To examine pharmacological and toxicological effects of Hovenia dulcis Thunberg and medical herbs extract on acute and chronic carbon tetrachloride-induced organ damaged rats, the hematological and serum biochemical tests were conduced with histopathology of 14 specific organs - liver, kidney, heart...
To examine pharmacological and toxicological effects of Hovenia dulcis Thunberg and medical herbs extract on acute and chronic carbon tetrachloride-induced organ damaged rats, the hematological and serum biochemical tests were conduced with histopathology of 14 specific organs - liver, kidney, heart, spleen, stomach, duodenum, colon, caecum, pancreas, testicles, seminal vesicle, epididymis-capu, epididymis-caudal and prostate. The obtained resulted were as follows. 1. Effect of short-term administration of 6 kinds of medicinal plants extracts including Hovenia dulcis extracts In hematological tests, the number of red blood corpuscles in HDT extracts group were detected as 711.25×104/dl on the third day of the test quite similar to that of normal group. HDTmix group showed a significant(p<0.01, p<0.05) decrease in number of red blood corpuscles as compared with CCl4 group. The mean number of white blood corpuscle in HDT extracts group were detected as 5.01×103/mm3 on the third day of the test, it showed significantly(p<0.05) decreasing tendency as compared with CCl4 group. Hemoglobin content in HDT extracts group showed significantly(p<0.05) increasing tendency on the third day of the test as compared with normal group, however significantly(p<0.05) decreased on the seventh day. In HDTmix group, it significantly(p<0.05) decreased on the third day of the test as compared with CCl4 group, and also significantly(p<0.05) decreased on the seventh day as 12.20mg/dl. In the present study, blood corpuscle volume constantly showed in normal reference ranges, but significantly(p<0.01, p<0.05) decreases were detected in HDT extracts group as compared with normal or CCl4 group, respectively. Mean red corpuscle volume in HDT extracts group was detected as 53.27fl on the third day of the test, it significantly(p<0.01) decreased as compared with normal group, Detected as 58.45fl on the seventh day, significantly(p<0.05) increased as compared with CCl4 group. HDTmix group also showed significantly(p<0.05, p<0.01) increased on the seventh day of the test as compared with normal and CCl4 group, respectively. Corpuscular hemoglobin also constantly showed normal reference ranges. However, it significantly(p<0.05) increased in HDTmix group on the first, third and seventh day of the test as compared with normal and CCl4 group. In Corpuscular hemoglobin concentration, it significantly(p<0.01) decreased on the first, third and seventh day of the test in HDT extract group as compared with normal and CCl4 group, and significantly(p<0.01) decreased in HDTmix group on the seventh day of the test as compared with normal and CCl4 group. In serum biochemical test, serum AST levels of HDTmix group significantly(p<0.01) increased on the fifth day of the test as compared to normal and CCl4 group, and then significantly(p<0.01) decreased on the seventh day. Mean ALT levels in HDT extracts group were detected as 1636.66 lU/L on the first day of the test, it significantly(p<0.01) increased as compared with normal group. However, serum ALT levels on the third day were markedly and significantly(p<0.01) decreased and then progressively decreased as 16.00 lU/L on the seventh day. Significant(p<0.01) increases of serum ALP levels were detected in HDTmix group on the first day of the test as compared with normal group, however, it markedly decreased from the fifth day. Serum ALP levels were significantly(p<0.05) increased in HDT extracts group on the first day of the test as compared with normal group, and it was significantly(p<0.05) decreased from the third day. Serum T-cholesterol levels showed increasing tendency on the third day of the test ranged in normal value, but significantly(p<0.01) decreased on the fifth day. Serum TG levels were significantly(p<0.01) decreased from the fifth day throughout the whole experimental periods. In the present study, variable changes on the serum T-bilirubin levels were detected ranged in normal values, it significantly(p<0.01, p<0.05) increased on the first day of the test as compared with normal group, but recovered as normal reference ranges on the seventh day. Serum BUN levels significantly(p<0.01) decreased in HDTmix group on the fifth day as compared with CCl4 group, and then decreased as 11.00 mg/dl on the seventh day. Serum Creatinine levels also variously changed in normal reference ranges. In CCl4 group, it significantly(p<0.01) increased on the fifth day of the test as compared with normal group, but HDTmix group showed significant(p<0.05) decrease