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Differential Effect of 7,12-Dimethylbenz[a]anthracene on Human and Mouse CYP1B1 from Livers of Castrated Transgenic Mice

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

Yhun Y. Sheen

College of Pharmacy, Ewha Womans University, Seoul, Korea

Soo Y. Choi

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

Yong K. Kim

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

Correspondence: Address correspondence to Yong Kyu Kim, PhD, Laboratory Animal Resources Team, National Institute of Toxicological Research, Korea FDA, 194 Tongilro Eunpyung-ku, Seoul 122-704, Korea. E-mail:kimyongkyu{at}hanmail.net

Humanized transgenic mice coexpressing tetracycline-controlled transactivator (tTA) and human cytochrome P450 1B1 (CYP1B1) (hCYP1B1) have been created by this group. The aims of this study was to determine if 7,12-dimethylbenz[a]anthracene (DMBA) functions as testosterone or doxycycline in its ability to induce or reduce expression of hCYP1B1 or endogenous mouse CYP1B1 (mCYP1B1). This was tested in the livers by treating castrated transgenic males and hCYP1B1/luciferase-transfected cells with DMBA. Herein, DMBA-treated group exhibited (i) gradual reduction of hCYP1B1 expression at the transcript, protein, and activity levels but gradually induced its transcript level during DMBA release; (ii) gradual reduction of hCYP1B1 at the transcript and protein levels, as in the case of doxycycline or testosterone; (iii) gradual induction of mCYP1B1 expression at the transcript and protein levels but gradually reduced its transcript level during DMBA release. In parallel, DMBA-treated transfected cells exhibited gradual increase in luciferase activity in a time- and dose-dependent manner. Thus, castrated transgenic males or in vitro system could be useful as models for the detection of polycyclic aromatic hydrocarbons (PAHs) or environmental toxicants by measuring either hCYP1B1 or mCYP1B1 expressions.

Key Words: CYP1B1 • DMBA • Doxycycline • Testosterone • Transgenic Mice

International Journal of Toxicology, Vol. 26, No. 1, 71-80 (2007)
DOI: 10.1080/10915810601120640


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