Journal Article

Steroid hormones modulate expression of cytochrome P450 enzymes in male hamster reproductive tract and leiomyosarcomas

Chad E. Hudson, Bradley A. Schulte, Thomas R. Sutter and James S. Norris

in Carcinogenesis

Volume 22, issue 5, pages 763-770
Published in print May 2001 | ISSN: 0143-3334
Published online May 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.5.763
Steroid hormones modulate expression of cytochrome P450 enzymes in male hamster reproductive tract and leiomyosarcomas

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Syrian hamsters treated with estrogen and androgen for 8 months develop leiomyosarcomas in the vas deferens. Metabolism of estrogen by cytochrome P450s (CYPs) produces catechols and reactive oxygen species, and may contribute to tumor formation. To examine this issue, male hamsters were treated with 17 β-estradiol (E2), testosterone propionate (TP) or both hormones. Reproductive tract tissues from control and treated animals were immunostained with antibodies specific for four CYP enzymes (1A1, 1A2, 1B1 and 3A1/2). Immunoreactive CYP1A1 was not found in the reproductive tract of control or treated animals. In untreated hamsters, CYP1A2 was detected only in principal cells of the caput epididymis. TP alone had no effect, but treatment with E2 induced expression of CYP1A2 in columnar epithelial cells throughout the epididymis and lining of the vas deferens. Treatment with E2 + TP blocked the induction of CYP1A2 seen in surface epithelial cells treated with E2 alone, but not the constitutive expression of this enzyme. Instead, simultaneous exposure to both hormones induced CYP1A2 in basal cells of the epididymis and vas deferens. CYP3A1/2 was not detected in the reproductive tract of control or TP-treated males, but immunostaining was induced in the inner layer of vas deferens smooth muscle by E2, and in all smooth muscle layers by dual hormone treatment. In controls, CYP1B1 was present in smooth muscle lining the epididymis and surrounding the vas deferens and dual hormone treatment increased staining intensity for CYP1B1 in these cells. Immunoreactive CYP1A2 was not detectable in leiomyosarcomas but the enzyme was present in both columnar and basal cells of the vas deferens epithelium adjacent to the tumors. In contrast, tumor cells showed heterogeneous expression of both CYP1B1 and CYP3A1/2. The relationships between hormone treatment, differential CYP expression and tumor formation strengthen our hypothesis that metabolism of estrogen is an important element in this model of hormonal carcinogenesis.

Keywords: CYPs, cytochrome P450s; E2, 17 β-estradiol; GST, glutathione S-transferase; LDL, low density lipoprotein; NGS, normal goat serum; NRS, normal rabbit serum; ROS, reactive oxygen species; TP, testosterone propionate.

Journal Article.  6595 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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