Possible model of liver carcinogenesis using inhibitors of NAD+ ADP ribosyl transferase in rats

The response of cellular NAD+ metabolism to DEN and/or ABA and the carcinogenesis of the liver initiated by DEN and ABA were studied in rats. The liver NAD+ level was depleted by an ip injection of 20 mg or 200 mg/kg body weight of DEN. ABA, administered ip at a dose of 600 mg/kg simultaneously with or 4 hours after DEN, prevented the depletion of NAD+ by DEN. These biochemical findings correlated with the changes of conspicuous intranuclear immunofluorescence of poly(ADP-ribose), which were studied by immunohistochemistry. When initiated by 20 mg/kg body weight DEN and 600 mg/kg ABA and then processed to selection pressure, the liver was found to be capable of developing hepatocellular carcinomas with or without PB promotion. These results suggest that the inhibition of poly(ADP-ribosylation) might lead to irreversible initiation of liver carcinogenesis by DEN in rats.     

Dose-related induction of hepatic preneoplastic lesions by diethylnitrosamine in C57BL/6 mice

The C57BL/6 mouse strain (or derivation of this strain) is used as a background for many transgenic mouse models. This strain has a relatively low susceptibility to chemically induced hepatocarcinogenesis compared with other commonly used experimental mouse strains. In the present study, the authors treated C57BL/6 mice with 25, 50, and 75 mg/kg of diethylnitrosamine (DEN) for 4 or 8 weeks by intraperitoneal injection to investigate the dose-response pattern of preneoplastic and neoplastic lesion formation in the liver. DEN induced preneoplastic lesions and cytokeratin 8/18-positive foci in a dose-dependent manner. In the 75 mg/kg for 8 weeks treatment group, hepatocellular adenoma, cholangioma and hemangioma, and cytokeratin 19-positive foci were also induced, but a significant decrease in body weight was observed. The suitable DEN treatment range for this strain was concluded to be from 75 mg/kg for 4 weeks (total amount = 300 mg/kg) to 50 mg/kg for 8 weeks (total amount = 400 mg/kg). These results should prove useful for future studies investigating hepatocarcinogenesis in both the background C57BL/6 strain and other transgenic mouse models derived from it.     

Influence of the nature and the dose of the initiator on the development of premalignant and malignant lesions in rat hepatocarcinogenesis

Using a triphasic protocol recently described to induce malignant tumors in rat liver, the question has been asked whether both the nature and the dose of the initiator influence the carcinogenic process. Two nitrosamines (diethylnitrosamine DEN and N-nitrosomorpholine NNM) have been used to initiate that process. With regard to the premalignant stages appearing in the liver up to 19 weeks after initiation, there is a dose-dependent relationship between the dose of initiator and both the percentage of the parenchyma occupied by and the number of GGT+ lesions. DEN is always more potent than equivalent doses of NNM. With regard to malignant tumors appearing within the period of observation (up to 44 weeks), the two highest doses (100 and 200 mg/kg) of DEN appear to be the only carcinogenic treatments. Cancer incidence (percentage of rats bearing histologically characterized malignant tumor) is the same after both treatments, but the tumor yield (number of tumors per rat bearing macroscopic tumors) is higher (+/- 2X) after 200 mg/kg than after 100 mg/kg.     

Possible prevention by abieslactone of development of diethylnitrosamine-initiated GST-P positive foci in the rat liver

Triterpenoid compounds, isolated from plants of Abies genus (Pinceae), are known to exert anti-tumor promotion activities in mouse skin carcinogenesis. In the present study, we investigated whether AVB-1 and acid and acid methyl ester derivatives have inhibitory effects on rat hepatocarcinogenesis by using a liver medium-term bioassay for carcinogens (Ito's test), immunohistochemically assessing the numbers and areas per cm(2) of preneoplastic lesions, glutathione S-transferase placental form (GST-P)-positive foci. In experiment 1, 6-week-old male Fisher 344 rats were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg b.w.) and subjected to two-thirds partial hepatectomy at week 3. From weeks 2 to 8, the compounds were given three times a week at a dose of 1 mg/kg b.w. by i.g. gavage and found to significantly decrease the number of GST-P-positive foci in the liver. In experiment 2, AVB-1 was given three times a week at doses of 3, 1, or 0.3 mg/kg b.w. by i.g. gavage from weeks 2 to 8. All doses of AVB-1 significantly decreased the numbers of GST-P-positive foci. Thus, our results suggest that AVB-1 is a chemopreventive agent for rat hepatocarcinogenesis.     

