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 beta-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.