on the fifth day as compared with CCl4 group. Remarkable decreases in degenerative changes detected in liver was observed after treatment of HDT extracts as compared with vehicle control at three and five days after administration of carbon tetrachloride, and degenerative changes of kidney also markedly decreased throughout the observation period. Degeneration of gastric mucous membrane also decreased in the limited area from one day after administering as well. Vacuolation of liver cell, infiltration of inflammatory cell and centro-lobular necrotic findings, classic carbon tetrachloride-induced liver damages were observed with focal necrosis, infiltration of inflammatory cells and fibrogenesis in the kidney. In addition, abnormal sperms, desquamate cells in lumen were also observed in some seminiferous tubule of testicles with atropic changes. Gastric mucosa ulcer and/or erosive lesions were observed with submucosal edema. Meanwhile in heart, any particular abnormal findings were not observed. These degenerative changes detected in liver, kidney, testicles and stomach showed increasing tendency from the third and fifth day, and then they gradually recovered. In addition, these histopathological changes were reconfirmed with histomorphometry in the present study. These degenerative changes detected in liver and kidney were markedly in hibited by treatment of HDTmix as compared with vehicle control regardless of checking time, and mucosal damages of stomach also decreased on one day or three days after administration. Significan (p<0.01 or p<0.05) decrease in degenerative regions of liver, numbers of degenerative hepatocytes, degenerative regions of kidney and abnormal glomerulus were markedly decreased as compared with vehicle control regardless of the inducing periods, and the ratio of ulcer/erosion of gastric mucous membrane and frequency of submucosal edema also significantly(p<0.05) decreased at first or third observation days. Antway, quite similar histopathological findings were detected on testis and heart as compared with vehicle control. HDTmix showed more favorable hepatoprotective and nephroprotective effects as compared with HDT extrcts, the protective effects on the gastric mucous membrane were quite similar to HDT extracts treated group. 2. Effect of long-term administration of 6 kinds of medicinal plants extracts including Hovenia dulcis extracts In hematology test, the number of red blood corpuscles had changed in normal range. The mean number of red blood corpuscles were detected as 743.05×104/dl and 739.90×104/dl, respectively as similar to that in silymarin group, 735.60×104/dl. The number of white blood corpuscle were variably changed ranged in normal values, but it significantly(p<0.05) decreased in HDTmix group on the 21th day of the test, quite similar to silymarin group. In all test groups throughout the entire test, Hemoglobin content were changed in normal range, but similar to that of silymarin, it significantly(p<0.05) increased in HDTmix group on the 21th day as compared with normal group. Change in blood corpuscle volume had been in normal range, total average of blood corpuscle volume in silymarin group was detected as 42.87×103/mm3, slight decreases were detected in HDT extracts group as 40.39×103/mm3 than silymarin group. Change in total average of blood corpuscle volume in HDTmix group showed slight decreased tendency as 41.31×103/mm3, but both two groups showed a similar change in blood corpuscle volume as silymarin group. Red corpuscle volume had changed in normal range, and HDT extracts and HDT mix group showed a similar results as compared with silymarin group. Corpuscular hemoglobin had changed in normal range and HDTmix group showed a similar result of test to silymarin group. In all groups throughout the entire test, Mean corpuscular hemoglobin concentration had changed in normal range. In serum biochemistry, serum AST levels were deceased from the 21th day of the test and then recovered to normal value from the 28th day throughout the entire test in all groups except for CCl4. Serum ALT levels were significantly(p<0.05) decreased in HDT mix group as compared with CCl4 group on seventh day of the test, and then more significantly(p<0.05) decreased from the 21th day. They were also significantly(p<0.01) decreased in Silymarin group as compared with CCl4 group on 28th day of the test, and serum ALP levels were also showed decreasing tendency from the 21th day. Serum T-cholesterol levels in both HDT extracts and HDTmix treated groups showed significantly(p<0.01) decreased as compared with CCl4 group on the seventh day of the test. Silymarin group also showed significantly(p<0.05) decreased as compared with CCl4 group on the seventh day of the test, and also significantly(p<0.01) decreased as 67.40 g/dl on the 