Peroxisomal enzymes and 8-hydroxydeoxyguanosine in rat liver treated with perfluorooctanoic acid

Although peroxisome proliferators are considered non-genotoxic agents, most of them, nevertheless, were found to promote and/or induce, hepatocellular carcinoma (HCC) in rodents. The aim of the present study is, first, to investigate whether the peroxisome proliferator perfluorooctanoic acid (PFOA) possesses inherent liver cancer promoting activity, and second, to study the possible mechanisms involved. To acheive these aims two protocols have been applied, a biphasic protocol (initiation by diethyl-nitrozamine (DEN) 200 mg/kg i.p. followed by treatment with 0.005% or 0.02% perflourooctanoic acid (PFOA) for 14 and 25 weeks) and a triphasic initiation, selection-promotion (IS) protocol (initiation by giving 200 mg/kg DEN i.p. followed by a selection procedure for 2 weeks consisting of giving 0.03% 2-acetylaminofluorene (2-AAF) in diet). In the middle of this treatment a single oral dose of carbon tetrachloride (2.0 ml/kg) was given, followed by giving diet containg 0.015% of PFOA for 25 weeks. After applying both protocols, our results showed slight increase in the catalase activity while acyl CoA oxidase activity was markedly increased. Both experiments indicated that PFOA has a liver cancer promoting activity. Other groups of rats were given either basal diet or diet containing 0.02% PFOA. Five or nine weeks later they were sacrificed and the levels of 8-hydroxydeoxyguanosine in the isolated DNA were estimated. The data showed a slight nonetheless insignificant increase in 8-hydroxydeoxyguanosine. From the present data, it is concluded that PFOA is a true liver cancer promoter that may not require extensive initial DNA damage for its promoting activity.     

Role of estrogens as promoters of hepatic neoplasia

The administration of estrogens to humans has been associated with the development of benign and possibly malignant hepatocellular neoplasms. This study was designed to investigate the mechanism of this association. We present a rat model that demonstrates that stilbestrol (DES) and ethinyl estradiol promote the development of hepatic neoplasms in rats previously initiated with diethylnitrosamine (DEN). Eighty male and 12 female Fischer-344 rats were given a single intraperitoneal injection of either DEN (200 mg. per kg. of body weight) or saline. Beginning 4 weeks after injection, the rats were given an estrogen or corn oil twice weekly for up to 50 weeks. Treatments were stopped at the time of sacrifice or 11 to 29 weeks prior to sacrifice. Estrogen treatments included high dose DES (5 mg. per dose), low dose DES (0.5 mg. per dose), and ethinyl estradiol (0.2 mg. per dose). Male and female rats given both DEN and high dose DES developed grossly visible hepatic hyperplastic nodules (mean, 9.1 per liver) after 20 weeks of DES. Nodules also developed if the onset of DES treatment was delayed until 28 weeks after initiation. Rats given DEN alone or DES alone did not develop nodules after 20 weeks. Microscopic hyperplastic foci also developed in rats given DEN plus DES, DES alone, and DEN alone. The foci in rats given DES alone were largely reversible on cessation of estrogen therapy. Mitotic activity in foci and nodules was prominent during estrogen therapy but declined markedly after cessation of therapy. Similar promoting activity of ethinyl estradiol was observed. Low dose DES was not effective in promoting tumor formation. The data indicate that estrogens promote hepatic neoplasia, perhaps by increasing hepatocyte mitotic activity and thereby facilitating the evolution of previously initiated cells into neoplastic clones. Comparison with human disease should be made with caution, especially because the estrogenic dose administered was approximately 200-fold the usual contraceptive dose in humans. However, the analogy between this model and the development of human oral contraceptive-associated hepatic tumors is evident. It is possible that some women have latent "initiated" cells that divide faster than the surrounding hepatocytes in response to estrogens.     

