{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:33:15Z","timestamp":1790713995093,"version":"4.1.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1995,9,26]]},"abstract":"<jats:p>Estradiol is converted to catechol estrogens via 2- and 4-hydroxylation by cytochrome P450 enzymes. 4-Hydroxyestradiol elicits biological activities distinct from estradiol, most notably an oxidant stress response induced by free radicals generated by metabolic redox cycling reactions. In this study, we have examined 2- and 4-hydroxylation of estradiol by microsomes of human uterine myometrium and of associated myomata. In all eight cases studied, estradiol 4-hydroxylation by myoma has been substantially elevated relative to surrounding myometrial tissue (minimum, 2-fold; mean, 5-fold). Estradiol 2-hydroxylation in myomata occurs at much lower rates than 4-hydroxylation (ratio of 4-hydroxyestradiol\/2-hydroxyestradiol, 7.9 +\/- 1.4) and does not significantly differ from rates in surrounding myometrial tissue. Rates of myometrial 2-hydroxylation of estradiol were also not significantly different from values in patients without myomata. We have used various inhibitors to establish that 4-hydroxylation is catalyzed by a completely different cytochrome P450 than 2-hydroxylation. In myoma, alpha-naphthoflavone and a set of ethynyl polycyclic hydrocarbon inhibitors (5 microM) each inhibited 4-hydroxylation more efficiently (up to 90%) than 2-hydroxylation (up to 40%), indicating &gt; 10-fold differences in Ki (&lt;0.5 microM vs. &gt; 5 microM). These activities were clearly distinguished from the selective 2-hydroxylation of estradiol in placenta by aromatase reported previously (low Km, inhibition by Fadrozole hydrochloride or ICI D1033). 4-Hydroxylation was also selectively inhibited relative to 2-hydroxylation by antibodies raised against cytochrome P450 IB1 (rat) (53 vs. 17%). These data indicate that specific 4-hydroxylation of estradiol in human uterine tissues is catalyzed by a form(s) of cytochrome P450 related to P450 IB1, which contribute(s) little to 2-hydroxylation. This enzyme(s) is therefore a marker for uterine myomata and may play a role in the etiology of the tumor.<\/jats:p>","DOI":"10.1073\/pnas.92.20.9220","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T09:21:01Z","timestamp":1149067261000},"page":"9220-9224","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":144,"title":["4-Hydroxylation of estradiol by human uterine myometrium and myoma microsomes: implications for the mechanism of uterine tumorigenesis."],"prefix":"10.1073","volume":"92","author":[{"given":"J G","family":"Liehr","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M J","family":"Ricci","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C R","family":"Jefcoate","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E V","family":"Hannigan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J A","family":"Hokanson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B T","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1995,9,26]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.92.20.9220","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T13:54:11Z","timestamp":1649858051000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.92.20.9220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,9,26]]},"references-count":0,"journal-issue":{"issue":"20","published-print":{"date-parts":[[1995,9,26]]}},"alternative-id":["10.1073\/pnas.92.20.9220"],"URL":"https:\/\/doi.org\/10.1073\/pnas.92.20.9220","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,9,26]]},"assertion":[{"value":"1995-09-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}