Yin ZZ, Jin HL, Yin XZ, Li TZ, Quan JS, Jin ZN. Effect of Boschniakia rossica on expression of GST-P, p53 and p21ras proteins in early stage of chemical hepatocarcinogenesis and its anti-inflammatory activities in rats. World J Gastroenterol 2000; 6(6): 812-818 [PMID: 11819701 DOI: 10.3748/wjg.v6.i6.812]
Corresponding Author of This Article
Professor Zong Zhu Yin, Institute for Cancer Research, Yanbian University College of Medicine, 121 Juzi Street, Yanji 133000, Jilin Province, China. Email: yinzz@public.yj.jl.cn
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World J Gastroenterol. Dec 15, 2000; 6(6): 812-818 Published online Dec 15, 2000. doi: 10.3748/wjg.v6.i6.812
Effect of Boschniakia rossica on expression of GST-P, p53 and p21ras proteins in early stage of chemical hepatocarcinogenesis and its anti-inflammatory activities in rats
Zong Zhu Yin, Hai Ling Jin, Xue Zhe Yin, Tian Zhu Li, Ji Shu Quan, Zeng Nan Jin Institute for Cancer Research, Yanbian University College of Medicine, Yanji 133000, Jilin Province, China
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to the work.
Correspondence to: Professor Zong Zhu Yin, Institute for Cancer Research, Yanbian University College of Medicine, 121 Juzi Street, Yanji 133000, Jilin Province, China. Email: yinzz@public.yj.jl.cn
Received: May 5, 2000 Revised: June 1, 2000 Accepted: June 9, 2000 Published online: December 15, 2000
Abstract
AIM: To investigate the effect of Boschniakia rossica (BR) extract on expression of GST-P, p53 and p21ras proteins in early stage of chemical hepatocarcinogenesis in rats and its anti-inflammatory activities.
METHODS: The expression of tumor marker-placental form glutathione S-transferase (GST-P), p53 and p21ras proteins were investigated by immunohistochemical techniques and ABC method. Anti-inflammatory activities of BR were studied by xylene and croton oil-induced mouse ear edema, carrageenin, histamine and hot scald-induced rat pow edema, adjuvant-induced rat arthritis and cotton pellet-induced mouse granuloma formation methods.
RESULTS: The 500 mg/kg of BR-H2O extract fractionated from BR-Methanol extract had inhibitory effect on the formation of DEN-induced GST-P-positive foci in rat liver (GST-P staining was 78% positive in DEN+AAF group vs 20% positive in DEN+AAF+BR group, P < 0.05) and the expression of mutant p53 and p21ras protein was lower than that of hepatic preneoplastic lesions (33% and 22% positive respectively in DEN+AAF group vs negative in DEN+AAF+BR group). Both CH2Cl2 and H2O extracts from BR had anti-inflamatory effect in xylene and croton oil-induced mouse ear edema (inhibitory rates were 26%-29% and 35%-59%, respectively). BR-H2O extract exhibited inhibitory effect in carrageenin, histamine and hot scald-induced hind paw edema and adjuvant-induced arthritis in rats and cotton pellet-induced granuloma formation in mice.
CONCLUSION: BR extract exhibited inhibitory effect on formation of preneoplastic hepatic foci in early stage of rat chemical-hepato-carcinogenesis. Both CH2Cl2 and H2O extracts from BR exerted anti-inflammatory effect in rats and mice.
Citation: Yin ZZ, Jin HL, Yin XZ, Li TZ, Quan JS, Jin ZN. Effect of Boschniakia rossica on expression of GST-P, p53 and p21ras proteins in early stage of chemical hepatocarcinogenesis and its anti-inflammatory activities in rats. World J Gastroenterol 2000; 6(6): 812-818
Boschnikia rossica (BR) Fedtsch. et Flerov is a parasitic plant growing on the root Alnus plants (Betulaceae)[1]. It is one of the valuable medicinal plants growing mostly on the Changbai Mountain at 1450-1800 meters above sea level, Jilin, China.It is also distributed in the Democratic People’s Republic of Korea (DPRK), Japan and Russia. Boschiakia rossica is named “Bu Lao Cao” (antisenile plant), because it has effects of tonifying the Kidney and strengthening Yang, and has been used as a tonic or invigorating medicine in China. Yin ZZ et al[2] isolated four iridoid compounds from Boschniakia rosseca of the Changbai Mountain by chromatographic techniques. Their structure was determined by means of the spectra of nuclear magnetic resonance (NMR) and mass spectra. We discovered that Methanol extract of Boschniakia rossica exerted inhibitory effect on the formation of di ethyl nitrosamine (DEN) induced GST-P-positive foci in the liver of F344 rats[3,4] and BR also has antioxidative activities[5,6]. In the present study, we report the inhibitory effect of BR-water extract fractioned from BR-Methanol extract on the expression of GST-P, p53 and p21ras proteins in early stage of rat chemical hepatocarcinogenesis and its anti-inflammatory activities in rats and mice.
