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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh085
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received November 28, 2003; accepted January 13, 2004
© 2004 Society of Toxicology

Systems Toxicology

Biliary Secretory Function in Rats Chronically Intoxicated with Aluminum

Marcela A. Gonzalez 1, Marcelo G. Roma 2, Claudio A. Bernal 3, Maria de Lujan Alvarez 2, and María C. Carrillo 2*

1 Cátedra de Fisiología Humana, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral
2 Instituto de Fisiología Experimental (IFISE)-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario
3 Cátedra de Bromatología y Nutrición, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral

* To whom correspondence should be addressed. E-mail: mcarill{at}fbioyf.unr.edu.ar.


  Abstract

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 per Kg of body weight of Al - as Al hydroxide [Al (+) rats] - or the vehicle (saline) [Al (-) rats], thrice a week, for 3 months. Serum and hepatic Al levels were increased by the treatment (~9 and 4 folds, respectively). This was associated with enhanced malondialdehyde formation (+110%), and 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%) were decreased as well. 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 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 with an impairment in Mrp2 expression. Possible mechanisms involved in these deleterious effects are discussed.

Key Words: Aluminum, liver, biliary function, multidrug resistance-associated protein 2 .


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