104-Week Feed Studies of Juzen-taiho-to in F344 Rats

Transcription

1 Ann. Rep. Tokyo Metr. Res. Lab. P.H., 51, , Week Feed Studies of Juzen-taiho-to in F344 Rats YOSHIMITSU SAKAMOTO, YUKIE TADA, KUNIAKI TAYAMA, AKEMICHI NAGASAWA, NOBUTAKA FUKUMORI, NORIO YANO KATSUHIRO YUZAWA, HIROSHI TAKAHASHI, TORAO IKEDA and NAOTO AOKI Chronic toxicity of Juzen-taiho-to, a Chinese medicine, in F344 rats was examined. Groups of F344 rats, each consisted of 20 males and 20 females, were fed a pelleted diet containing Juzen-taiho-to at concentrations of 0 (control), 0.2, 0.8 and 3.2% for 104 weeks. The dose of 0.2% Juzen-taiho-to corresponds to the therapeutic dose in humans. Following the completion of the experiment, no difference was observed in survival between the treated and control groups of both sexes. There was no evidence of adverse effects of the treatment on the body and organ weights, hematology and serum biochemical examination. A variety of non-neoplastic and neoplastic lesions was observed in all groups, including the controls, but all were those known to occur spontaneously in F344 rats. No significant increase in the severity and/or incidence of any lesion was found for either sex in the treated groups. Under the present experimental condition, there was no evidence of toxic effects and carcinogenicity of Juzen-taiho-to in rats. Additionally, chronic nephropathy (a spontaneous lesion) was milder in the treated groups than the control groups. This result suggests that Juzen-taiho-to may retard the progression of chronic nephropathy. Keywords Juzen-taiho-to, chinese medicine, F344 F344 rats, week feeding test 1-5) 6) 13 7) 13 8) 9) F F344/DuCrj 1 7) CE The Tokyo Metropolitan Research Laboratory of Public Health 24, Hyakunincho, Shinjuku-ku, Tokyo, Japan

2 302 Ann. Rep. Tokyo Metr. Res. Lab. P.H., 51, 2000 Table Survival, Body Weight, Food Consumption, lntake of Juzen-taiho-to and Water Consumption Juzen-taiho-to intake Body weight (g) Mean food Mean water consumption Daily Total consumption Dose Survival Initial final (g/rat/day) (mg/kg/day) (g/kg/104 wks) (g/rat/day) Male 0% 16/20 a) b) % 15/ % 16/ % 16/ , Female 0% 16/ % 18/ % 18/ % 15/ , , a) initial number/number at autopsy b) mean SD % 0.2%g/50kg100 mg/kg E 400 KK Automatic Analyzer 7150 Table Table 10% 7) Fisher s exact test % Table 80% 75 90% g11g Table 17 33g13 21g 0.2% Table % 0.2% (CA) 3.2% (UN) (TG) (UA) TG 3.2% UA 3.2% Table

3 51, Table Biochemical Examination in Male and Female Rats Dose 0% (control) 0.2% 0.8% 3.2% Male 16 a) ALP lu/l b) c) ALT lu/l 41 9 d) c) d) AST lu/l d) c) d) ALB g/dl T-CHO mg/dl CRE mg/dl TG mg/dl c) * TP g/dl UA mg/dl UN mg/dl CA mg/dl * * NA mg/dl Female 16 a) ALP lu/l b) ALT lu/l e) AST lu/l ALB g/dl T-CHO mg/dl CRE mg/dl TG mg/dl TP g/dl UA mg/dl UN mg/dl * CA mg/dl * NA meq/l Abbreviation : ALP=alkaline phosphatase, ALT= alanine aminotransferase, AMY= amylase, AST= aspartate aminotransferase, ALB=albumin, T-CHO=total cholesterol, CRE=creatinine, TG=triglyceride, TP=total protein UA=uric acid, UN=urea nitrogen, CA=calcium, NA=sodium a) No. of rats examined. b) Values are means SD c) n=14 d) n=15 e) n=17 * : Significantly diffrent from control, (p<0.05) %1 Table Coleman 9) gradee (end stage) grade E Table grade 15/16 (94%) 0.2% /15 (60%) 0.8% /16 (44%) 3.2% /16 (44%) /16 (56%) 0.2% /18 (33%) 0.8% /18 (39%) 3.2% /15 (13%)