MATERIALS AND METHODS
Chemicals
Diethylnitrosamine (DEN), 2-Acetylaminofluorene (AAF), determination kit for GGT and histamine were purchased from Sigma Chemical Co. (USA). Vectastain ABC kit (pk 4001) was obtained from Vector Laboratories Inc. (USA); anti-GST-P antibody was kindly supplied by Professor Shigeki Tsuchida, Second Department of Biochemistry, Hirosaki University School of Medicine, Japan. p53 (DO-1) and pan ras (F-132) monoclonal antibody were purchased from Santa Cruz Biotechnology.
Preparation of the extract of Boschniakia rossica
Boschniakia rossica harvested from the Changbai Mountain area was used and the plants were identified by the authors. They were dried, cut, made into powder and extracted for overnight with Methanol five times. The Methanol extract was fractioned with CH2Cl2 and H2O, and H2O extract was vaccum-concentrated. The extract was dried by speed vaccum.
Animals and treatment
Male Wistar rats, aged 6 wks and weighing 160 g-180 g were used in the experiments of hepatocarcinogenesis. The male Wistar rats (180 g-200 g) and Kunming strain mice (20 g-22 g) were used in the anti inflammatory ex periment. Animals were housed in groups of 5 animals in plastic cages with stainless-steel grid tops at room temperature with a 12 h light/dark cycle.
Enzyme-altered hepatic foci and hyperplastic nodules were induced by the modified protocol of Solt and Farber. The animals were divided into 3 groups. The rats in groups B and C were given a single i.p. injection of DEN (200 mg/kg body weight) dissolved in saline to initiate hepatocarcinogenesis. After 2 wk on basal diet, the rats received 0.004% 2-AAF in the diet for the following 6 wk. Group C, after 2 wk of injection of DEN, was given the diet containing 0.004% 2-AAF+ 500 mg/kg BR for the following 6 wk as a BR treatment group. Group A, as a control group, was intraperitoneally injected with the saline instead of DEN and then maintained on basal diet for 8 wk. All rats of experimental and control groups were subjected to two-thirds partial hepatectomy (PH) at the 3rd week. Rats in each group were killed for examination at the 8th week.
Immunohistochemical staining for GST-P, p53 and p21ras [12-16]
Rat liver slices were fixed with ice-cold aceton and embedded in paraffin. Immunohistochemical staining for GST-P was performed by ABC method using anti-GST-P antibody; immunohistochemical staining for p53 and p21ras proteins was performed using p53 (DO-1) and pan ras (F-132) monoclonal antibody, respectively.
Quantitative analysis
The number and the area of GST-P-positive hepatic foci larger than 0.1 mm in diameter were analyzed using the microscopic quantitative analyzer (OC.M 19 m/m Square 10/10 × 10, Tokyo, Japan).
Investigation of anti-inflammatory activities of BR extract[17-19]
Xylen or croton oil-induced mouse ear edema An edema was induced on the right ear by topical application of xylen in mice 30 min after oral administration of 500 mg/kg-1000 mg/kg BR-H2O extract or BR-CH2Cl2 extract. The left ear was controled. Ear edema was measured by comparing the difference in weight (mg) between the same size of left and right ears 30 min after xylen-induction and 4 h after crotonoil-induction of inflammation and swelling degree and inhibition rate were calculated.
Carrageenin-induced rat paw edema An edema was induced on the rat right hind paw by aponeurosis injection of 0.15 mL of 1% carrageenin in 0.9% saline. Test drug (500 mg/kg-1000 mg/kg of BR-H2O extract) was given orally 30 min before the injection of carrageenin. The volume of the right paw was measured before injection and at 1, 2, 3, 4, 6 and 24 h after induction of inflammation. The edema was expressed as an increase in paw volume due to carrageenin injection. The results were obtained by measuring the volume difference before and after injection of the right paw. The swelling degree of paw and inhibition rate of edema were calculated.
Histamine-induced rat paw edema An edema was induced on the right hind paw of rat by subplantar injection of 200 μg/0.1 mL of histamine. Test drug (500 mg/kg of BR-H2O extract) was given 30 min before the injection of histamine. The volume of the right paw was measured before injection and 0.5, 1, 2, 3 and 4 h after induction of inflammation. The swelling degree of paw and inhibition rate of edema were calculated.
Hot scald-induced rat paw edema Edema was induced on the right hind paw of rat by hot scald. The right hind paw of rat soaked in thermostate water bath main tained at 53 °C ± 0.5 °C and cut-off time was 14 s and test drug (500 mg/kg of BR-H2O extract) was given 30 min before the hot scald test. The volume of the right paw was measured before test and 1, 2, 3, 4, 5, 6 and 24 h after induction of inflammation. The swelling degree of paw and inhibition rate of edema were calculated.