14th day. Change in serum TG levels were significantly(p<0.01, p<0.05) increased from the 14th day of the test, but decreased from the 21th day. Serum T-bilirubin levels has changed in normal range throughout the entire test. Serum BUN levels were also changed in normal range, and HDT extracts and HDTmix group showed decreasing tendency from the 21th day of the test. Serum Creatinine levels were changed in normal range, significantly(p<0.01) increases were detected in CCl4 group on the 21th day of the test as compared with normal group, but HDTmix group was showed lower value than CCl4 group as 0.44 g/dl. Liver degenerative changes induced by carbon tetrachloride were markedly decreased in all tested groups as compared with vehicle control from 7th day of administration, decrease in pseudolobulation by fibrogenesis also remarkably decreased from the 21th day throughout the entire test. From the seventh day of administration, degenerative regions and the number of degenerative hepatocytes were also significantly(p<0.01 or p<0.05) decreased respectively, in all groups as compared with vehicle control throughout the entire test. Meanwhile, more favorable hepatoprotective effects was detected in HDTmix than HDT extracts. In kidney, remarkable decrease in histopathological damages of kidney was observed in HDT extracts and HDTmix groups from the seventh day of administration. The nephroprotective effects of silymarin were restricted to the 21 and 28 days after administration. More favorable nephroprotective effects were recognized in HDTmix than HDT extracts, and more favorable hepatoprotective effects were detected in the both HDT extracts and HDTmix than silymarin. Favorable protective effects against abnormal cell mass and atrophic changes of testis were detected in the HDT extracts and HDTmix treated groups from the 7days after administration, however, similar histopathological change of testis were detected in silymarin-treated group as compared with vehicle control group throughout the entire test. More favorable protective effects against testicular damages were observed in HDTmix group than HDT extracts group. However, no meaningful changes were detected in silymarin-treated group. In heart, no particular abnormal changes were detected in all experimental groups including vehicle control. In stomach, remarkable decrease in histopathological changes of stomach such as local erosion or ulcer of gastric mucous membrane and submucosal edema were recognized from the seventh day after administration in the both HDT extracts and HDTmix as compared with vehicle control. More favorable gastric mucous membrane and submucosal protection effects were determined in HDTmix than HDT extracts. However, no meaningful changes were detected in silymarin treated group in the present study. In duodenum, more favorable duodenal mucosa protective effects were recognized in HDTmix group than HDT extracts treated groups, it means a synergic effects of some medicinal herbal extracts with HDT extracts. Anyway, no duodenal mucosal protective effects were observed silymarin-treated group. In the colon and cecum, any particular histopathological change was not recognized in all experimental groups including vehicle control. In the spleen, more favorable protective effects agains hypo immune activity were detected in HDTmix group than HDT extracts treated groups. However, no meaningful changes were detected in silymarin treated group. 3. Toxicity test of 6 kinds of medical plants extracts including Hovenia dulcis extracts Focal inflammatory cell infiltration was restricted to 1 animal (1/4; 25%) of 100mg/kg of HDT extracts-treated groups. Focal fatty changes in the liver were were detected in one animal (1/4; 25%) of HDT extracts 1000mg/kg-dosing group, and 1 (1/5; 20%) and 2 (2/5; 40%) animals in HDTmix 100 and 1000mg/kg-dosing groups, respectively. Focal tubular necrosis in the kidney were restricted to one animal (1/5; 20%) in HDTmix 1000mg/kg-dosing group only. Hyperplasia of white pulps on the spleen was detected in all dosing groups tested in this study. They were detected in 2 (2/4; 50%), 1 (1/4; 25%) and 3 (3/5, 60%) animals in HDT extracts 100, 1000 and 2000mg/kg-dosing groups, respectively and were observed in 4 (4/5; 80%), 5 (5/5; 100%) and 4 (4/4; 100%) animals in HDTmix 100, 1000 and 2000mg/kg-dosing groups, respectively. Slight erosive/ulcerative signs on the surface mucosa of the stomach were restricted to one animal (1/4; 25%) in HDT extracts 1000mg/kg-dosing group with one animal (1/5; 20%) in 100mg/kg of HDTmix-dosing group only. Abnormal spermatozoa in the lumen of the epididymis-caudal was restricted to one animal (1/5 20%) in HDTmix 1000mg/kg-dosing group only. These signs were considered as accidental findings or pharnmacological effects not test article-treatment related toxicological findings because no-dose-dependent was detected in the both HDT extracts and HDTmix-dosing groups.
