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Carcinogenicity Study of Indian Madder Color by 104-week Gavage Exposure in F344 Rats : 천초근(Indian madder color)의 F344 랫드에서 104 주 경구투여에 의한 발암성 연구
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 김대용 | - |
| dc.contributor.author | 강민수 | - |
| dc.date.accessioned | 2017-07-13T16:41:49Z | - |
| dc.date.available | 2017-07-13T16:41:49Z | - |
| dc.date.issued | 2013-02 | - |
| dc.identifier.other | 000000009699 | - |
| dc.identifier.uri | https://hdl.handle.net/10371/120182 | - |
| dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 수의학과 수의병리학전공, 2013. 2. 김대용. | - |
| dc.description.abstract | 천초근(Indian madder color, IMC), 즉 Rubia cordifolia Linne의 뿌리는 식용 색소와 섬유의 염색, 그리고 전통약재로 사용되었다. 그러나, 다른 천초근(Madder color, MC)의 추출물의 연구에서 랫드 간세포와 신장 세뇨관 상피세포에 대한 발암성이 보고되었다. IMC와 MC, 두 종은 유사하므로 IMC 발암성의 가능성이 제기되었으므로 이에 대한 평가가 필요하게 되었다. 그러므로 IMC의 발암성평가를 위해서, F344 rat를 이용한 104 주 발암성 연구를 수행하였다. 40, 200 및 1,000 mg/kg의 투여용량으로 104주 동안 일주일에 다섯 번씩 IMC추출물을 경구 투여하였다. 생존 분석에서 수컷 1,000 mg/kg 투여 그룹에서 비록 빈사동물의 수는 유의성있게 증가되었으나(P<0.05), 폐사와 빈사를 합친 개체 수의 변화는 유의성이 없었다. 투여 77 주 이전에 체중과 사료섭취량은 일부 변화가 관찰되었으나(P<0.05) 용량상관성을 보이지는 않았다. 부검 시 관찰된 대퇴골, 두개골의 뼈에서 주로 관찰된 분홍색으로의 변색은 암수1,000 mg/kg 투여 그룹에서 유의성(P<0.01)있게 증가되었다. 간세포의 난원세포증식은 수컷 40, 200, 그리고 1,000 mg/kg 투여 그룹에서 증가하였다. 그리고 신장 유두부위 광물화(mineralization)는 수컷 1,000 mg/ kg 투여 그룹에서 증가하였으나 수질부의 광물질화(mineralization)는 암컷 1,000 mg/kg 투여 그룹 (P<0.01)에서 감소하였다. 대조군에 비해 암수의 1,000 mg/kg 투여 그룹에서 종양성(neoplastic) 병변은 큰 차이를 보여주지 않았다. 그러므로 본 연구은 104 주 동안 IMC의 투여에 의한 발암성이 없는 것으로 나타났다. 이러한 결과에서 IMC의 NOAEL은 1,000 mg/kg 이었다. | - |
| dc.description.abstract | Indian madder color (IMC), one of Radix Rubiae in herbal medicine, has been used for food coloring, and dye of textiles. However, madder color, another kind of Radix Rubiae, has been reported to have carcinogenicity in the liver and kidney of laboratory animals. So a carcinogenicity evaluation of IMC was needed because they are close-related species. For the risk assessment of IMC, 104-week carcinogenicity study was carried out. F344 rats were treated with hydrothermal extract of IMC for five times per week during 104 weeks by oral gavage at dose levels of 40, 200 and 1,000 mg/kg. In survival analysis, the number of overall unscheduled dead rats was not significantly changed, though the number of moribund rats in male 1,000 mg/kg dose group was significantly increased (P<0.05). The body weight and food consumption were changed significantly until 77 weeks (P<0.05), but the changes did not show dose-dependency. Macroscopically, cases with pink discoloration of bone, mainly in femur and skull was significantly increased in male and female 1,000 mg/kg dose groups (P<0.01). Microscopically, hepatic oval cell hyperplasia was significantly increased in male 40, 200 and 1,000 mg/kg dose groups. And renal papillary mineralization and pigmentation was significantly increased in male 1,000 mg/kg dose group (P<0.01). And no significant difference in neoplastic lesions was in male and female 1,000 mg/kg dose groups compared to control. These results do not show that IMC had a toxic effect at 1,000 mg/kg dose. From these results, oral treatment of IMC for 104 weeks in F344 rats had no carcinogenicity and the no-observed-adverse-effect level of IMC was 1,000 mg/kg dose. | - |
| dc.description.tableofcontents | Abstract i
Table of Contents ii Literature Review 1 Carcinogenicity study 1 Carcinogenicity study of herbal medicine 3 Indian madder color (IMC) 4 Chemical constituents of IMC 4 Pharmacological effect of IMC 6 Carcinogenicity study of Rubiae Radix 8 Chapter 1. A 104-week carcinogenicity study of Indian madder color by gavage in F344 rats 9 Introduction 10 Materials and Methods 12 Chemicals 12 Experimental animals 12 Study design overview 13 Administration 14 Clinical signs 14 Body weight 14 Food consumption 14 Ophthalmic examination 15 Hematology 15 Serum biochemistry 15 Necropsy findings and organ weights 16 Histopathology 16 Statistical methods 17 Results 19 Chemicals 19 Survival analysis 19 Body weight 20 Clinical sign and ophthalmological results 20 Hematological and serum biochemistry results 21 Organ weights 21 Necropsy findings 21 Cause of death 21 Histopathological findings 22 Discussion 24 Chapter 2. Histopathological analysis in the IMC carcinogenicity study 27 Introduction 28 Methods 30 Histopathology 30 Statistical methods 31 Results 32 Scheduled dead rats 32 Unscheduled dead rats 33 Scheduled and unscheduled rats 37 Discussion 39 Conclusions 45 References 46 국문초록 120 Figures and Tables Figure 1. Flower, leaves, stalk and root of Rubia cordifolia Linne (left) and dried roots (right). 50 Figure 2-1. LuP metabolism in the rats. 51 Figure 2-2. AlP metabolism in the rats. 52 Figure 3. Kaplan-Meier survival curves (male). Survival curve of 1,000mg/kg dose group (G4), were dropped rapidly but the survival rate are insignificant by log-rank test. 53 Figure 4. Kaplan-Meier survival curves (female). There is no dose-dependent change in the graph and have no statistical significance by log-rank test. 54 Figure 5. Body weight graph of males and females. Body weight of treatment groups increase similarly with control group. 