Orner G A, Donohoe R M, Hendricks J D, Curtis L R, Williams D E
Toxicology Program, NIEHS Marine/Freshwater Biomedical Sciences Center, Oregon State University, Corvallis 97331-6602, USA.
Fundam Appl Toxicol. 1996 Nov;34(1):132-40. doi: 10.1006/faat.1996.0183.
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.
脱氢表雄酮（DHEA）是一种肾上腺类固醇，对包括癌症、肥胖症、糖尿病和心血管疾病在内的多种病症具有化学保护作用。然而，DHEA在实验动物中也是一种致癌物，可能是通过其作为性类固醇前体或过氧化物酶体增殖剂的功能。据报道，结构类似物16α-氟-5-雄烯-17-酮（8354）具有增强的化学预防活性，且没有DHEA的类固醇前体和过氧化物酶体增殖作用。本研究在虹鳟鱼中比较了DHEA和8354，虹鳟鱼对过氧化物酶体增殖有抗性，但对DHEA的致癌和肿瘤促进作用高度敏感。将虹鳟鱼苗暴露于黄曲霉毒素B1（AFB1）或进行假暴露，然后给它们喂食含有444 ppm DHEA或8354的饲料6个月。与启动对照组相比，启动后用DHEA处理显著增加了肝脏肿瘤的发生率、多发性和大小。类似物8354略微增加了肿瘤发生率（p = 0.06），但对多发性或大小没有影响。单独用DHEA处理的虹鳟鱼中有6%发生了肿瘤，而喂食对照饲料或含8354饲料的未启动虹鳟鱼未发生肿瘤。DHEA（48倍）或8354（6倍）处理可提高血清雄烯二酮水平。DHEA处理的虹鳟鱼血清β-雌二醇滴度升高，而8354处理的虹鳟鱼则未升高。DHEA（434倍）或8354（21倍）均可显著诱导卵黄蛋白原。两种化合物均未增加过氧化物酶体β-氧化，且DHEA处理的动物中过氧化氢酶活性降低。两种类固醇在体外均是虹鳟鱼肝葡萄糖-6-磷酸脱氢酶的有效抑制剂，DHEA和8354的IC50分别为24和0.5 microM。这项研究表明，在虹鳟鱼中，DHEA的肿瘤促进作用可能归因于其作为性类固醇前体的功能，与过氧化物酶体增殖无关。这些致癌特性在类似物8354中有所降低，8354已被提倡作为DHEA化学预防的替代品。