To examine pharmacological and toxicological effects of Hovenia dulcis Thunberg and medical herbs extract on acute and chronic carbon tetrachloride-induced organ damaged rats, the hematological and serum biochemical tests were conduced with histopathology of 14 specific organs - liver, kidney, heart, spleen, stomach, duodenum, colon, caecum, pancreas, testicles, seminal vesicle, epididymis-capu, epididymis-caudal and prostate. The obtained resulted were as follows. 1. Effect of short-term administration of 6 kinds of medicinal plants extracts including Hovenia dulcis extracts In hematological tests, the number of red blood corpuscles in HDT extracts group were detected as 711.25×104/dl on the third day of the test quite similar to that of normal group. HDTmix group showed a significant(p<0.01, p<0.05) decrease in number of red blood corpuscles as compared with CCl4 group. The mean number of white blood corpuscle in HDT extracts group were detected as 5.01×103/mm3 on the third day of the test, it showed significantly(p<0.05) decreasing tendency as compared with CCl4 group. Hemoglobin content in HDT extracts group showed significantly(p<0.05) increasing tendency on the third day of the test as compared with normal group, however significantly(p<0.05) decreased on the seventh day. In HDTmix group, it significantly(p<0.05) decreased on the third day of the test as compared with CCl4 group, and also significantly(p<0.05) decreased on the seventh day as 12.20mg/dl. In the present study, blood corpuscle volume constantly showed in normal reference ranges, but significantly(p<0.01, p<0.05) decreases were detected in HDT extracts group as compared with normal or CCl4 group, respectively. Mean red corpuscle volume in HDT extracts group was detected as 53.27fl on the third day of the test, it significantly(p<0.01) decreased as compared with normal group, Detected as 58.45fl on the seventh day, significantly(p<0.05) increased as compared with CCl4 group. HDTmix group also showed significantly(p<0.05, p<0.01) increased on the seventh day of the test as compared with normal and CCl4 group, respectively. Corpuscular hemoglobin also constantly showed normal reference ranges. However, it significantly(p<0.05) increased in HDTmix group on the first, third and seventh day of the test as compared with normal and CCl4 group. In Corpuscular hemoglobin concentration, it significantly(p<0.01) decreased on the first, third and seventh day of the test in HDT extract group as compared with normal and CCl4 group, and significantly(p<0.01) decreased in HDTmix group on the seventh day of the test as compared with normal and CCl4 group. In serum biochemical test, serum AST levels of HDTmix group significantly(p<0.01) increased on the fifth day of the test as compared to normal and CCl4 group, and then significantly(p<0.01) decreased on the seventh day. Mean ALT levels in HDT extracts group were detected as 1636.66 lU/L on the first day of the test, it significantly(p<0.01) increased as compared with normal group. However, serum ALT levels on the third day were markedly and significantly(p<0.01) decreased and then progressively decreased as 16.00 lU/L on the seventh day. Significant(p<0.01) increases of serum ALP levels were detected in HDTmix group on the first day of the test as compared with normal group, however, it markedly decreased from the fifth day. Serum ALP levels were significantly(p<0.05) increased in HDT extracts group on the first day of the test as compared with normal group, and it was significantly(p<0.05) decreased from the third day. Serum T-cholesterol levels showed increasing tendency on the third day of the test ranged in normal value, but significantly(p<0.01) decreased on the fifth day. Serum TG levels were significantly(p<0.01) decreased from the fifth day throughout the whole experimental periods. In the present study, variable changes on the serum T-bilirubin levels were detected ranged in normal values, it significantly(p<0.01, p<0.05) increased on the first day of the test as compared with normal group, but recovered as normal reference ranges on the seventh day. Serum BUN levels significantly(p<0.01) decreased in HDTmix group on the fifth day as compared with CCl4 group, and then decreased as 11.00 mg/dl on the seventh day. Serum Creatinine levels also variously changed in normal reference ranges. In CCl4 group, it significantly(p<0.01) increased on the fifth day of the test as compared with normal group, but HDTmix group showed significant(p<0.05) decrease on the fifth day as compared with CCl4 group. Remarkable decreases in degenerative changes detected in liver was observed after treatment of HDT extracts as compared with vehicle