Adjuvant-induced arthritis in rats The Arthritis was induced by injection of 0.1 mL complete Freud's adjuvant into the subplantar region of the right hind paw of rats. Five hundred mg/kg of BR-H2O extract was orally administrated 30 min before the injection of adjuvant and the BR extract was giver daily for 3 d after induction of inflammation. From the 8th day the BR extract was given daily for 7 d more. The volume of the right paw was measured before injection and at 18 h, and on day 3, 6, 9, 12, 15, 18, 21 and 24 after induction of inflammation. The swelling degree of paw and inhibition rate of edema were calculated.
Cotton pellet-induced granuloma formation Pellets of surgical aseptic cotton weighing 15 mg were implanted in both scapular regions in mice. The test drug (250 mg/kg-500 mg/kg) was administered daily for 7 d, and on the 8th day, the granulomatous tissues were removed. The pellets were dried overnight at 60 °C and weighed. The dry weight was considered the weight of the granuloma. The results of this subacute inflammation were compared with the control group.
Statistical analysis
Statistical analysis was made using the χ² test and the Student’s t test. Values of P < 0.05 were considered statistically significant.
RESULTS
Effect of Boschniakia rossica extract on expression of GST-P, p53 and p21ras proteins during chemical hepatocarcinogenesis in rats
Immunohistochemical investigation of expression of GST-P, p53 and p21 protein in DEN-induced preneoplastic hepatic foci (group B), in administration of BR extract in the Solt-Farber protocol of rats (group C) and control (group A) are summarized in Table 1. GST-P staining was 78% positive in group B and 20% positive in group C, while in group A it was negative (B vs C, P < 0.0 5). Expression of oncogene products p53 and p21ras protein in group B was 33% and 22% positive, while in groups A and C it was negative. The number (no/cm2) and area (mm2/cm2) of GST-P-positive hepatic foci in group C given DEN-AAF+BR was significantly decreased as compared with the values of group B given DEN-AAF (B vs C, P < 0.001 and P < 0.05) and these quantitative values are shown in Table 1 and Figure 1.
Table 1 Effect of Boschniakia rossica on the expression of GST-P, p53 and p21 protein in early stages of rat chemical hepatocarcinogenesis.
Figure 1 Immunohistochemical staining for GST-P in rat hepatic preneoplastic lesions induced by Solt-Farber protocol (A and B), in rat liver treated with DEN and AAF plus BR for 6 wk (C and D), and in normal rat liver (E).
A, GST-P-strongly positive minifoci in group B × 400; B, GST-P-strongly positive large foci in group B, × 100; C, GST-P-positive single cell in group; C, × 400; D, GST-P-weakly positive two cells in group; D, × 400; E, GST-P was negative in group A, normal rat liver, × 200; F, Hematoxilin and eosin staining for preneoplastic hepatic foci in group B, × 200.
Effect of extract from BR on the anti-inflammatory activities in rats and mice
Both CH2Cl2 and water extract from BR have inhibitory effect in the xylene and croton oil-induced mouse ear edema, its inhibitory rate was 26%-29% and 35%-59% respectively (Table 2 and Table 3) and exert inhibitotory effect in the cotton pellet-induced granuloma formation in mice (Table 8 and Table 9). BR-H2O extract fractionated from BR-Methanol extract exhibited inhibitory effect in carrageenin, hot scald and histamine-induced rats hind paw edema (Table 4, Table 6 and Table 7) and adjuvant-induced arthritis in rats (Table 5).
Table 2 Effect of BR-extract on xylene-induced mouse ear edema.
Changes in GST-P, p53 and p21ras proteins during chemical hepatocarcinogenesis in rats
Placental form of glutathione S-transferase (GST-P) was first isolated from rat placenta as a sensitive marker enzyme in chemical hepatocarcinogenesis of rat by Sato et al[20-24] in 1984. GST-P is considered to be an accurate marker for very early “initiated cells”[21,24]. GST-π, purified from human term placenta, is related to rat GST-P in many properties and is grouped into the class Pi. It is of important clinical value. GST-π is also a useful human tumor marker for hepatoma, esophageal, gastric and colonic carcinomas and its preneoplastic lesions[12-15,25-32]. Thereafter, using DEN as a initiator and AAF as a promoter, modified system based on Solt-Farber method was designed to screen the medium-term bioassay of chemical-induced carcinogenesis by Ito et al[33]. This screening system was used in this study and successfully induced the preneoplastic GST-P-positive hepatic foci and nodules. Recently Tsuda H et al[34] developed a trial for an initiation bioassay system. Initiation potential was assayed on the basis of significant increase in values of preneoplastic GST-P positive foci. This protocol may be useful for detection of the initiation potential of carcinogens irrespective of their mutagenicity.
