Effects of gomisin A on the promotor action and serum bile acid concentration in hepatocarcinogenesis induced by 3'-methyl-4-dimethylamino-azobenzene.

The effects of gomisin A, a lignan component of Schizandra fruits, on the promotion stage of hepatocarcinogenesis initiated by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB) in male Donryu rats were investigated. When different types of tumor promotors, phenobarbital (PB) and deoxycholic acid (DCA), were administered for 5 weeks after initiation by 3'-MeDAB, preneoplastic alterations in the liver, determined by glutathione S-transferase placental form (GST-P), were markedly increased. Gomisin A significantly inhibited the increase in number and size of GST-P positive foci, regardless of the promotor. This lignan inhibited the increase in serum bile acid concentration by administration of DCA, but hardly influenced the serum bile acids in the PB-combined group. These results suggest that the inhibitory effect of gomisin A on the promotive action of DCA is based on improving bile acid metabolism, but regarding the action of PB, the effect could not be elucidated from the metabolism of bile acids.

Inhibition of early 3-methyl-4-dimethylaminoazobenzene-induced hepatocarcinogenesis by gomisin A in rats.

The effects of gomisin A, a lignan component of Schizandra fruits, on hepatocarcinogenesis caused by 3'-methyl-4- dimethylaminoazobenzene (3'-MeDAB) in male Donryu rats were investigated. Gomisin A significantly inhibited the appearance of foci stained for glutathione S-transferase placental form (GST-P) in the liver of rats given feed with 0.06% 3'-MeDAB. Gomisin A (30 mg/kg/daily, po) decreased the concentration of 3'-MeDAB-related azo dyes in the liver, and increased their excretion in the bile. The ratio of diploid to tetraploid nuclei increased during ingestion of 3'-MeDAB, but gomisin A delayed the increase. After the withdrawal of 3'-MeDAB, carcinogen-related azo dyes were not detected in the liver or bile, but the proportion of diploid nuclei remained high, although it decreased with a 0.03% gomisin A diet. The results suggested that the effects of gomisin A are related to improved liver function and reversal of abnormal ploidization.

Suppressive effect of estrogen on hepatocellular tumorigenesis induced in mice by 3'-methyl-4-dimethylaminoazobenzene.

Treatment of female C57BL/6 x DS-F1 mice with 3'-methyl-4- dimethylaminoazobenzene (3'-Me-DAB) neonatally resulted in the development of hepatocellular adenomatous nodules. Ovariectomy at 1 month of age greatly hastened the time of appearance of these nodules and significantly increased their incidence. The incidence of adenomatous nodules in females ovariectomized at 1 month of age was about 70% at 12 months of age, and was decreased to 4% by implantation of a pellet containing estradiol-17 beta (E2 pellet) at 1 month of age (at the time of ovariectomy). The incidence of adenomatous nodules at 12 months of age was not decreased significantly when the implanted E2 pellet was removed at 4 or 6 months of age, but was decreased significantly when it was removed at 8 or 10 months of age. Implantation of E2 pellets into ovariectomized females at 4 and 6 months of age decreased the incidence of adenomatous nodules as effectively as their implantation at 1 month of age. The implantation of E2 pellets into ovariectomized females at 8 or 10 months of age resulted in significantly lower incidences of adenomatous nodules at 12 months of age, than that in females ovariectomized at 1 month of age. The present results suggest that the ovarian hormone, estrogen suppresses the development of hepatocellular tumors induced by 3'-Me-DAB, exerting its effect from about 6 months of age.

Effects of gomisin A on hepatocarcinogenesis by 3'-methyl-4-dimethylaminoazobenzene in rats.

We examined the effects of gomisin A on tumor promotion in the liver after a short-term feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) to rats, compared with the effects of phenobarbital. Male Donryu rats were fed ad libitum a diet containing 0.06% 3'-MeDAB and 0.03% or 0.01% gomisin A or water containing 0.05% phenobarbital. Gomisin A and phenobarbital did not cause any proliferative and neoplastic lesions by themselves in 40 weeks of feeding. Altered foci in the liver increased with a peak at 12 weeks after the rats were fed 3'-MeDAB. Gomisin A decreased the number of hepatic altered foci such as the clear cell and basophilic cell type foci in the early stages. Phenobarbital enhanced neoplastic alterations so that the number and size of the foci were much larger in the phenobarbital-combined group than in the 3'-MeDAB-control group. Thus, phenobarbital acted as a promoter of cells initiated by 3'-MeDAB; on the other hand, gomisin A showed a weak suppressive effect on tumor promotion.