4 304 Ann. Rep. Tokyo Metr. Res. Lab. P.H., 51, 2000 Table Organ Weights in Male and Female Rats Dose 0% (control) 0.2% 0.8% 3.2% Male 16 a) Brain (mg) 2, b) 0 2, , , (514 57) c) (506 53) (494 27) (510 74) Liver (g) ( ) 0( ) 0( ) 0( ) Kidney (R) (mg) 1, , , , (355 49) (354 58) (332 17) (340 42) Spleen (mg) 01, d) 1, , , ( ) 0( ) 0( ) 0( ) Testis (R) (mg) 02,295 1,080 1, , , ( ) 0( ) 0( ) 0( ) Prostate (mg) (55 18) 0(58 20) 0(56 21) 0(64 20) Adrenal (R) (mg) ( ) 0( ) 0( ) 0( ) Female 16 a) Brain (mg) 1, b) 0 1, , , (692 77) c) (670 91) (667 74) (669 68) Liver (g) ( ) 0( ) 0( ) 0( ) Kidney (R) (mg) (339 61) (341 59) (329 34) (336 29) Spleen (mg) e) e) ( ) (176 43) (183 40) (190 57) Ovary (R) (mg) ( ) ( ) ( ) ( ) Uterus (mg) (307 77) 0( ) (296 77) (309 80) Adrenal (R) (mg) ( ) 0( ) 0( ) ( ) a) Number of rats weighed. b) Absolute weights (mean SD). c) Relative weights (mg or g/100gbody weight ; mean SD). d) N=15 e) N=17 Table Incidence and Severity of Chronic Nephropathy of Male and Female Rats Table 90% 70 90%5% 0.2%35% 0.8% 25% 3.2% 20% 25% 0.2% 25% 0.8% 40% 3.2% 25% 0.8% Dose No. of rats Grade a) observed Male 0% (Control) % % % Female 0% (Control) % % % a) : Grade by Coleman et. al 9)

5 51, Table Neoplastic Lesions of Male and Female Rats Male Female Site and types of tumours 0% 0.2% 0.8% 3.2% 0% 0.2% 0.8% 3.2% Effective no. of rats Pituitary Adenoma 11 a) Thyroid Follicular cell adenoma Follicular cel carcinoma C-cell adenoma Parathyroid Adenoma Adrenal gland Pheochromocytoma Liver Adenoma Pancreas lslet cell adenoma Tongue Suamous cell papiloloma Lung Adenoma Adenocarcinoma Haematopoieteic organ Mononuclear cell leukemia Urinaly bladder papilloma Testis Interstitial cell tumour Uterus Endometrial stromal polyp Ovary Cystadenoma Thecoma Prepeutial/clitoral gland Adenoma Squamous cell papiloma Mammary gland Adenoma Fibroadenoma Adenocarcinoma Skin/Subcutis Fibroma Lipoma Keratoacanthoma Malignant fibrous histiocytoma Zymbal gland Anenoma Squamous cell carcinoma Abdominal cavity Mesothelioma a) No. of rats with tumors.

6 306 Ann. Rep. Tokyo Metr. Res. Lab. P.H., 51, 2000 C % 10) 11) 109 UN CA TG UA UN UA (CRE) 12) 13 7 UN UA CRE UN UA UN UA TG 13 7) CA 9) 0.2% ) ) F % , 1996, 19, , 1995, 1 9, 13-17, , , , , , , , , , , 1997 Coleman G., Bartholod S.W., Osbaldiston G.W., et.al. : J.Gerontology, 32, ,

7 51, , , pp 33-36, , 1988, 13 Haseman j.k., Hailey J.R. and Morris R.W. : Toxicologic Pathology, 26, , Maita K., Hirano M., Harada T., et.al. : J. Toxicol. Science, 12, , Maekawa A., Kurokawa Y., Thakahashi M., et.al.: Gann, 74, , 1983