Tomato oleoresin inhibits DNA damage but not diethylnitrosamine-induced rat hepatocarcinogenesis

Various studies have shown that lycopene, a non-provitamin A carotenoid, exerts antioxidant, antimutagenic and anticarcinogenic activities in different in vitro and in vivo systems. However, the results concerning its chemopreventive potential on rat hepatocarcinogenesis are ambiguous. The aim of the present study was to investigate the antigenotoxic and anticarcinogenic effects of dietary tomato oleoresin adjusted to lycopene concentration at 30, 100 or 300 ppm (administered 2 weeks before and during or 8 weeks after carcinogen exposure) on liver of male Wistar rats treated with a single intraperitoneal dose of 20 or 100mg/kg of diethylnitrosamine (DEN), respectively. The level of DNA damage in liver cells and the development of putative preneoplastic single hepatocytes, minifoci and foci of altered hepatocytes (FHA) positive for glutathione S-transferase (GST-P) were used as endpoints. Significant reduction of DNA damage was detected when the highest lycopene concentration was administered before and during the DEN exposure (20mg/kg). However, the results also showed that lycopene consumption did not reduce cell proliferation in normal hepatocytes or the growth of initiated hepatocytes into minifoci positive for GST-P during early regenerative response after 70% partial hepatectomy, or the number and area of GST-P positive FHA induced by DEN (100mg/kg) at the end of week 10. Taken together, the data suggest a chemopreventive effect of tomato oleoresin against DNA damage induced by DEN but no clear effectiveness in initiating or promoting phases of rat hepatocarcinogenesis.     

Pathology of diethylnitrosamine toxicity in the fish Rivulus marmoratus

Rivulus marmoratus were exposed to 0, 10, 21, 45, 95, or 200 mg/liter diethylnitrosamine (DEN) for 6 weeks and examined 12 weeks after the end of exposure. Fatty change, hepatocellular glycogenosis, multiple basophilic foci, enlarged and distorted cells with or without an enlarged nucleus, and hyaline bodies and cytological alterations observed after exposure to DEN. Hemangiomas, cholangiomas, biliary cystadenomas, and glandular, trabecular and anaplastic hepatocellular carcinomas were observed at the 18th week. Only those fish exposed to 95 mg/liter DEN had cavernous hemangiomas and peliosis-like lesions, which could be a preneoplastic lesion preceding cavernous hemangiomas. Adenomatous hyperplasia of thyroid and granulomas were other chronic reactions caused by DEN toxicosis.     

The sequential analysis of liver cell necrosis: inhibition of diethylnitrosamine- and dimethylnitrosamine-induced acute liver cell death by posttreatment with diethyldithiocarbamate.

Posttreatment with diethyldithiocarbamate (DEDTC) largely prevented the development of acute hepatocellular necrosis induced by diethylnitrosamine (DEN) and dimethylnitrosamine (DMN) in male Fischer rats as monitored by the release of glutamate-pyruvate transaminase and sorbitol dehydrogenase into the serum and by histologic examination. Liver cell necrosis was evident with a dose of 25 mg of DEN/kg and was progressive with increasing doses of DEN. DEDTC (50 mg/kg; three times at 4-hour intervals) was given at 4 or 8 hours after the administration of DEN (100 mg/kg), time points at which at least 50% and 75%, respectively, of the administered DEN had disappeared from both the serum and liver. Under these conditions, DEDTC prevented liver cell necrosis, except for a few isolated cells. Similar inhibition was also observed when DEDTC was given 4 hours after the administration of a necrogenic dose of DMN (20 mg/kg). DEDTC, when administered 4 hours after DEN, delayed the rate of clearance of DEN and of ethylation of DNA and RNA but did not significantly affect the total extent of ethylation of rat liver nucleic acids. These results offer further support for the multistep hypothesis for the development of liver cell necrosis.     

DES induced sperm destruction in Lakeview hamsters

DES toxicity on sperm production after five consecutive sublethal i.p. injections of 8, 40 and 200 mg/kg was investigated in Lakeview hamsters. Testis weight, caudal sperm number, sperm morphology and body weight were monitored at week 1, 4 and 10 after treatment. DES doses of 8 mg/kg or above caused complete destruction of caudal sperm and reduced testes size to almost 10% of control within 10 weeks. Some sperm production resumed after the 8 mg/kg dose at the 10th week but more than half of these cells were abnormal in shape. Body weights remained almost stable for the first 4 weeks and then increased gradually by 25% at the 10th week.     

Analysis of carcinogenic activity of some pesticides in a medium-term liver bioassay in the rat.

