 对大口黑鲈淀粉酶胃蛋白酶胰蛋白酶的影响 ( 平均值 ± 标准差 ) Tab. 5 Effects of dietary CSH on the amylase, pepsase and trypsinase of Largemouth bass (means±s.e.) Groups D1 D2 D3 D4 D5 Amylase (U/mg protein) Pepsin (U) Trypsinase (U/mg protein) 0.04± ± ± ± ± ±2.2 b 74.1±7.6 b 82.6±4.5 b 152.7±10.6 c 45.1±5.9 a 2271±33 b 2150±57 b 2866±47 c 3232±120 d 1804±62 a

5 ( - ) Fig. 1 Transversal section of the liver in Japanese sea bass (H & E) A B C mg/kg (Scale Bar=10µm) A, B C, C,, ( ) A, B and C presented the liver of control, 648mg/kg, 32400mg/kg groups, respectively (Scale Bar=10µm). Note that the frequency of pyknosis was increasing in Fig B and C, and showing fatty cell in Fig. C (Arrow) 2 ( - ) Fig. 2 Transversal section of the gut in Japanese sea bass (H & E) A B C mg/kg (Scale Bar=10 µm) A,, ; B ( ); C, ( ) A, B and C presented the gut of control, 648mg/kg, 32400mg/kg groups, respectively (Scale Bar=10µm). Note that the abnormal symptom of intestine villus in Fig B and C, and showing enlarged folds and decreased crypt depth in Fig. C (Arrow), SS, (GH), GH -I (IGF-1) (Insulin) ( T3 T4 ) [5] CSH SS, β- (β-endorphin) GH [11] CSH, CSH ( mol/l) GH, (10 1 mol/l) CSH GH CSH SS GHRH [1], [6,7],, 150 mg/kg,, GH [2] CSH, (CSH 360 mg/kg) [12], 90 mg/kg CSH, [13] mg/kg,, 400 mg/kg, 800 mg/kg [3], mg/kg, CSH, 3.2

6 6 : (D5),, D4, 648 mg/kgcsh,, Roland & Cazenave SS 24h,, 5d, [15] H 2 O 2, [16], [17] (Cystinosis) (ketosis) [5,18,19] CSH LD mg/kg bw, mg/kg bw, CSH [5],, kg 100 kg mg/kg bw; kg mg/kg bw;, 50 mg/kg bw [5] CSH,,, [5], [20] CSH, NOAEL 3.3,,,, 6,,,,,, 20,,, ( 30%) mg/kg,,,,,,, [21] Szabo & Reichlin, CS SS CS 4h 69% 40% SS, CS, CS [22],, CS, CS 300 mg CS, 90 mg CS 150 mg CS ; CS [23] CSH mg/ kg w d (D5 ),, 13.5 mg/kg w d (D4 ),,, D3 56d CSH (NOAEL) 6.5 mg/kg w d,, mg/kg,, 1 mg [5] CSH,,

7 mg/kg CSH, 648 mg/kg, 56d CSH (NOAEL) 6.5 mg/kg w d 100, : [1] Ran X Q, Li W S, Lin H R. Regulation of the expression of growth hormone mrna and the release of growth hormone by somatostatin and cysteamine in orange-spotted groupers Epinephelus coioides [J]. Acta Zoologica Sinica, 2004, 50(2): [,,. SRIF CSH., 2004, 50(2): ] [2] Yu Z G, Xia D Q, Wu T T. Effects of cysteamine hydrochloride and diludin on growth, hormone and physio-biochemical parameters levels in Oreochromis aureus [J]. Journal of Nanjing Agricultural University, 2005, 28(4): [,,.., 2005, 28(4): 96 99] [3] Han J, Yu N. Effects of cysteamine on growth of carps and level of biochemical indexes of blood [J]. Cereal & Feed Industry, 2007, 10: [,.., 2007, 10: 36 43] [4] Biaglow J E, Issels R W, Gerweck L E, et al. Factors influencing the oxidation of cysteamine and other thiols: Implications for hyperthermic sensitization and radiation protection [J]. Radiation Research, 1984, 100: [5] EMEA (European Medicines Agency). Mercaptamine hydrochloride summary report. Committee for Veterinary Medicinal Products (EMEA/MRL/518/98-FINAL) [6] EC (European Committee) No. 1831/2003. Community Register of Feed Additives. Appendixes 3 & 4. Annex: list of additives [7] e-crf (Electronic Code of Federal Regulations). Title 21, Part 573: Food additives permitted in feed and drinking water of animals [8] GB/T Principle of aquafeed safety evaluation Subacute toxicity test [GB/T ] [9] EFSA (Eruopean Food Safety Authority). Technical Guidance: Tolerance and efficacy studies in target animals, prepared by the Panel on Additive and Products or Substances used in Animal Feed [J]. The EFSA Journal, 2008, 778: 1 14 [10] AOAC (1996) Official Methods of Analysis of the Association of Official Analytical Chemists [M]. AOAC, Arlington [11] Xiao D, Lin H R. Effect of cysteamine hydrochloride on growth hormone secretion from hypothalamus-pituitary tissue in juvenile grass carp (Ctenopharyngodon idellus) [J]. Acta Zoologica Sinica, 2003, 49(5): [12] Ai X J, Han Z K, Chen W H. Influences of cysteamine of plasma concentrations of SS and some metabolic hormone in sheep [J]. Acta Veterinaria et Zootechnica Sinica, 2001, 32(6): [,,. CS SS., 2001, 32(6): ] [13] Chen K. Effect of cysteamine hydrochloride on growth of tilapia [J]. Freshwater Fisheries, 2005, 35(1): 7 9 [.., 2005, 35(1): 7 9] [14] Yu Q P, Lin S G, Li G P, et al. Effect of cysteamine hydrochloride on activities of hepatopancreatic digestive enzyme of tilapia [J]. Feed Research, 2007, (8): [,,,.., 2007, (8): 23 25] [15] Lehy T, Dubrasque M, Bonfils S. Effect of somatostatin on normal and gastric-stimulated cell proliferation in the gastric and intestinal mucosae of the rat [J]. Digestion, 1979, 19: [16] Roland J, Cazenave P A. Ly-49 antigen defines anαβtcr population in i-iel with an extrathymic maturation [J]. International Immunology, 1992, 4: [17] Jeitner T M, Lawrence D A. Mechanisms for the cytotoxicity of cysteamine [J]. Toxicological Sciences, 2001, 63: [18] Sieron G, Jendryczko A, Drozdzo M, et al. Decreased activities of catalase and glutathione peroxidase and reduced glutathione content in uterine cervix cancer [J]. Ginekologia Polska, 1988, 59: [19] FDA (Food and Drug Administration, USA). List of Orphan Products Designations and Approvals. 1999, 22 [20] Liu H Y, Zhang W, Xue M, et al. Acute toxicity study for melamine on Japanese sea bass (Lateolabrax japonicus) [J]. Acta Hydrobiologica Sinica, 2009, 33(2): [,,,.,, 2009, 33(2): ] [21] EMEA (European Medicines Agency). Public summary of positive opinion for orphan designation of cysteamine hydrochloride for the treatment of cystinosis. Committee for Orphan Medicinal Products (EMEA/COMP/488783/ 2008draft). 2009

