RT Journal Article
SR Electronic
T1 Human Placental Lactogen Induces CYP2E1 Expression Via PI 3-kinase Pathway in Female Human Jepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.113.055384
DO 10.1124/dmd.113.055384
A1 Jin Kyung Lee
A1 Hye Jin Chung
A1 Liam Fischer
A1 James Fischer
A1 Frank J. Gonzalez
A1 Hyunyoung Jeong
YR 2014
UL http://dmd.aspetjournals.org/content/early/2014/01/09/dmd.113.055384.abstract
AB 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 (CYP) 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 due to inter-species differences in PL physiology. Taken together, these results indicate that PL induces CYP2E1 expression via PI3 kinase pathway in human hepatocytes.