Abnormal oxidative metabolism of estradiol in women with breast cancer.

Abstract

The three dominant oxidative biotransformations of estradiol were examined in 10 normal women and 33 females with breast cancer by using a recently devised radiometric method. Estradiol tracers, labeled with 3H specifically in the 17a, C-2, or 16a position, were used to measure both the rate and extent of 17P-ol oxidation (the initial metabolic step) and the subsequent 2-and 16a-oxidative reactions. The mean ± SEM values for the extent of estradiol metabolism at these three specific sites were 76.9 ± 5.3%, 31.1 ± 4.0%, and 9.3 ± 0.8%, respectively, in normal subjects. Corresponding data in patients with breast cancer-i.e., 73.0 ± 4.2%, 32.7 ± 2.7%, and 14.9 ± 1.5%-revealed a significantly greater extent of 16a-hydroxylation in the latter population. Because the 16a-hydroxylated compounds (including estriol) are themselves potent estrogens, these changes may have important hyperestrogenic consequences that could have a bearing on the etiology of the disease.Endocrine factors have been implicated in the initiation or promotion, or both, of mammary tumorigenesis based on data collected from several sources. These include both experimental studies using animal models and epidemiological and clinical investigations in human subjects (1). Thus, certain features of the menstrual history and age at parity, which can lengthen the period ofexposure to estrogens secreted by the ovaries, appear to be associated with an increased risk for the disease (2, 3). On the other hand, oophorectomy prior to age 35 can lessen the risk of breast cancer (3). Because an augmentation in estrogen secretion could be implicated in the etiology of the human disease, numerous studies have been conducted to detect such an increase in women with, or at high risk to develop, breast cancer (4). Although some investigators have reported significant differences in urinary or plasma estrogen levels, or both, between these subjects and normal individuals (5-7), these findings have not been consistent and have been challenged by others (8, 9). An alternative and possibly more viable hypothesis that an alteration in estrogen metabolism is associated with breast cancer (4, 10) has also been the subject of extensive investigations.The metabolism of estradiol, which is primarily oxidative, consists ofan initial oxidation ofthe 17/3-hydroxy group to yield estrone. This steroid is subsequently metabolized mainly through either of two alternate hydroxylative pathways; namely, hydroxylation at the C-2 or the 16a position (11). These hydroxylations are of particular interest in that they constitute competing reactions whose products are themselves active compounds characterized by markedly different biological properties. The 16a-hydroxyestrogens-estriol and 16a-hydroxyestrone-demonstrate uterotropic activity comparable to that of the parent hormone, estradiol (12, 13). On the other hand, the principal 2-hydroxyestrogens-2-hydroxyestrone and 2-methoxyestrone exhibit virtually no peripheral estrogenic effects but appear to play a regulatory role in neur...

Sequence diversity and haplotype structure at the human CYP3A cluster

“…CYP3A4 catalyzes the hydroxylation of estrogen to two active metabolites, at least one of which has been associated with mammary tumors in rodents 34 and humans. 35,36 In addition, CYP3A enzymes are involved in the activation of numerous environmental pro-carcinogens into their active carcinogenic forms, making a role for CYP3A variation in cancer susceptibility biologically plausible. 37 However, the results of association studies of CYP3A variation and breast cancer risk are inconsistent.…”

Lower prevalence of breast cancer and cancers of the reproductive system among former college athletes compared to non-athletes

“…Fatness is associated with an increased extraglandular conversion of androgen to oestrogen (Grodin et al, 1973;Forney et al, 1981;Siiteri, 1981) and the metabolism of oestrogen to more potent forms, (Fishman et al, 1975) which have been observed in association with breast cancer (Schneider et al, 1982;Bradlow et al, 1983). Also, excess body weight is associated with a diminished capacity of serum sex-hormone-binding globulin and an elevated percentage of serum oestradiol in the free state (Siiteri, 1981).…”

Understanding the human health effects of chemical mixtures.

“…Estrogens have been proposed to induce carcinogenesis by multiple mechanisms including covalent modification of the estrogen receptor (110,111), induction of chromosomal abnormalities (112,113), an epigenotoxic mechanism (114), conversion of 17β-estradiol to catechol estrogens and redoxactive and adduct-forming estrogen quinones (108,115), and subsequent ROSmediated DNA damage (116,117).…”