Stimulation of rat liver growth by a 1,3-dithiole derivative, KZ-1026

The oral administration of 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-butanedione (KZ-1026) to normal rats at doses of 50, 100 and 200 mg/kg/day for 3 days accelerated liver enlargement in association with a dose-dependent increase in the total amounts of protein, RNA and DNA in the liver. The liver weight at 24 hr after the third dose of 200 mg/kg reached 174% of the control. With respect to the effect on liver enlargement, KZ-1026 differed from phenobarbital, since KZ-1026, unlike phenobarbital, increased hepatic DNA content without significant effects on P-450 and aminopyrine-N-demethylase. Incorporation of [3H]thymidine into liver DNA was stimulated by a single dose of KZ-1026 (200 mg/kg), and it peaked at 24 hr post dose (18 times the control), followed by an increase in the number of liver nuclei. Liver growth was also accompanied by an increasing hepatic reserve cell mass, expressed by the capacity of eliminating exogenous galactose from the blood stream. Pretreatment with KZ-1026 (200 mg/kg/day) for 3 days significantly improved the survival rate of subtotally hepatectomized rats from 39% to 78%. These findings indicate that KZ-1026 accelerates hepatocyte proliferation, resulting in an enhancement of liver functional mass in normal rats.