COMPARISON OF THE ENHANCING EFFECTS OF DEHYDROEPIANDROSTERONE WITH THE STRUCTURAL ANALOG 16-ALPHA-FLUORO-5-ANDROSTEN-17-ONE ON AFLATOXIN B-1 HEPATOCARCINOGENESIS IN RAINBOW-TROUT

Dehydroepiandrosterone (DHEA) is an adrenal steroid with chemoprotecti ve effects against a wide variety of conditions including cancer, obes ity, diabetes, and cardiovascular disease, However, DHEA is also a car cinogen in laboratory animals, possibly through its function as a prec ursor of sex steroids or peroxisome proliferation, The structural anal og 16 alpha-fluoro-5-androsten-17-one (8354) has been reported to have enhanced chemopreventive activity without the steroid precursor and p eroxisome proliferating effects of DHEA, This study compares DHEA and 8354 in rainbow trout, a species that is resistant to peroxisome proli feration but is highly susceptible to the carcinogenic and tumor enhan cing effects of DHEA. Trout were exposed as fry to aflatoxin B-1 (AFB( 1)) or given a sham exposure, then were fed diets containing 444 ppm D HEA or 8354 for 6 months. Postinitiation treatment with DHEA significa ntly increased liver tumor incidence, multiplicity, and size compared to initiated controls, The analog 8354 slightly increased tumor incide nce (p = 0.06) but had no effect on multiplicity or size, Six percent of trout treated with DHEA alone developed tumors, whereas no tumors o ccurred in noninitiated trout fed control or 8354-containing diets, Se rum levels of androstenedione were elevated by DHEA (48-fold) or 8354 (6-fold) treatment, Serum beta-estradiol titers were increased in DHEA - but not 8354-treated trout. Vitellogenin was induced significantly b y either DHEA (434-fold) or 8354 (21-fold), Peroxisomal beta-oxidation was not increased by either compound and catalase activity was decrea sed in DHEA-treated animals, Both steroids were potent inhibitors in v itro of trout liver glucose-6-phosphate dehydrogenase with IC50s of 24 and 0.5 mu M for DHEA and 8354, respectively. This research suggests that in trout the tumor enhancing effects of DHEA may be due to its fu nction as a sex steroid precursor and are unrelated to peroxisome prol iferation. These carcinogenic properties are reduced in the analog 835 4 which has been advocated as an alternative to DHEA for chemopreventi on. (C) 1996 Society of Toxicology.