control at three and five days after administration of carbon tetrachloride, and degenerative changes of kidney also markedly decreased throughout the observation period. Degeneration of gastric mucous membrane also decreased in the limited area from one day after administering as well. Vacuolation of liver cell, infiltration of inflammatory cell and centro-lobular necrotic findings, classic carbon tetrachloride-induced liver damages were observed with focal necrosis, infiltration of inflammatory cells and fibrogenesis in the kidney. In addition, abnormal sperms, desquamate cells in lumen were also observed in some seminiferous tubule of testicles with atropic changes. Gastric mucosa ulcer and/or erosive lesions were observed with submucosal edema. Meanwhile in heart, any particular abnormal findings were not observed. These degenerative changes detected in liver, kidney, testicles and stomach showed increasing tendency from the third and fifth day, and then they gradually recovered. In addition, these histopathological changes were reconfirmed with histomorphometry in the present study. These degenerative changes detected in liver and kidney were markedly in hibited by treatment of HDTmix as compared with vehicle control regardless of checking time, and mucosal damages of stomach also decreased on one day or three days after administration. Significan (p<0.01 or p<0.05) decrease in degenerative regions of liver, numbers of degenerative hepatocytes, degenerative regions of kidney and abnormal glomerulus were markedly decreased as compared with vehicle control regardless of the inducing periods, and the ratio of ulcer/erosion of gastric mucous membrane and frequency of submucosal edema also significantly(p<0.05) decreased at first or third observation days. Antway, quite similar histopathological findings were detected on testis and heart as compared with vehicle control. HDTmix showed more favorable hepatoprotective and nephroprotective effects as compared with HDT extrcts, the protective effects on the gastric mucous membrane were quite similar to HDT extracts treated group. 2. Effect of long-term administration of 6 kinds of medicinal plants extracts including Hovenia dulcis extracts In hematology test, the number of red blood corpuscles had changed in normal range. The mean number of red blood corpuscles were detected as 743.05×104/dl and 739.90×104/dl, respectively as similar to that in silymarin group, 735.60×104/dl. The number of white blood corpuscle were variably changed ranged in normal values, but it significantly(p<0.05) decreased in HDTmix group on the 21th day of the test, quite similar to silymarin group. In all test groups throughout the entire test, Hemoglobin content were changed in normal range, but similar to that of silymarin, it significantly(p<0.05) increased in HDTmix group on the 21th day as compared with normal group. Change in blood corpuscle volume had been in normal range, total average of blood corpuscle volume in silymarin group was detected as 42.87×103/mm3, slight decreases were detected in HDT extracts group as 40.39×103/mm3 than silymarin group. Change in total average of blood corpuscle volume in HDTmix group showed slight decreased tendency as 41.31×103/mm3, but both two groups showed a similar change in blood corpuscle volume as silymarin group. Red corpuscle volume had changed in normal range, and HDT extracts and HDT mix group showed a similar results as compared with silymarin group. Corpuscular hemoglobin had changed in normal range and HDTmix group showed a similar result of test to silymarin group. In all groups throughout the entire test, Mean corpuscular hemoglobin concentration had changed in normal range. In serum biochemistry, serum AST levels were deceased from the 21th day of the test and then recovered to normal value from the 28th day throughout the entire test in all groups except for CCl4. Serum ALT levels were significantly(p<0.05) decreased in HDT mix group as compared with CCl4 group on seventh day of the test, and then more significantly(p<0.05) decreased from the 21th day. They were also significantly(p<0.01) decreased in Silymarin group as compared with CCl4 group on 28th day of the test, and serum ALP levels were also showed decreasing tendency from the 21th day. Serum T-cholesterol levels in both HDT extracts and HDTmix treated groups showed significantly(p<0.01) decreased as compared with CCl4 group on the seventh day of the test. Silymarin group also showed significantly(p<0.05) decreased as compared with CCl4 group on the seventh day of the test, and also significantly(p<0.01) decreased as 67.40 g/dl on the 14th day. Change in serum TG levels were significantly(p<0.01, p<0.05) increased from the 14th day of the test, but decreased from the 21th day. Serum T-bilirubin levels has changed