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 6 beta-, 7 alpha-, and 11 beta-hydroxymetabolites of androgens and corticoids were significantly increased in women with preeclampsia. In addition, the levels of oxysterols, including 7 alpha-, 7 beta-, 4 beta-, 20 alpha-, 24S-, and 27-hydroxycholesterol, were markedly higher, while the levels of 16 alpha-OH-DIEA, 16 alpha-OH-androstenedione, and cholesterol were significantly decreased in patients. The 6 beta-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-4 beta, C-7 alpha, C-7 beta, C-24S, C-27, and C-20 alpha (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". (C) 2013 Elsevier Ltd. All rights reserved.