55 Figure 6. Average food consumption of males. Food consumption in male has significant changes in the graph, but they are fluctuating. 56 Figure 7. Average food consumption of females. Graph show the food consumption per day in females and is fluctuating but they have similar pattern. 57 Figure 8. Organ distribution of LGL leukemia/lymphoma in males. In male incidence of LGL leukemia/lymphoma is high over 60% and all of them can be recognizable by spleen suggesting primary site. 58 Figure 9. Organ distribution of LGL in females. In females, incidences of LGL leukemia/lymphoma are also high in the spleen and liver. 59 Figure 11. Spleen, LGL leukemia/lymphoma. Neoplastic round cells are abundant in red pulp with prominent congestion. 60 Figure 12. Liver, LGL leukemia/lymphoma. Neoplastic round cells are infiltrating into the sinusoid and the hepatic parenchyma. The cells tend to be pleomorphic and large, with round to irregular-shaped nuclei and cytoplasmic granules. 61 Figure 13. Testes, interstitial cell adenoma. Tumors are composed of neoplastic cells compressing adjacent tubules, abundant finely vacuolated/granular eosinophilic cytoplasm. 62 Figure 14. Adrenal gland, pheochromocytoma. Note the large mass of proliferating cells which has cytology variable range from small, dark, lymphocyte-like cells to plump pale basophilic cells. 63 Figure 15. Pituitary gland, the pars distalis adenoma. Note the well delineated mass of cells that compresses the surrounding parenchyma. The neoplastic cells are arranged in compact branching cords with marked hemangiectasis. 64 Figure 16. Thyroid gland, follicular adenoma. Neoplastic cells are monomorphic and arranged in the prominent tubular structures at the margin of the mass. 65 Table 1. Alizarin, lucidin and rubiadin concentration using the water-based or ethanol-based extract methods (Kim et al., 2007) 66 Table 2. Guidelines of carcinogenicity and chronic study by regulatory agencies 67 Table 3. Survival table 68 Table 4. Summary of hematological test 69 Table 5. Summary of clinical biochemistry test 71 Table 6. Significant changes of absolute and relative testis weights (scheduled sacrificed rats, Absolute (g) & relative (%) organ weights) 73 Table 7. Necropsy findings with significant changing when compare dose groups to control group 74 Table 8. Cause of death summary in all examined rats 76 Table 9-1. Group percent of neoplasm incidences (scheduled dead rats) 77 Table 9-2. Group percent of neoplasm incidences (unscheduled dead rats) 78 Table 9-3. Group percent of neoplasm incidences (unscheduled dead rats, week 81-105) 79 Table 10-1. Incidences of all lesions of unscheduled dead rats (week 51-80) 80 Table 10-2. Incidences of all lesions of unscheduled dead rats (week 81-105) 81 Table 11. Incidences of histopathological lesions in the liver of scheduled dead rats 82 Table 12. Incidences of histopathologic lesions in the kidney of scheduled dead rats 83 Table 13. Statistically significant neoplasm in unscheduled female groups with Fishers exact test 84 Table 14. LGL leukemia/lymphoma in the all examined rats with poly-3 test 85 Table 15. Nonneoplastic lesion incidence in selected organs (all examined rats) 86 Table 16. Summary table of increased lesions from the results of poly-3 test. 87 Table 17. Pathological findings with grade in the adrenal gland 88 Table 18. Pathological findings with grade in the kidney 89 Table 19. Pathological findings with grade in the preputial gland 90 Table 20. Pathological findings with grade in the lung 91 Table 21. Pathological findings with grade in the sternum (bone marrow) 92 Table 22. Pathological findings with grade in the spleen 93 Table 23. Pathological findings with grade in the liver 94 Table 24. Incidences of neoplastic and other proliferative lesions in all examined rats (in life time) 97 Table 25. Histopathology summary in the scheduled dead rats 104 | - |
| dc.format | application/pdf | - |
| dc.format.extent | 3584377 bytes | - |
| dc.format.medium | application/pdf | - |
| dc.language.iso | en | - |
| dc.publisher | 서울대학교 대학원 | - |
| dc.subject | F344 rat | - |
| dc.subject | Indian madder color | - |
| dc.subject | Carcinogenicity test | - |
| dc.subject | No-observed-adverse-effect level | - |
| dc.subject.ddc | 636 | - |
| dc.title | Carcinogenicity Study of Indian Madder Color by 104-week Gavage Exposure in F344 Rats | - |
| dc.title.alternative | 천초근(Indian madder color)의 F344 랫드에서 104 주 경구투여에 의한 발암성 연구 | - |
| dc.type | Thesis | - |
| dc.contributor.AlternativeAuthor | Min-Soo Kang | - |
| dc.description.degree | Doctor | - |
| dc.citation.pages | v, 121 | - |
| dc.contributor.affiliation | 수의과대학 수의학과 | - |
| dc.date.awarded | 2013-02 | - |
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