联苯双酯对肝癌发生的化学预防作用观察

Chemopreventive effect of an anti-hepatitis drug―dimethyl dicarboxylate biphenyl against hepatoma

目的探讨联苯双酯(DDB)对肝癌发生的化学预防作用。方法采用抗微核实验和抗DNA损伤实验观察DDB的抗突变作用;采用巴豆油诱发的小鼠耳肿胀实验初步探讨DDB的抗促癌活性;建立二乙基亚硝胺(DEN)/苯巴比妥(PB)联合诱发的小鼠肝癌模型,观察小鼠肝脏的病理改变以及DDB对肝癌发生率的影响。结果小鼠提前灌服DDB50、100、200mg/kg,由环磷酰胺(CTX)引起的骨髓嗜多染红细胞(PCE)微核数分别为39.1±6.6、26.9±6.2、20.8±5.9个,与单用CTX(微核数为49.3±8.1个)相比明显降低(P<0.05或P<0.001);在佛波酯(TPA)作用的同时分别加入1、2、4μmol/LDDB,DNA-EB结合物的荧光强度较单加TPA时显著升高(P<0.05或P<0.001);50、100、200mg/kgDDB均能明显抑制致炎剂巴豆油引起的小鼠耳部急性炎性反应,抑制率分别为15.9%、31.4%、32.0%;应用DDB能改善肝脏的病理状态;100和200mg/kgDDB预防给药均能降低肝肿瘤的发生率,其中200mg/kgDDB对肝细胞性肝癌和肝细胞瘤的抑制率分别为57.1%和22.8%。结论 DDB对化学毒物诱发的肝癌发生有一定抑制活性,同时具有降低肝癌发生率的潜能。

Objective To evaluate the chemopreventive effect of dimethyl-4,4’-dimethoxy-5,6,5’,6’-dimethylene dioxybiphenyl-2,2’-dicarboxylate（DDB）against liver carcinogenesis.Methods Micronucleus formation and DNA damage assay were used to detect the anti-mutagenic activity of DDB.Croton oil-induced mouse ear edema model was used to investigate the anti-promotion effect of DDB.The pathological changes in liver and the influence of DDB on the incidence of hepatoma were examined by the hepatoma model of rats induced by diethylnitrosamine（DEN）plus phenobarbital（PB）.Results After pretreatment with DDB in doses of 50,100and 200mg/kg,the number of micronucleus in polychromatic erythrocytes（PCE）of mouse bone marrow induced by cytoxan（CTX）was 39.1±6.6,26.9± 6.2and 20.8±5.9,respectively,which were significantly less when compared with that only induced by CTX alone（49.3±8.1,P〈0.05 or P〈0.001）.When 12-O-tetradicanoyl-phorbol-13-acetate（TPA）was added with 1,2,4umol/L DDB,the fluorescence intensity of DNA-EB was significantly higher than that when TPA added alone（P〈0.05or P〈0.001）.50,100,200mg/kg DDB inhibited the acute inflammatory response induced by croton oil（the inhibitory rates were 15.9%,31.4%and 32.0%,respectively）.DDB also ameliorated the pathological changes in liver.The pretreatment of 100and 200mg/kg DDB lowered the incidence of hepatocellular carcinoma.The inhibitory ratio of 200mg/kg DDB on the hepatocellular cancer and hepatoma were 57.1%and 22.8%,respectively.Conclusion DDB has an inhibitory effect on carcinogenesis of the liver induced by chemical carcinogen,with a potency of lowering the incidence of hepatoma.