8 6 : 1149 [22] Li Z G, Qi B M, Wang Q X, et al. Effect of cysteamine hydrochloride on intestinal histological structure of tilapia [J]. Feed Research, 2007, (9): [,,,.., 2007, (9): 25 28] [23] Szabo S, Reichlin S. Somatostatin in rat tissues is depleted by cysteamine administration [J]. Endocrinology, 1981, 109: TOLERANCE AND EFFICACY OF CYSTEAMINE HYDROCHLORIDE IN THE DIETS OF LARGEMOUTH BASS (MICROPTERUS SALMOIDES) GE Hong-Yun 1, DING Jian-Hua 2, ZHANG Wei 1, XUE Min 1, ZHENG Yin-Hua 1,3, WU Xiu-Feng 1, ZHAO Wei-Xiang 3, WANG Qiu-Yan 3 and GUO Li-Ya 1,3 (1. Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing ; 2. Aquaculture Technique Distribution Station, Taiyuan ; 3. Beijing Enhalor Biotechnique Co. Ltd. Beijing ) Abstract: The effects of dietary cysteamine hydrochloride (CSH) on growth performance, hematology and histopathology of liver and intestine of largemouth bass (Micropterus salmoides) were conducted for safety assessment of CSH in fish diet. The CSH was designed at levels of 0, 108, 324, 648 and 32400mg/kg diet respectively. The highest dose group was 100 times higher than optimum. The control diet had inclusion with 38.93% crude protein, 9.82% crude fat and MJ/kg gross energy. Each diet was fed to triplicate groups of the experimental fish [initial body weight was (14.25±0.1)g] rearing in a re-circulating system for 8 weeks. The experimental fish were fed twice daily and at the start and end of the experiment, the fish were starved for 24h and batch weighed. Results showed that special growth rate, feed intake and the activity of pepsase, trypsinase in intestine of fish fed diet with 648mg/kg CSH level were significantly higher than those of control group. However, feed conversion ratio, survival, hematological indexes and amylase activity in intestine did not show significant difference from those of control and lower CSH inclusion level groups. In the highest concentration (32400mg/kg), the growth performance, survival and the activity of pepsase, trypsinase of fish were decreased significantly. The frequency of pyknosis in liver and abnormal symptom of intestine in fish fed 648mg/kg diet were observed. Accordingly, the NOAEL of tested additive (including 27% CSH) in the diets of largemouth bass was 24 mg/kg w d. The NOAEL of CSH in the diets of largemouth bass was 6.5 mg/kg w d. Key words: Largemouth bass; Cysteamine hydrochloride; Tolerance; No observed adverse effect level (NOAEL)

中草药 Chinese Traditional and Herbal Drugs 第 46 卷第 9 期 2015 年 5 月 1339 非酒精性脂肪性肝病 (nonalcoholic fatty liver disease,nafld) 是一种与胰岛素抵抗遗

中草药 Chinese Traditional and Herbal Drugs 第 46 卷第 9 期 2015 年 5 月 1339 非酒精性脂肪性肝病 (nonalcoholic fatty liver disease,nafld) 是一种与胰岛素抵抗遗 1338 中草药 Chinese Traditional and Herbal Drugs 第 46 卷第 9 期 2015 年 5 月九味肝泰胶囊对高脂饮食诱导大鼠非酒精性脂肪肝的治疗作用陈菲 1 2,, 艾国 3, 盛柳青 1, 麻佳蕾 1, 黄正明 1. 金华职业技术学院医学院, 浙江金华