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Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine Nashville, Tennessee 37232
The Department of Medicinal Chemistry, University of Washington School of Pharmacy Seattle, Washington 98195
The Department of Biological Chemistry and Dana-Farber Cancer Institute, Harvard Medical School Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. F. Peter Guengerich, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Abstract
The participation of rat hepatic P-450 in the conversion of 17β-estradiol to catechol estrogens was examined by means of enzyme reconstitution and immunoinhibition studies. It was thus demonstrated that three rat liver microsomal cytochrome P-450 forms, designated P-450UT-A, P-450PCN-E, and P-450ISF-G, each contribute to the 2- and 4-hydroxylation of 17β-estradiol catalyzed by hepatic microsomal preparations. Two of these enzymes, P-450UT-A and P-450PCN-E, are expressed constitutively, are male-specific, and are regulated by testosterone as well as influenced by the administration of various chemicals. Consistent with these observations, 17β-estradiol 2- and 4-hydroxylation activities both increased rapidly during puberty in male rats and were induced by treatment of rats with phenobarbital or pregnenolone 16
-carbonitrile. Castration of male rats at birth or at 5 weeks of age suppressed the levels of 17β-estradiol 2- and 4-hydroxylase activities measured at 10 weeks of age. This suppression of activity was reversed upon administration of testosterone during the neonatal period (days 1 and 3 of life) or by capsule implantation at 5 weeks of age. These patterns of 17β-estradiol 2- and 4-hydroxylation are discussed in terms of the previously characterized response of the multiple rat hepatic P-450 forms to ontogenic, hormonal, and xenobiotic factors. (Endocrinology 118: 1952–1960, 1986)
Footnotes
* This work was supported in part by USPHS Grants ES-01590 and ES-00267 (to F.P.G.) and AM-33765 (to D.J.W.).
Burroughs Wellcome Scholar in Toxicology (1983–1988).
1 The abbreviations used include: P-450, liver microsomal cytochrome P-450; and IgG, immunoglobulin G fraction (of antisera). The nomenclature and its rationale for the P-450 forms are presented elsewhere (10–12). Other preparations in the literature that appear to correspond to the more significant ones dealt with in this report include the following: P-450UT-A (10), male-specific P-450 (13), P-450 2c (14), and P-450 h (15); P-450PCN-E (10), P-450PCN (16), P-450 PB 2a (17), and RLM 3 (18); P-450ISF-G (10), P-450 d (19), (isosafrole-induced) P-450 (20), P-450HCB (21), P-448 II (22), and MC-2 (23).
Received August 13, 1985.
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