Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48 h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-β1 or the HNF4α inhibitor ≡I6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation
ISSN: 0006-2952

hal-01216205
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01216205
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01216205/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01216205/file/Protein%20kinase%20C-dependent%20regulation.pdf
DOI : 10.1016/j.bcp.2015.10.007

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Aryl hydrocarbon receptor-dependent genomic effects of environmental polycyclic aromatic hydrocarbons (PAHs) have been shown to be modulated by non-genomic protein kinase C (PKC)-related pathways. The present study was designed to determine whether PKC activation may also impair estrogenic genomic response triggered by PAHs. Treatment by the PKC activator phorbol 12-myristate 13-acetate (PMA) was found to markedly and differentially impair the up-regulation of estrogenic markers triggered by the estrogenic PAH benzanthracene (BZA) in cultured human mammary cells; BZA-mediated mRNA up-regulation of pS2 and amphiregulin was thus increased, whereas that of progesterone receptor and CXCL12 was repressed. BZA/PMA cotreatment however failed to alter BZA-mediated increase of activity of a luciferase gene reporter construct driven by an estrogen response element, thus discarding any global effect of PMA toward BZA-triggered estrogen receptor activation. Various chemicals inhibiting PKCs or extracellular signal-regulated kinase (ERK) as well as the knock-down of PKCδ expression counteracted the PMA-mediated increase of pS2 mRNA up-regulation triggered by BZA, demonstrating that it was dependent on PKCs, including PKCδ isoform, and ERKs. This non-genomic modulation of estrogenic effects of PAHs by PKC activation may have to be considered when considering the deleterious effects of these environmental contaminants towards the endocrine system.
ISSN: 0887-2333

inserm-00872862
http://www.hal.inserm.fr/inserm-00872862
DOI : 10.1016/j.tiv.2012.05.006
PUBMED : 22643241