Comparison of the Enhancing Effects of Dehydroepiandrosterone with the Structural Analog 16{alpha}-Fluoro-5-androsten-17-one on Aflatoxin B1 Hepatocarcinogenesis in Rainbow Trout

Dehydroepiandrosterone (DHEA) is an adrenal steroid with chemoprotectiveeffects against a wide variety of conditions including cancer,obesity, diabetes, and cardiovascular disease. However, DHEAis also a carcinogen in laboratory animals, possibly throughits function as a precursor of sex steroids or peroxisome proliferation.The structural analog 16-fluoro-5-androsten-17-one (8354) hasbeen reported to have enhanced chemopreventive activity withoutthe steroid precursor and peroxisome proliferating effects ofDHEA. This study compares DHEA and 8354 in rainbow trout, aspecies that is resistant to peroxisome proliferation but ishighly susceptible to the carcinogenic and tumor enhancing effectsof DHEA. Trout were exposed as fry to aflatoxin B₁ (AFB₁) orgiven a sham exposure, then were fed diets containing 444 ppmDHEA or 8354 for 6 months. Postinitiation treatment with DHEAsignificantly increased liver tumor incidence, multiplicity,and size compared to initiated controls. The analog 8354 slightlyincreased tumor incidence (p=0.06) but had no effect on multiplicityor size. Six percent of trout treated with DHEA alone developedtumors, whereas no tumors occurred in noninitiated trout fedcontrol or 8354-containing diets. Serum levels of androstenedionewere elevated by DHEA (48-fold) or 8354 (6-fold) treatment Serumß-estradiol titers were increased in DHEA-but not8354-treated trout. Vitellogenin was induced significantly byeither DHEA (434-fold) or 8354 (21-fold). Peroxisomal ß-oxidationwas not increased by either compound and catalase activity wasdecreased in DHEA-treated animals. Both steroids were potentinhibitors in vitro of trout liver glucose-6-phosphate dehydrogenasewith IC50s of 24 and 0.5 µM for DHEA and 8354, respectively.