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Induction of cytochrome P450 (CYP) 2E1 expression by placental lactogen.
Author(s) -
Lee Jin Kyung,
Chung Hye Jin,
Pan Xian,
IngelmanSundberg Magnus,
Jeong Hyunyoung
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1102.4
Subject(s) - transcription factor , biology , promoter , stat5 , endocrinology , medicine , gene expression , microbiology and biotechnology , gene , signal transduction , genetics
Pregnancy alters hepatic drug metabolism, but the underlying mechanism remains to be identified. In this study, we evaluated the effects of pregnancy‐specific somatotropins [placental lactogen (PL), prolactin (PRL), and growth hormone variant (GH‐v)] on expression of major hepatic CYPs. In human hepatocytes, PL significantly increased the expression of mRNA and protein of CYP2E1 (2.8–5.1 fold), leading to 74% increases in chlorzoxazone 6‐hydroxylation activity. In contrast, PRL and GH‐v had insignificant effects on CYP expression. Considering that somatotropins share common downstream signaling pathways, transcription factors that uniquely modulate PL action were identified by (1) microarray analysis of human hepatocytes treated with vehicle, PL, or PRL, (2) followed by in silico promoter analysis. The results revealed that responsive elements for 7 classes of transcription factor (CREB, ETS factor, class B bHLH transcription factors, homeodomain transcription factors, paralog hox genes, Krüppel like factors, and STAT) exist in promoters of 60% of 125 PL‐responsive genes. PL increased CYP2E1 promoter activity in STAT5‐expressing HepG2 cells. Collectively, our findings indicate that PL increased CYP2E1 expression, in part through STAT5; CYP2E1‐mediated drug metabolism may be increased during pregnancy, resulting in differential drug efficacy and/or toxicity in pregnant women. ( HD065532 )