Eight pesticides were tested in a medium-term bioassay based upon the induction of preneoplastic lesions in the liver. Rats were initially given diethylnitrosamine intraperitoneally at a dose of 200 mg/kg body weight and 2 weeks later were treated with the pesticides for 6 weeks and then killed; all rats had a partial hepatectomy at week 3. Hepatocarcinogenic potential was assessed by comparing the number and area of glutathione S-transferase placental form positive foci in the liver with those of controls given diethylnitrosamine (DEN) alone. Positive results were seen with p,p-DDT and Triadimefon. Permethrin (mixture of 39% cis form and 61% trans form) showed borderline results. Permethrin (25/75), Deltamethrin, Cypermethrin (52/48), while Trimorphamide and Propineb gave negative results. Our findings provide experimental evidence to indicate that compounds active in this assay have a potential for liver carcinogenicity in rodents.     

Effect of various doses of palm vitamin E and tocopherol on aspirin-induced gastric lesions in rats

This study examined the effects of vitamin E on the prevention of aspirin-induced gastric lesions. The study was divided into two phases. Phase 1 determined the effects of various doses of palm vitamin E on the factors affecting mucosal integrity. Thirty-two male rats of the Sprague-Dawley strain (200-250 g) were randomly divided into four groups. Group I was fed a normal diet (control), Groups II, III and IV were fed a diet supplemented with palm vitamin E in a dose of 60 mg/kg food, 100 mg/kg food and 150 mg/kg food, respectively. The rats were killed after 4 weeks of feeding for the determination of gastric malondialdehyde (MDA), acid and mucus content. There was a significant decrease in gastric MDA and gastric acid in all the palm vitamin E supplemented groups compared to control. However, these doses of palm vitamin E had no significant effect on gastric mucus. The phase 2 study determined the effect of multiple doses of palm vitamin E and tocopherol on the prevention of aspirin-induced gastric lesions. Fifty rats of the same weight and strain were randomized into seven groups. Group I was fed a normal diet; groups II to IV were fed with a palm vitamin E enriched diet in doses of 60 mg, 100 mg and 150 mg/kg food, respectively; groups V to VII were fed with a tocopherol-enriched diet in doses of 20 mg, 30 mg and 50 mg/kg food, respectively. After 4 weeks of feeding with the respective diets the rats were challenged with a single intra-gastric dose of 400 mg/kg body weight aspirin suspended in propylene glycol. The rats were killed 6 h post-aspirin exposure for the determination of gastric lesion index and gastric parameters as mentioned in the phase I study. The gastric lesions index was significantly lower in all the vitamin E groups compared to control. The lowest ulcer index was observed in the groups that received 100 mg of palm vitamin E and 30 mg tocopherol in the diet. However, there was no significant difference in ulcer indices between palm vitamin E and tocopherol-treated groups. The lower ulcer index was only accompanied by lower gastric MDA content. We conclude that both palm vitamin E in doses of 60 mg, 100 mg and 150 mg/kg food as well as tocopherol in doses of 20 mg, 30 mg and 50 mg/kg food are equally effective in preventing aspirin-induced gastric lesions. The most probable mechanism is through their ability in limiting the lipid peroxidation that is involved in aspirin-induced gastric lesions.     

Induction of lung lesions in female rats following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin

2,3,7,8,-Tetrachlorodibenzo-p-dioxin (TCDD) has been classified as a known human carcinogen, and epidemiologic studies identify the lung as one of the target organs. Few experimental studies have attempted to characterize pulmonary effects of TCDD exposure. In this study, we characterize the induction of lesions in the lung by chronic oral TCDD exposure in diethylnitrosamine (DEN)-initiated or noninitiated female Sprague-Dawley rats. Two or 18 weeks after initiation, rats were treated with TCDD continuously for 14, 30, or 60 weeks by biweekly oral gavage (1,750 ng TCDD/kg) at a dose equivalent to 125 ng/kg body weight per day (controls received corn oil). To assess the time dependence and reversibility of potential changes, some groups included withdrawal periods of 16 or 30 weeks after 30 weeks of TCDD treatment. TCDD treatment alone for 60 weeks caused significant increases in alveolar-bronchiolar (AB) metaplasia. TCDD treatment of DEN-initiated animals for 60 weeks resulted in a significant increase in bronchiolar epithelial hyperplasia. These increases were not observed in animals treated with TCDD for 30 weeks followed by corn oil for 30 weeks, indicating that the development of these lesions required continuous exposure to TCDD. AB hyperplasia increased in an age-dependent manner after DEN initiation but was unaffected by TCDD treatment. Expression of the aromatic hydrocarbon receptor (AHR) and induction of CYP1A1 was observed only in bronchiolar Clara and ciliated cells, indicating that the mechanism of induction of AB metaplasia may be mediated by the AHR. TCDD elimination half-life was monophasic in the lung, and serum and was estimated to be 39.7 days and 44.6 days, respectively, independent of age, tissue TCDD concentration, or body weight. This is the first report to identify the AB region as a target for TCDD-induced metaplastic and proliferative changes after chronic oral exposure.     

