Telang N T, Axelrod D M, Wong G Y, Bradlow H L, Osborne M P
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York New York 10021.
Steroids. 1991 Jan;56(1):37-43. doi: 10.1016/0039-128x(91)90113-a.
In vivo experiments on strains of mice that differ in the risk of developing mammary cancer have demonstrated a correlation between the extent of 16 alpha-hydroxylation of estradiol and incidence of mammary cancer. The ability of human mammary terminal duct lobular unit (TDLU), the site of neoplastic transformation, to metabolize estradiol or to accumulate estradiol metabolites has not been unequivocally established. Using a newly developed human mammary TDLU explant culture system and a radiometric assay for estradiol metabolism, we compared the site-specific metabolism of estradiol by the 17-oxidation, 2-hydroxylation, and 16 alpha-hydroxylation pathways in noninvolved human mammary tissue. The relative extent of estradiol 16 alpha-hydroxylation was found to be increased in TDLU from patients in the luteal phase of the menstrual cycle in relation to either those from patients in the follicular phase or from postmenopausal subjects. This study demonstrates that TDLU can metabolize estradiol extrahepatically and that 16 alpha-hydroxylation in the target tissue is dependent on the phase of the menstrual cycle. Furthermore, the specific, risk-related increase in 16 alpha-hydroxylation suggests that intrinsic metabolic ability of the target tissue leading to the formation of 16 alpha-hydroxyestrone from estradiol may be a determinant in, or a marker for, the relative risk of developing mammary cancer.
对患乳腺癌风险不同的小鼠品系进行的体内实验表明，雌二醇16α-羟基化程度与乳腺癌发病率之间存在关联。乳腺肿瘤转化发生部位——人乳腺终末导管小叶单位（TDLU）代谢雌二醇或积累雌二醇代谢物的能力尚未得到明确证实。我们使用新开发的人乳腺TDLU外植体培养系统和一种用于雌二醇代谢的放射性测定法，比较了在未受累人乳腺组织中，通过17-氧化、2-羟基化和16α-羟基化途径进行的雌二醇位点特异性代谢。结果发现，与处于卵泡期的患者或绝经后受试者的TDLU相比，处于月经周期黄体期的患者的TDLU中，雌二醇16α-羟基化的相对程度有所增加。这项研究表明，TDLU能够在肝外代谢雌二醇，且靶组织中的16α-羟基化取决于月经周期阶段。此外，16α-羟基化与风险相关的特异性增加表明，靶组织从雌二醇形成16α-羟基雌酮的内在代谢能力可能是患乳腺癌相对风险的一个决定因素或标志物。
