Effect of P-450 inducers on biliary excretion of glutathione and its hydrolysis products. Correlation between hepatic gamma-glutamyltranspeptidase activity and the proportion of glutathione hydrolysis products in bile.
This study was designed to determine if a relationship exists between hepatic gamma-glutamyltranspeptidase (gamma-GT) activity and the biliary excretion of glutathione (GSH) and its hydrolysis products. Rats were pretreated with the following microsomal enzyme inducers: pregnenolone-16 alpha-carbonitrile (PCN), dexamethasone (DEX), 3-methylcholanthrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), phenobarbital (PB), ethanol (ETOH), trans-stilbene oxide (TSO), butylated hydroxyanisole (BHA), isosafrole (ISF), clofibrate, and benzo(a)pyrene. Hepatic gamma-GT activity was quantitated spectrophotometrically; bile and liver samples were analyzed by HPLC for reduced and oxidized GSH and their hydrolysis products (cysteine, cysteinylglycine, and cysteinylglycine disulfide). Administration of the inducers had only minor effects on hepatic GSH concentration, as BHA was the only agent to increase GSH concentration. However, these inducers had a pronounced effect on the biliary excretion of total thiol-derived sulfur as PCN, PB, and ISF produced an increase, whereas TCDD, ETOH, and TSO caused a decrease. The relative amount of the GSH hydrolysis products in bile was highly dependent on gamma-GT activity. For example, hepatic gamma-GT activity was increased by PCN, DEX, BHA, TSO, and ISF. They also increased the GSH hydrolysis products to total thiol-derived sulfur ratio in bile. In conclusion, the ratio of GSH hydrolysis products to total thiol-derived sulfur excreted in rat bile reflects the hepatic gamma-GT activity.
Madhu
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417.
Mitchell
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Klaassen
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D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D003577:Cytochrome P-450 Enzyme System; D005723:gamma-Glutamyltransferase; D005978:Glutathione