1. Biliary secretory function in rats chronically intoxicated with aluminum.
- Author
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Gonzalez MA, Roma MG, Bernal CA, Alvarez Mde L, and Carrillo MC
- Subjects
- Aluminum Hydroxide administration & dosage, Aluminum Hydroxide blood, Aluminum Hydroxide poisoning, Animals, Bile drug effects, Bile Acids and Salts antagonists & inhibitors, Bile Acids and Salts metabolism, Catalase antagonists & inhibitors, Catalase metabolism, Cholestasis chemically induced, Cholesterol metabolism, Chronic Disease, Drug Administration Schedule, Drug Evaluation, Preclinical methods, Gene Expression, Glutathione antagonists & inhibitors, Glutathione chemistry, Glutathione drug effects, Glutathione metabolism, Glutathione Peroxidase antagonists & inhibitors, Glutathione Peroxidase metabolism, Glutathione Transferase chemistry, Glutathione Transferase metabolism, Injections, Intraperitoneal, Liver chemistry, Liver drug effects, Male, Mitochondrial Proteins antagonists & inhibitors, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Oxidative Stress drug effects, Proteins antagonists & inhibitors, Proteins metabolism, Rats, Rats, Wistar, Ribosomal Proteins antagonists & inhibitors, Ribosomal Proteins genetics, Ribosomal Proteins metabolism, Saccharomyces cerevisiae Proteins antagonists & inhibitors, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, Sulfobromophthalein metabolism, Sulfobromophthalein pharmacokinetics, Thiobarbituric Acid Reactive Substances chemistry, Thiobarbituric Acid Reactive Substances metabolism, Aluminum poisoning, Bile metabolism, Bile Canaliculi drug effects, Bile Canaliculi metabolism, Glutathione analogs & derivatives
- 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/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 (approximately 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.
- Published
- 2004
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