in normal range throughout the entire test. Serum BUN levels were also changed in normal range, and HDT extracts and HDTmix group showed decreasing tendency from the 21th day of the test. Serum Creatinine levels were changed in normal range, significantly(p<0.01) increases were detected in CCl4 group on the 21th day of the test as compared with normal group, but HDTmix group was showed lower value than CCl4 group as 0.44 g/dl. Liver degenerative changes induced by carbon tetrachloride were markedly decreased in all tested groups as compared with vehicle control from 7th day of administration, decrease in pseudolobulation by fibrogenesis also remarkably decreased from the 21th day throughout the entire test. From the seventh day of administration, degenerative regions and the number of degenerative hepatocytes were also significantly(p<0.01 or p<0.05) decreased respectively, in all groups as compared with vehicle control throughout the entire test. Meanwhile, more favorable hepatoprotective effects was detected in HDTmix than HDT extracts. In kidney, remarkable decrease in histopathological damages of kidney was observed in HDT extracts and HDTmix groups from the seventh day of administration. The nephroprotective effects of silymarin were restricted to the 21 and 28 days after administration. More favorable nephroprotective effects were recognized in HDTmix than HDT extracts, and more favorable hepatoprotective effects were detected in the both HDT extracts and HDTmix than silymarin. Favorable protective effects against abnormal cell mass and atrophic changes of testis were detected in the HDT extracts and HDTmix treated groups from the 7days after administration, however, similar histopathological change of testis were detected in silymarin-treated group as compared with vehicle control group throughout the entire test. More favorable protective effects against testicular damages were observed in HDTmix group than HDT extracts group. However, no meaningful changes were detected in silymarin-treated group. In heart, no particular abnormal changes were detected in all experimental groups including vehicle control. In stomach, remarkable decrease in histopathological changes of stomach such as local erosion or ulcer of gastric mucous membrane and submucosal edema were recognized from the seventh day after administration in the both HDT extracts and HDTmix as compared with vehicle control. More favorable gastric mucous membrane and submucosal protection effects were determined in HDTmix than HDT extracts. However, no meaningful changes were detected in silymarin treated group in the present study. In duodenum, more favorable duodenal mucosa protective effects were recognized in HDTmix group than HDT extracts treated groups, it means a synergic effects of some medicinal herbal extracts with HDT extracts. Anyway, no duodenal mucosal protective effects were observed silymarin-treated group. In the colon and cecum, any particular histopathological change was not recognized in all experimental groups including vehicle control. In the spleen, more favorable protective effects agains hypo immune activity were detected in HDTmix group than HDT extracts treated groups. However, no meaningful changes were detected in silymarin treated group. 3. Toxicity test of 6 kinds of medical plants extracts including Hovenia dulcis extracts Focal inflammatory cell infiltration was restricted to 1 animal (1/4; 25%) of 100mg/kg of HDT extracts-treated groups. Focal fatty changes in the liver were were detected in one animal (1/4; 25%) of HDT extracts 1000mg/kg-dosing group, and 1 (1/5; 20%) and 2 (2/5; 40%) animals in HDTmix 100 and 1000mg/kg-dosing groups, respectively. Focal tubular necrosis in the kidney were restricted to one animal (1/5; 20%) in HDTmix 1000mg/kg-dosing group only. Hyperplasia of white pulps on the spleen was detected in all dosing groups tested in this study. They were detected in 2 (2/4; 50%), 1 (1/4; 25%) and 3 (3/5, 60%) animals in HDT extracts 100, 1000 and 2000mg/kg-dosing groups, respectively and were observed in 4 (4/5; 80%), 5 (5/5; 100%) and 4 (4/4; 100%) animals in HDTmix 100, 1000 and 2000mg/kg-dosing groups, respectively. Slight erosive/ulcerative signs on the surface mucosa of the stomach were restricted to one animal (1/4; 25%) in HDT extracts 1000mg/kg-dosing group with one animal (1/5; 20%) in 100mg/kg of HDTmix-dosing group only. Abnormal spermatozoa in the lumen of the epididymis-caudal was restricted to one animal (1/5 20%) in HDTmix 1000mg/kg-dosing group only. These signs were considered as accidental findings or pharnmacological effects not test article-treatment related toxicological findings because no-dose-dependent was detected in the both HDT extracts and HDTmix-dosing groups.
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