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Preventive Effect of FK143, a 5-Reductase Inhibitor, on Chemical Hepatocarcinogenesis in Rats

Second Department of Surgery, Shimane Medical University, Izumo 693-8501, Japan [S. M., N. N., D. K. D., A. Y., O. N. E-A.]; Second Department of Biochemistry, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan [K. S.]; and First Department of Internal Medicine, Yamaguchi University School of Medicine, Ube 755-8505, Japan [K. O.]

The incidence of hepatocellular carcinoma (HCC) is more prevalent in males than in females. 5-Dihydrotestosterone is the most potent form of androgen and is converted from testosterone by 5-reductase. The antitumor effect of a 5-reductase inhibitor (FK143) was evaluated in a rat chemical hepatocarcinogenesis model (Solt-Farber). Male Fischer 344 rats were used in three groups: (a) control group; (b) low-dose FK143 (FKL) group (20 ppm FK143); and (c) high-dose FK143 (FKH) group (200 ppm FK143). The numbers of both glutathione S-transferase placental form-positive foci (P < 0.05) and hyperplastic nodules (HNs; P < 0.01) in the liver were significantly lower in the FKL group than in the control group. The numbers (P < 0.05) and tumor volume (P < 0.01) of HCCs per liver were significantly lower in the FKL group when compared with the control group. All HCCs were well differentiated in the FKL group, whereas 38% and 36% of HCCs were moderate to poorly differentiated in the control group and the FKH group, respectively. The proliferating cell nuclear antigen labeling index:apoptotic index ratios of enzyme-altered foci, HNs, and HCCs were significantly lower in the FKL group than in the control group. Serum 5-dihydrotestosterone was significantly lower in both the FKL and FKH groups. However, a high dose of FK143 (200 ppm) provided no protection against hepatocarcinogenesis, and the level of serum testosterone was elevated in this group when compared with that in the control group. The low dose of FK143 significantly suppressed the formation of enzyme-altered foci, HNs, and HCCs in rat hepatocarcinogenesis. This may indicate that 5-dihydrotestosterone enhances hepatocarcinogenesis. We conclude that an optimal dose of FK143 may have a suppressive effect on hepatocarcinogenesis.