Involvement of the H+/organic cation antiporter in nicotine transport in rat liver.

Nicotine is an addictive alkaloid in cigarette smoke and is responsible for tobacco dependence. It is important to consider the blood-to-liver transport of nicotine to understand the nicotine elimination from the body because most of the nicotine is converted to inactive metabolites by cytochrome P450 localized in the endoplasmic reticulum of the hepatocytes. In this study, the blood-to-liver transport of nicotine was investigated by means of an in vivo portal vein injection technique in rats, and the in vitro uptake by freshly isolated rat hepatocytes was used to clarify its mechanism. The results obtained showed that the in vivo blood-to-liver transport of [(3)H]nicotine was significantly inhibited by 50 mM nicotine and pyrilamine, suggesting involvement of a carrier-mediated transport process in the blood-to-liver transport of nicotine. The in vitro uptake study using freshly isolated rat hepatocytes showed a time- and concentration-dependent uptake of [(3)H]nicotine with a Km value of 141 µM, and the uptake was increased under alkaline extracellular conditions. In addition, intracellular acidification caused an increase in [(3)H]nicotine uptake, suggesting that the influx transport of nicotine is driven by an oppositely directed H(+) gradient in hepatocytes. Moreover, [(3)H]nicotine uptake was strongly inhibited in the presence of cationic drugs, such as pyrilamine, whereas only weak inhibitory effects were shown by substrates of typical organic cation transporters, such as tetraethylammonium, 1-methyl-4-phenylpyridinium, choline, and l-carnitine. In conclusion, a carrier-mediated system controlling the blood-to-liver transport of nicotine appears to be present on the sinusoidal membrane of hepatocytes. The pattern of inhibition and ion dependence is suggestive of an H(+)/organic cation antiporter-mediated nicotine transport system.