title: Human placental lactogen induces CYP2E1 expression via PI 3-kinase pathway in female human hepatocytes.
abstract: The state of pregnancy is known to alter hepatic drug metabolism. Hormones that rise during pregnancy are potentially responsible for the changes. Here we report the effects of prolactin (PRL), placental lactogen (PL), and growth hormone variant (GH-v) on expression of major hepatic cytochromes P450 expression and a potential molecular mechanism underlying CYP2E1 induction by PL. In female human hepatocytes, PRL and GH-v showed either no effect or small and variable effects on mRNA expression of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5. On the other hand, PL increased expression level of CYP2E1 mRNA with corresponding increases in CYP2E1 protein and activity levels. Results from hepatocytes and HepaRG cells indicate that PL does not affect the expression or activity of HNF1α, the known transcriptional activator of basal CYP2E1 expression. Furthermore, transient transfection studies and Western blot results showed that STAT signaling, the previously known mediator of PL actions in certain tissues, does not play a role in CYP2E1 induction by PL. A chemical inhibitor of PI3-kinase signaling significantly repressed the CYP2E1 induction by PL in human hepatocytes, suggesting involvement of PI3-kinase pathway in CYP2E1 regulation by PL. CYP2E1-humanized mice did not exhibit enhanced CYP2E1 expression during pregnancy, potentially because of interspecies differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (J.K.L., H.J.C., L.F., J.F., H.J.); College of Pharmacy, Gyeongsang National University, Jinju, South Korea (H.J.C.); Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (F.J.G.); and Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois (H.J.).
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Liam
authors.initials: L
authors.lastname: Fischer
authors.forename: James
authors.initials: J
authors.lastname: Fischer
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Hyunyoung
authors.initials: H
authors.lastname: Jeong
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D019382:Human Growth Hormone / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010928:Placental Lactogen / Q000494:pharmacology / Q000502:physiology*; D011247:Pregnancy / Q000378:metabolism; D061251:Primary Cell Culture; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D019392:Cytochrome P-450 CYP2E1; D019382:Human Growth Hormone; D004364:Pharmaceutical Preparations; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010928:Placental Lactogen; D011388:Prolactin