Effect of Alcohol Ingestion on Carcinogenesis by Synthetic Estrogen and Progestin in the Rat Liver

We examined the effect of alcohol ingestion on hepatocarcinogenesis induced hy oral administration of synthetic female hormones, 0.075 mg of ethynylestradiol (EE) and 6.0 mg of norethindrone acetate (NA), every day for 12 months in female Wistar rats. Administration of 10% ethanol in drinking water for 5 days a week every week resulted in the development of hepatocellular carcinoma (HCC) in 38.4% of the hormone‐treated rats at 12 months, which is approximately 5 times the incidence of HCC observed following EE and NA treatment alone. The number of hyperplastic nodules was significantly higher than the number observed in the case of EE and NA treatment alone after 4 months of the experimental period. The additional alcohol treatment also increased the value of unoccupied nuclear estrogen receptors (ERn) at months 6 and 8 of the experimental period, and increased the value of total ERn in the rat liver after 6 months of the experimental period. This indicates that additional alcohol treatment may increase occupied ERn (estrogen‐ER complex) in the rat liver. A (32)P‐postlabeling analysis of liver DNA revealed that the maximum number of extra spots consisting of modified nucleotides induced by EE and NA appeared earlier when the additional alcohol treatment was imposed. Consequently, alcohol affects the hepatocarcinogenesis by EE and NA, promoting not only the change in kinetics of ER, but also DNA adduct formation induced by EE and NA in the rat liver.