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An In Vivo Bioassay for Detecting Antiandrogens Using Humanized Transgenic Mice Coexpressing the Tetracycline-Controlled Transactivator and Human CYP1B1 Gene

Division of Laboratory Animal Resources, Korea Food and Drug Administration, National Institute of Toxicological Research, Seoul, Korea

Hyun G. Kang

College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Chongju, Korea

Yhun Y. Sheen

College of Pharmacy, Ewha Womans University, Seoul, Korea

Seok H. Lee

National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea

Yong K. Kim

Division of Laboratory Animal Resources, Korea Food and Drug Administration, National Institute of Toxicological Research, Seoul, Korea

Correspondence: Address correspondence to Dr. Yong K. Kim, Division of Laboratory Animal Resources, National Institute of Toxicological Research, Korea FDA, 5 Nokbun-dong, Eunpyngku, Seoul, 122-704, Korea. E-mail:kimyongkyu{at}hanmail.net

The typical strategy used in analysis of antiandrogens involves the morphological changes of a marker in castrated rats Hershberger assay for the prostate, seminal vesicle, levator ani plus bulbocavernosus muscles (LABC), Cowper’s gland, and glans penis. However, there are disadvantages to this approach, such as the time required, and the results may not correspond to those in actual human exposure. To evaluate its ability for detecting antiandrogens, in vivo the dose effect of di-(2-ethylhexyl) phthalate (DEHP) and time effect of five antiandrogens, DEHP, di-n-butyl phthalate (DBP), diethyl phthalate (DEP), linuron (3-(4-dichlorophenyl)-methoxy-1-methylurea), and 2,4'-DDE (1,1-dichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)ethylene), were investigated using humanized transgenic mice coexpressing tetracycline-controlled transactivator (tTA) and the human cytochrome P450 (CYP) enzyme CYP1B1 (hCYP1B1). Adult transgenic males were treated with each of the five antiandrogens, and their tTA-driven hCYP1B1 expressions analyzed by real-time polymerase chain reaction (PCR) and/or Western blot and for O-debenzylation activity. Herein, the treatments of adult males with the five antiandrogens were shown to affect the increased levels of tTA-driven hCYP1B1 expression in both dose-dependent and repeated experiments. Thus, this novel in vivo bioassay, using humanized transgenic mice, is useful for measuring antiandrogens, and is a means to a more relevant bioas-say relating to actual human exposure.

Key Words: Androgen • Antiandrogen • CYP1B1 • Tetracycline • Trans-genic

International Journal of Toxicology, Vol. 24, No. 3, 157-164 (2005)
DOI: 10.1080/10915810590948370


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