Histologic and histochemical changes in the aorta and myocardium of rats under the influence of atherogenic diet and phosphatidylcholine (EPL).

The prophylactic and therapeutic action of EPL on arteriosclerotic changes induced with fat-rich diet in the aorta and myocardium of white rats was studied. Histologic and histochemical studies showed that EPL administered prophylactically in doses of 280 mg/kg and 900 mg/kg body weight does not significantly inhibit development of arteriosclerotic lesions if fat-rich diet is continued. A distinct prophylactic action of EPL was first seen at a dosage of 2800 mg/kg. The therapeutic action of EPL on pathologic changes in the blood vessels also depends on dosage. The higher the dosage of EPL, the less pronounced the changes. At a dosage level of 2800 mg/kg, changes are slight and sporadic.     

Comparative effect of palm vitamin E and ranitidine on the healing of ethanol-induced gastric lesions in rats

The effect of palm vitamin E on the healing of ethanol-induced gastric lesion was compared with ranitidine. Fifty-six male rats of Sprague-Dawley species (200-250 g of weight) were randomly divided into three groups (N = 14). Gastric mucosal injury was induced by orogastric tube administration of 0.5 ml 100% ethanol. Immediately after induction, Group I (k) rats was fed with a normal diet (control), group II (p) was fed palm vitamin E enriched diet (150 mg/kg food), Group III(r) was treated with ranitidine 30 mg/kg body weight intraperitoneally and Group IV (p + r) was fed with palm vitamin E and treated with ranitidine 30 mg/kg body weight intraperitoneally of the same dose. The rats were killed at the end of 1 week and 3 weeks of treatment or feeding. The rate of gastric healing was faster in palm vitamin E treated group compared to control and ranitidine treated groups as shown by a lower mean ulcer index. The effect was seen as early as the first week of treatment whereas ranitidine did not show any healing effect even after 3 weeks of therapy. Neither gastric acidity nor gastric mucus production are involved in gastroprotective effect of palm vitamin E. The most probable mechanism is via reducing lipid peroxidation process as shown by a significant decrease in gastric MDA.     

Liver tumor promoting effects of fenbendazole in rats.

In order to examine whether fenbendazole has tumor-promoting activity, a total of 70 male Fischer 344 rats were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone; beginning 1 wk later, rats were given a diet containing 3,600; 1,800; 600; 200; 70; or 0 ppm of fenbendazole for 8 wk. Subgroups of 5 rats each from the DEN+ 1,800; DEN+0; 1,800; and 0 ppm groups were euthanatized after 1 wk of fenbendazole treatment, and the remaining animals were euthanatized at 8 wk. After 1 wk, relative liver weights (ratios to body weights) were significantly increased in the DEN+ 1,800 and 1,800 ppm groups, and based on light microscopy, periportal hepatocellular hypertrophy was evident in these groups. After 8 wk, relative liver weights were significantly increased in the groups given > or =600 ppm with or without DEN initiation. Periportal hepatocellular hypertrophy, characterized by a marked increase in smooth endoplasmic reticulum, was observed in the groups given > or =600 ppm with or without DEN initiation. Induction of cytochrome P-450 (CYP) 1A2, 2B1, or 4A1 was noted in the fenbendazole-treated groups with or without DEN initiation; that associated with CYP 1A2 was most marked. Positive immunostaining for anti-CYP 1A1/2 or CYP 2B1/2 was observed diffusely in the livers of animals in the DEN+1,800 and DEN+3,600 ppm groups. The numbers and areas of connexin 32 (Cx32)-positive spots per square centimeter in centrilobular hepatocytes were significantly decreased in an almost dose-dependent manner with fenbendazole treatment after DEN initiation. In situ hybridization for Cx32 mRNA revealed a remarkable decrease in its expression in the centrilobular hepatocytes in the DEN+70 ppm group. The numbers of glutathione S-transferase placental-form positive single cells (plus mini foci) were significantly increased in the DEN+ 1,800 and DEN+3,600 ppm groups. Since those agents that induce CYP 2B1/2 isozymes and reduce Cx32 in centrilobular hepatocytes have been suggested to be liver tumor promoters, the present results indicate that fenbendazole may be a liver tumor promoter.     

