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Received for publication March 21, 2005.
Revised June 2, 2005.
Accepted for publication July 8, 2005.
Primary hepatocyte cultures are considered as an useful in vitro system for pharmacological/toxicological studies. Although expression of drug metabolizing enzymes and canalicular drug transporters has been well documented in this cellular model, less information is available about sinusoidal drug transporter activities. This has led us to investigate functional expression of the major sinusoidal transporters in primary human and rat hepatocytes. Using radio-labelled substrates and chemical transporter inhibitors, activities of organic cation transporter 1 (OCT1/Oct1), organic anion transporting polypeptides (OATPs/Oatps), organic anion transporter 2 (OAT2/Oat2) and Na+-taurocholate transporter (NTCP/Ntcp) were detected in cultured human and rat hepatocytes. In parallel, mRNA expression of these transporters was demonstrated using RT-quantitative PCR assays. Functional expression of sinusoidal transport proteins markedly decreased with time in primary rat hepatocyte cultures; by contrast, it remained relatively constant in primary human hepatocytes all along the culture, illustrating the fact that liver-specific functions, including drug detoxifying pathways, are usually better preserved in cultured human hepatocytes than in their rodent counterparts. Primary hepatocytes, especially human hepatocytes, thus exhibit a pattern of sinusoidal transporter expression close to that found in vivo, highlighting the interest of hepatocyte cultures for drug detoxification studies.
Key words:
active transport, drug transport, hepatic uptake, hepatobiliary transport, hepatocytes, in vitro toxicity assays, organic anion transport, organic cation transport
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