3-Methylcholanthrene-inhibition of hepatocarcinogenesis in the rat due to 3'-methyl-4-dimethylaminoazobenzene or 2-acetylamino-fluorene: a comparative study.

Male Leeds strain rats were given a diet containing either 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) or 0.05% 2-acetylaminofluorene (2-AAF), alone or together with 0.0067% 3-methylcholanthrene (MeCh). MeCh both reduced the incidence of hepatic neoplasms induced by 3'-MeDAB and delayed their development. With 2-AAF, however, inhibition of hepatocarcinogenesis by MeCh only appeared to operate during the period of treatment; thereafter the incidence of tumours rose rapidly and this was accentuated if dietary MeCh continued to be administered after the period of combined 2-AAF and MeCh treatment, suggesting a secondary, promoting effect of MeCH. In contrast, the inhibition by MeCh of carcinogenesis of Zymbal's gland due to 2-AAF was almost complete. Thus, in the long term MeCh has different effects upon 3'-MeDAB and 2-AAF carcinogenesis in the rat liver.

gamma-Glutamyltransferase and the inhibition of azo dye-produced neoplasia by concomitant administration of disulfiram.

The concentration and total amount of DNA in the livers of SD rats fed 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) gradually increased and reached a maximum in developing tumors. In SD rats fed 3'-Me-DAB plus disulfiram (DSF), the concentration of DNA was higher than in controls, but it soon became stabilzed and the total amount of DNA in the liver did not differ substantially from that in rats fed DSF alone. In rats given 3'-Me-DAB, neoplastic nodules and liver carcinomas appeared after 3 months, but in those fed both compounds these formations were absent even after 6 months. The activity of gamma-glutamyltransferase (GT-ase), a marker of chemically induced carcinogenesis in rat liver, gradually increased to extremely high levels in tumors even after 75 days when the diet of the animals was changed to a normal one. In rats fed 3'-Me-DAB plus DSF, GT-ase activity increased for the greater part of 80 days, gradually leveled off around the 100th day, and returned to almost normal levels when the rats were given a normal diet after 100 days. We concluded that DSF 1) did not interfere with 3'-Me-DAB-induced proliferation of preneoplastic cells and the increase in GT-ase associated with this reversible adaptation to the influx of 3'-Me-DAB; and 2) inhibited malignant transformation and, consequently, prevented the formation and proliferation of neoplastic cells and the increase in constitutive GT-ase related to neoplasia.

Is the selenium drinking water standard justified?

Four cases are presented which suggest that the present U.S.E.P.A. drinking water standard for selenium of 10 micrograms/L in inappropriate. The rationale upon which this standard is based is that selenium is carcinogenic, induces dental caries formation, and is highly toxic to animals. However, a critical assessment of this literature can not support these claims. Case no. 1 demonstrates that there is insufficient evidence to classify selenium as a carcinogen. Data derived from the three respective groups of researchers claiming a carcinogenic effect induced by selenium are obscure due to 1) the inability to accurately identify malignancies, 2) the apparent opposite effects of different selenium compounds, and 3) the lack of proper controls. Case no. 2 reviews recent evidence that selenium reduces the incidence of cancer in laboratory animals and in man, an effect which can probably be attributed to the antioxidant properties of selenium compounds. Case no. 3 provides evidence which does not permit the classification of selenium as a cariogenic element. Epidemiological studies supporting such a claim are inadequate since they lack properly matched control groups. Animal data do not support this link as well. Case no. 4 is a review of studies which clearly demonstrate the essentiality of selenium, an aspect of selenium metabolism that was not considered when the 10 micrograms/L standard was promulgated. In light of the four cases presented and an assessment of selenium toxicity in man, it is concluded that the 10 micrograms/L standard can not be justified. Instead, it is suggested that 50 micrograms/L selenium should provide sufficient protection from the toxic effects of this element. This is consistent with the current state of knowledge with respect to the potential adverse health effects associated with selenium.

Effects of selenium on azo dye hepatocarcinogenesis.

Groups of male Sprague--Dawley rats were maintained on three regimens: I. basal diet plus 0.05% 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), II. same as I plus 6 ppm selenium (Na2SeO3) in the drinking water, and III. same as I plus 6 ppm selenium added to the diet in the form of a high selenium yeast. The 3'-MeDAB was incorporated in the diet for 8 weeks and then removed. The selenium supplements in Groups II and III were continued for an additional 4 weeks. At sacrifice the liver tumor incidence from was ascertained as the ratio of animals with tumors/total number of surviving animals per group. Selenium reduced the incidence from 92% (11/12) in the Group I control, to 46% (7/15) in Group II and to 64% (9/14) in Group III.