Liver, Pancreas, and Biliary TractVitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat☆,☆☆
Section snippets
Materials
All chemicals were obtained in analytical purity from the suppliers. Bovine serum albumin (fraction V) was obtained from Calbiochem (La Jolla, CA), bile acids from Sigma Chemical Co. (St. Louis, MO), digitonin from Sigma, and parenteral vitamin E (all-rac-α-tocopherol, Ephynal) from Hoffmann–LaRoche (Nutley, NJ).
Development of experimental model of IV TCDC toxicity
The first phase of this study was the development of an IV model of TCDC toxicity in the rat that produced a significant but reversible hepatic injury. For all experiments, young adult
In vivo TCDC toxicity model and mitochondrial lipid peroxidation
IV bolus injections of TCDC in rats caused a significant increase in serum AST and ALT concentrations in a dose-dependent manner (Table 1), with peak values attained 4 hours after injection.
Empty Cell Dose of IV TCDC (μmol/100 g body wt) Time after IV TCDC dose 0 (n = 4) 5 (n = 4) 10 (n = 5) 20 (n = 4) 0 h AST 62 ± 1 73 ± 9 92 ± 8 70 ± 6 ALT 54 ± 5 52 ± 6 53 ± 3 64 ± 9 4 h AST 66 ± 6 121 ± 24 3679 ± 1105 1456 ± 748 ALT 51 ± 8 92 ± 23 1855 ± 701 1712 ± 554 8 h AST 59 ± 14 110 ± 12 2233 ± 1906
Discussion
Recent investigations into the pathogenesis of cholestatic liver injury have focused on the role of hydrophobic bile acids.22, 23, 24, 25, 26, 27 In this study, we developed a novel in vivo model of bile acid toxicity that uses a single-bolus IV injection of TCDC, a conjugate of the bile acid most implicated in cholestatic liver injury.5, 6, 7 An IV dose of 10 μmol/100 g body wt in young adult male rats produced a significant but reversible injury to hepatocytes, which was maximum at 4 hours
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Address requests for reprints to: Ronald J. Sokol, M.D., Department of Pediatrics, The Children's Hospital, Box B290, 1056 East 19th Avenue, Denver, Colorado 80218. Fax: (303) 764-8025.
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Supported in part by grants RO1DK38446 and IP30DK34914 from the National Institutes of Health and the Abbey Bennett Liver Research Fund.