Abstract
The induction potentials of ligand-activated nuclear receptors on metabolizing enzyme genes are routinely tested for new chemical entities. However, regulations of drug transporter genes by the nuclear receptor ligands are underappreciated, especially in differentiated human hepatocyte cultures. In this study, gene induction by the ligands of constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AhR) was characterized in sandwich-cultured human hepatocytes (SCHH) from multiple donors. The cells were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), omeprazole (OP), 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) and phenobarbital (PB) for three days. RNA samples were analyzed by qRT-PCR method. As expected, CITCO, the direct activator, and PB, the indirect activator of CAR, induced CYP3A4 (31 and 40-fold), CYP2B6 (24 and 28-fold) and UGT1A1 (2.9 and 4.2-fold), respectively. Conversely, TCDD and OP, the activators of AhR, induced CYP1A1 (38 and 37-fold), and UGT1A1 (4.3 and 5.0-fold), respectively. In addition, OP but not TCDD induced CY3A4 by about 61-fold. Twenty-four hepatic drug transporter genes were characterized, and of those, SLC51B was induced the most by PB and OP by about 3.3 and 6.5 fold, respectively. Marginal inductions (about 2-fold) of SLC47A1 and SLCO4C1 genes by PB, and ABCG2 gene by TCDD were observed. In contrast, SLC10A1 gene was suppressed about 2-fold by TCDD and CITCO. While clinical relevance of SLC51B gene induction or SLC10A1 gene suppression warrants further investigation, the results verified that the assessment of transporter gene inductions are not required for new drug entities, when a drug does not remarkably induce metabolizing enzyme genes by CAR and AhR activation.
Highlights
There are about 450 membrane transporters divided into two superfamilies, the solute carrier (SLC) and the ATP Binding Cassette (ABC) transporters
sandwich-cultured human hepatocytes (SCHH) were incubated with TCDD (0.08–50 nM), OP (0.08–50 μM), 6-(4-chlorophenyl) imidazo[2 (CITCO) (0.008–5 μM) and PB (1.6–1,000 μM) for 72 h
CYP1A1, CYP3A4 and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) mRNA inductions by OP were observed in a concentration-dependent manner to a maximum of 37, 61 and 5.0-fold increase at 50 μM, respectively (Table 3)
Summary
There are about 450 membrane transporters divided into two superfamilies, the solute carrier (SLC) and the ATP Binding Cassette (ABC) transporters. About 20 of these membrane proteins are involved in hepatic uptake and biliary excretion of a wide variety of prescription drugs and their metabolites (Vildhede et al, 2015), and play a key role in determining drug pharmacokinetics (PK) and hepatic exposure. Fluctuations of expressions and functional activities of drug transporters can result in changes of plasma level and/or liver exposure of substrate drugs. Active hepatic uptake mediated by sinusoidal transporters e.g., organic anion transporting polypeptides (OATP) can be the rate-determining step of drug elimination for the substrates that are either metabolically stable or unstable (Hagenbuch and Meier, 2004). Given the critical roles played by hepatic transporters in systemic clearance and liver exposure, it is important to understand the factors affecting transporter expression. Characterizing transporter gene regulation is a crucial step to improve the understanding of transporter-mediated drug absorption, disposition and elimination, and subsequently their association to drug efficacy and toxicity
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