Alteration of human hepatic drug transporter activity and expression by cigarette smoke condensate

Abstract

Smoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B1, OATP2B1, OAT2, NTCP, OCT1 and BSEP, and enhanced that of MRP4. Such changes in transporter gene expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a reference activator of the aryl hydrocarbon receptor (AhR) pathway, and were counteracted, for some of them, by siRNA-mediated AhR silencing. This suggests that CSC alters hepatic drug transporter levels via activation of the AhR cascade. Importantly, drug transporter expression regulations as well as some transporter activity inhibitions occurred for a range of CSC concentrations similar to those required for inducing drug metabolizing enzymes and may therefore be hypothesized to be relevant for smokers. Taken together, these data established human hepatic transporters as targets of cigarette smoke, which could contribute to known alteration of pharmacokinetics and some liver adverse effects caused by smoking. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummarySmoking is well-known to impair pharmacokinetics, through inducing expression of drug metabolizing enzymes. In the present study, we demonstrated that cigarette smoke condensate (CSC) also alters activity and expression of hepatic drug transporters, which are now recognized as major actors of hepatobiliary elimination of drugs. CSC thus directly inhibited activities of sinusoidal transporters such as OATP1B1, OATP1B3, OCT1 and NTCP as well as those of canalicular transporters like P-glycoprotein, MRP2, BCRP and MATE1, in hepatic transporters-overexpressing cells. CSC similarly counteracted constitutive OATP, NTCP and OCT1 activities in human highly-differentiated hepatic HepaRG cells. In parallel, CSC induced expression of BCRP at both mRNA and protein level in HepaRG ce...

Atorvastatin modulates drug transporters and ameliorates nicotine-induced testicular toxicity

“…This agrees with the observations of Sayyed et al. () that cigarette smoke condensate suppresses activity of various SLC and ABC transporters and also impairs expression of some of them. Testosterone is the regulator of this transporter (Asaka, Terada, Okuda, Katsura, & Inui, ).…”

Expression of MATE1, P-gp, OCTN1 and OCTN2, in epithelial and immune cells in the lung of COPD and healthy individuals

“…CYP1B1 in the lung [ 44 ]. Downregulation of MATE1, and other transporters, by cigarette smoke extract and the potent AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has previously been seen in HepRG cells, a hepatocyte cell line [ 45 ]. However, regulation of P-gp by AhR has to our knowledge not been described in the literature, and no change in P-gp expression was observed in lung tissue from smokers or COPD patients when compared to healthy tissue [ 7 , 46 ].…”

Regulation of Cytosolic Sulfotransferases in Models of Human Hepatocyte Development

“…Genes that are primarily expressed in fetal hepatocytes, such as CYP3A7 and pyruvate kinase muscle isozyme, are more highly expressed in undifferentiated HepaRG cells, whereas genes that are predominantly expressed in adult hepatocytes, such as CYP3A4 and CYP2E1, are more highly expressed in differentiated HepaRG cells (Tsuji et al, 2014;Bucher et al, 2017). HepaRG cells are becoming established as a useful model for studying hepatocellular differentiation, xenobiotic metabolism and toxicity, and development of liver diseases (Sharanek et al, 2015;Nunn et al, 2016;Rodrigues et al, 2016;Sayyed et al, 2016;Xia et al, 2016). In this study, we have defined the temporal patterns of SULT expression in HepaRG cells during differentiation.…”