title: 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.
abstract: Dehydroepiandrosterone (DHEA) is an adrenal steroid with chemoprotective effects against a wide variety of conditions including cancer, obesity, diabetes, and cardiovascular disease. However, DHEA is also a carcinogen in laboratory animals, possibly through its function as a precursor of sex steroids or peroxisome proliferation. The structural analog 16 alpha-fluoro-5-androsten-17-one (8354) has been reported to have enhanced chemopreventive activity without the steroid precursor and peroxisome proliferating effects of DHEA. This study compares DHEA and 8354 in rainbow trout, a species that is resistant to peroxisome proliferation but is highly susceptible to the carcinogenic and tumor enhancing effects of DHEA. Trout were exposed as fry to aflatoxin B1 (AFB1) or given a sham exposure, then were fed diets containing 444 ppm DHEA or 8354 for 6 months. Postinitiation treatment with DHEA significantly increased liver tumor incidence, multiplicity, and size compared to initiated controls. The analog 8354 slightly increased tumor incidence (p = 0.06) but had no effect on multiplicity or size. Six percent of trout treated with DHEA alone developed tumors, whereas no tumors occurred in noninitiated trout fed control or 8354-containing diets. Serum 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 by either DHEA (434-fold) or 8354 (21-fold). Peroxisomal beta-oxidation was not increased by either compound and catalase activity was decreased in DHEA-treated animals. Both steroids were potent inhibitors in vitro of trout liver glucose-6-phosphate dehydrogenase with IC50s of 24 and 0.5 microM for DHEA and 8354, respectively. This research suggests that in trout the tumor enhancing effects of DHEA may be due to its function as a sex steroid precursor and are unrelated to peroxisome proliferation. These carcinogenic properties are reduced in the analog 8354 which has been advocated as an alternative to DHEA for chemoprevention.
authors.affiliation: Toxicology Program, NIEHS Marine/Freshwater Biomedical Sciences Center, Oregon State University, Corvallis 97331-6602, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Orner
authors.forename: R M
authors.initials: RM
authors.lastname: Donohoe
authors.forename: J D
authors.initials: JD
authors.lastname: Hendricks
authors.forename: L R
authors.initials: LR
authors.lastname: Curtis
authors.forename: D E
authors.initials: DE
authors.lastname: Williams
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D003687:Dehydroepiandrosterone / Q000633:toxicity*; D004357:Drug Synergism; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000139:chemically induced*; D017686:Oncorhynchus mykiss
chemical_list: D000736:Androstenes; D016588:Anticarcinogenic Agents; D002273:Carcinogens; C066783:16-fluoro-5-androsten-17-one; D003687:Dehydroepiandrosterone; D016604:Aflatoxin B1