ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 79, 189-195 (2004)
Toxicological Sciences vol. 79 no. 1 © Society of Toxicology; all rights reserved.
Biliary Secretory Function in Rats Chronically Intoxicated with Aluminum
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* Human Physiology Area, Litoral National University, Institute of Experimental Physiology (IFISE)-CONICET, National University of Rosario, and Bromatology and Nutrition Area, Litoral National University, Argentine
Received November 28, 2003; accepted January 13, 2004
The effects of a chronic aluminum (Al) exposure on biliary secretory function, with special emphasis on hepatic handling of non–bile salt organic anions, was investigated. Male Wistar rats received, intraperitoneally, either 27 mg/kg body weight of Al, as Al hydroxide [Al (+) rats], or the vehicle saline [Al (–) rats] three times a week for 3 months. Serum and hepatic Al levels were increased by the treatment (
9- and 4-fold, respectively). This was associated with enhanced malondialdehyde formation (+110%) and a reduction in GSH content (–17%) and in the activity of the antioxidant enzymes catalase (–84%) and GSH peroxidase (–46%). Bile flow (–23%) and the biliary output of bile salts (–39%), cholesterol (–43%), and proteins (–38%) also decreased. Compartmental analysis of the plasma decay of the model organic anion bromosulphophthalein revealed that sinusoidal uptake and canalicular excretion of the dye were significantly decreased in Al (+) rats (–53 and –43%, respectively). Expression of multidrug resistance–associated protein 2 (Mrp2), the main, multispecific transporter involved in the canalicular excretion of organic anions, was also decreased (–40%), which was associated with a significant decrease in the cumulative biliary excretion of the Mrp2 substrate, dinitrophenyl-S-glutathione (–50%). These results show that chronic Al exposure leads to oxidative stress, cholestasis, and impairment of the hepatic handling of organic anions by decreasing both sinusoidal uptake and canalicular excretion. The alteration of the latter process seems to be causally related to impairment of Mrp2 expression. We have addressed some possible mechanisms involved in these deleterious effects.
Key Words: aluminum; liver; biliary function; multidrug resistance–associated protein 2.