title: Cytochrome P450-mediated metabolic alterations in preeclampsia evaluated by quantitative steroid signatures.
abstract: Although preeclampsia has been suggested potential risk factors including placental and systemic inflammation, oxidative stress, and abnormal steroid metabolism during pregnancy, the pathogenesis of preeclampsia has not fully been elucidated, particularly in steroid metabolism. The association between various cytochrome P450 (CYP)-mediated steroid metabolic markers and preeclampsia risk was therefore investigated. The serum levels of 54 CYP-mediated regioselective hydroxysteroids and their substrates were quantitatively evaluated from both pregnant women with preeclampsia (n=30; age, 30.8±4.5 years) and normotensive controls (n=30; age, 31.0±3.5 years), who were similar with respect to maternal age, gestational age, and body mass index. The levels of 6ß-, 7a-, and 11ß-hydroxymetabolites of androgens and corticoids were significantly increased in women with preeclampsia. In addition, the levels of oxysterols, including 7a-, 7ß-, 4ß-, 20a-, 24S-, and 27-hydroxycholesterol, were markedly higher, while the levels of 16a-OH-DHEA, 16a-OH-androstenedione, and cholesterol were significantly decreased in patients. The 6ß-hydroxylation of androgens and corticoids by CYP3A4 (P<0.01), the activation of 20,22-desmolase (a cholesterol side-chain cleavage enzyme) by CYP11A1 (P<0.00001), and the multi-hydroxylation of cholesterol at C-4ß, C-7a, C-7ß, C-24S, C-27, and C-20a (P<0.0001) by catalytic or enzymatic reaction (e.g. CYP3A4, CYP7A1, CYP27A1, and CYP46A1) were differed between preeclamptic women and control subjects. In particular, an increased oxysterols (induction>2.0-fold) were positively correlated with the conditions of preeclampsia. Our metabolic profiling suggests the CYP-mediated alterations in steroid metabolism and hydroxylation in pregnancy-induced hypertension. These multiple markers could serve as background information for improved clinical diagnosis and management during pregnancy. This article is part of a Special Issue entitled "Pregnancy and Steroids".
authors.affiliation: Future Convergence Research Division, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea; Department of Chemistry, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Ju-Yeon
authors.initials: JY
authors.lastname: Moon
authors.forename: Myeong Hee
authors.initials: MH
authors.lastname: Moon
authors.forename: Ki Tae
authors.initials: KT
authors.lastname: Kim
authors.forename: Dae Hoon
authors.initials: DH
authors.lastname: Jeong
authors.forename: Young Nam
authors.initials: YN
authors.lastname: Kim
authors.forename: Bong Chul
authors.initials: BC
authors.lastname: Chung
authors.forename: Man Ho
authors.initials: MH
authors.lastname: Choi
mesh_terms: D000328:Adult; D002138:Calibration; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000592:standards; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D006914:Hydroxysteroids / Q000097:blood; D011225:Pre-Eclampsia / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology; D011247:Pregnancy; D012015:Reference Standards; D055815:Young Adult
chemical_list: D012739:Gonadal Steroid Hormones; D006914:Hydroxysteroids; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; GC–MS; Preeclampsia; Steroid oxidation; Steroid signatures