Twenty-four-month oral carcinogenicity study of ebrotidine in rats

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species.     

Resveratrol prevents high-fat diet-induced obesity and oxidative stress in rabbits

The rapid epidemiological progression of obesity worldwide has been associated with increased consumption of diets, rich in fat and sugar. Mediterranean diets rich in resveratrol are associated with reduced risk of obesity and oxidative stress. The aim of the experiment was to investigate the protective effect of resveratrol on high fat diet (HFD) induced obesity and oxidative stress changes in rabbits. Thirty rabbits divided into six groups of five animals each were used for the experiment: Group 1?=?control (C), Group 2?=?high fat diet (HFD) only, Group 3?=?resveratrol 200?mg/kg (R200), Group 4?=?resveratrol 400?mg/kg (R400), Group 5?=?HFD?+?R200 and group 6?=?HFD?+?R400. After four weeks of treatment, the HFD group showed significant (P?<?0.05) increase in body weight of the animals, when compared with the groups co- administered with resveratrol and high-fat diet, and resveratrol alone groups. Activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) decreased significantly (P?<?0.05) in the HFD groups co-administered with resveratrol when compared with HFD group only. In conclusion, administration of HFD to rabbits increased body weight and decreased antioxidant enzyme activities which were mitigated by resveratrol administration.     

Hepatoprotective effect of ethanolic extract of Trichosanthes lobata on paracetamol-induced liver toxicity in rats

ABSTRACT: BACKGROUND: Trichosanthes lobata (family cucurbitaceae) is used to treat malarial fever and liver disorders. This study aims to investigate possible hepatoprotective activities of ethanolic extract of Trichosanthes lobata against paracetamol-induced hepatotoxicity. METHODS: Hepatotoxicity was induced in Wistar male rats by oral administration, 2 g/kg body weight on 7th day after the administration of ethanolic extract of Trichosanthes lobata and silymarin (100 mg/kg). Ethanolic extract of Trichosanthes lobata was administered orally at doses of 200 mg/kg and 400 mg/kg body weight daily for 7 days. Several serum markers, aspartate transaminase, alanine transaminase, alkaline phosphatase, bilirubin, total protein was measured to assess the effect of the extract on paracetamol (acetaminophen)-induced hepatic damage. The study included histopathological examination of liver sections. RESULTS: Blood samples from rats treated with ethanolic extract of Trichosanthes lobata (200 mg/kg body weight and 400 mg/kg body weight) had significant reductions in serum markers in paracetamol administered animals, indicating the effect of the extract in restoring the normal functional ability of hepatocytes. Silymarin (100 mg/kg, p.o.) was used as a reference drug. CONCLUSION: The ethanolic extract of Trichosanthes lobata exhibits protective effects against paracetamolinduced hepatotoxicity.     

Evaluation of the Toxicological Profile of the Leaves and Young Twigs of Caesalpinia Bonduc (Linn) Roxb

Acute and sub-acute toxicological effects of ethanolic extract of the leaves and young twigs of Caesalpinia bonduc were carried out on albino rats. Single extract doses from 2000 to 5000 mg/kg body weight were administered orally and monitored for 14 days in acute study, while extract doses from 200 to 1600 mg/kg body weight were orally administered daily for 28 days in sub-acute study and recovery was assessed 14 days after dosing. Biochemical, haematological and histopathological examinations were carried out. There was no mortality in the experimental animals in all acute treatment doses. However, there were significant alterations in the biomarkers and induced cellular damage to the liver in all acute treatment doses. In the sub-acute toxicity treatment, the assessed biomarkers were unaffected at extract dose of 200 mg/kg body weight compared to control, while significant changes were observed in rats administered with extract doses of 400 mg/kg body weight and above. No significant difference was observed between the tested groups and the recovery groups in the sub-acute toxicity study. In conclusion, the ethanolic extract of C. bonduc could be toxic to selected organs of the rat body in acute and sub-acute treatments.