Effect of glutathione depletion on sulfate activation and sulfate ester formation in rats.
Sulfation of organic compounds requires activation of inorganic sulfate via formation of adenosine 3'-phosphate 5'-phosphosulfate (PAPS). Inorganic sulfate can be formed by sulfoxidation of cysteine, which can be derived from GSH. Thus, a decrease in hepatic GSH may impair formation of inorganic sulfate, the synthesis of PAPS, and the sulfation of chemicals. This hypothesis was tested by investigating the effect of GSH depletion on the levels of inorganic sulfate in serum and of PAPS in liver, and on the capacity to form the sulfate conjugate of harmol in rats. Phorone (2 mmol/kg, i.p.) decreased hepatic GSH (97%), serum inorganic sulfate (63%), and hepatic PAPS (48%). Diethyl maleate and vinylidene chloride (6 mmol/kg, each, i.p.) were less effective than phorone in decreasing GSH in liver and inorganic sulfate in serum, and they did not alter hepatic PAPS levels. Three hours after phorone treatment, the nadir of hepatic PAPS concentration, harmol was injected in order to assess sulfation in vivo. After administration of harmol (100 and 300 mumol/kg, i.v.), less harmol sulfate and more harmol glucuronide were found in the serum of phorone-treated rats as compared to control rats. At the higher dosage of harmol, phorone reduced the biliary excretion of harmol sulfate while increasing the biliary excretion of harmol glucuronide. These results indicate that severe GSH depletion decreases PAPS formation and sulfation of chemicals. However, an increase in glucuronidation may compensate for the impaired sulfation.
Gregus
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Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
White
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C
Howell
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Klaassen
C D
CD
D000818:Animals; D004000:Dichloroethylenes / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006247:Harmine / Q000031:analogs & derivatives / Q000494:pharmacology; D007659:Ketones / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism*
D004000:Dichloroethylenes; D007659:Ketones; D008298:Maleates; D013431:Sulfates; C029297:vinylidene chloride; D010724:Phosphoadenosine Phosphosulfate; C001326:harmol; D006247:Harmine; C018637:phorone; C014476:diethyl maleate; D005978:Glutathione