We investigated the effect of Boschniakia rossica on formation of GST-P positive preneoplastic hepatic foci during chemical hepatocarcinogenesis. The results demonstrated that BR-H2O extract fractionated from BR-Methanol extract with CH2Cl2 and H2O has inhibitory effect on DEN-induced GST-P positive preneoplastic hepatic foci in early stage of rat chemical hepatocarcinogenesis. We consider that it is related to its antioxidative action of Boschniakia rossica[4]. Recently there are reports that GST-P is as a sensitive marker for preneoplastic hepatic foci during chemical hepatocarcinogenesis in rats[35-40]. It indicated that GST-P and GST-π are very sensitive tumor markers for basic research, prevention and cure of cancer.
Rat chemical hepatocarcinogenesis can be divided into several steps: initiation, promotion, and progression stages. During the initiation stage, alterations of specific genes and in particular the activation of cellular proto-on cogenes occurs. During the promotion stage, groups of preneoplastic cells have been observed in many organs prior to appearance of malignant cancers, and in rat chemical hepatocarcinogenesis enzyme-altered foci and hyperplastic nodules have been excited[21]. Recently many scientists reported expression of ras, jun oncogene[42,47-49], p53 tumor suppressor gene[41,43,45,52-54], and nm23 tumor metastasis suppressor gene[44,46,50,51] in hepatocellular carcinoma, esophageal, gastric, and colonic carcinomas. Smith et al[41] reported a p53 gene mutation occuring in foci of enzym-altered hepatocytes induced by diethylnitrosamine in F 344 rats. We observed the relation to the expression of GST-P, ras gene product p21ras protein and suppressor gene product p53 protein in preneoplastic hepatic foci of rat liver. The results suggest that one-third of GST-P positive foci were positive for p53 protein and approximately one-forth of GST-P positive foci were also positive for p21ras protein in group B, while in rat liver of group C treated with DEN and AAF plus BR for 6 wk p53 protein and p21ras were not immunohistochemically detectable. Our result is similar to the report by Smith et al[41], and also is similar to that GST-P appearing at an early stage of chemical hepatocarcinogenesis, when oncogene product c-jun was not immunohistochemically detectable, reported by Suzuki et al[42]. These results indicate that BR-H2O extract fractionated from BR-Methanol extract exhibited an inhibitory effect on DEN-induced preneoplastic hepatic foci in rats administered with BR for 6 wk during chemical hepatocarcinogenesis.
Anti-inflammatory activities of Boschniakia rossica
Results of the present study demonstrated that BR-extract exerted significant anti-inflammatory activities. An inhibitory effect of H2O extract and CH2Cl2 extract from BR was observed in the acute inflammatory process, such as xylen and croton oil-induced mouse ear edema, carrageenin induced rat hind paw edema and inflammatory factors such as histamine and hot scald-induced rat hind paw edema. Anti-inflammatory action of BR was also observed in the chronic inflammation process, such as cotton pellet- induced granuloma formation in mice and immune inflammation process, such as adjuvant-induced arthritis in rats. The experimental model of inflammation induced by carrageenin is highly sensitive to non-steroidal anti-inflammatory drugs, and it has long been accepted as a useful phlogistic tool for investigating new anti-inflammatory drugs. The oral administration of the BR-H2O extract (500 mg/kg) inhibited the edema formation by 49.8% and 65.8% in 2 and 24 h, respectively, after the administration of carrageenin in rats. Indomethacin, the standard anti-inflammatory drug used in this experiment, inhibited the edema by 46.5% and 40% in 2 and 24 h. The anti-inflammatory effect of extract from BR was also observed in the cotton pellet-induced granulo ma formation in mice. The daily oral administration of 250 mg/kg and 500 mg/kg of BR-CH2Cl2 extract, using this model, showed on the eighth day an inhibitory effect of 25% and 35%, and 250 mg/kg and 500 mg/kg of BR-H2O extract 35% and 34%, respectively. The mechanism of anti-inflammarory action of Boschniakia rossica-can be related to the chemical structure of BR. Recio et al[55] reported that Iridoids is an anti-inflammatory agent. The results obtained in present study suggest that CH2Cl2 extract and H2O extract from BR have anti-inflammatory effects. We isolated four iridoid compounds, a group of cyclopentano[c]pyran monoter penoids, from Boschniakia rossica, and among them 8-epideoxyloganic acid was shown to exhibit a strong anti-inflammarory activity. Based on the results obtained in this study, we conclude that extract from BR exerted an anti-inflammatory effect.
Footnotes
Edited by Ma JY
Project supported by the National Natural Science Foundation of China, No.39660021
NS: normal saline; Ind:indomethacin; BR: Boschniakia rossica
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