Sulfation of acetaminophen and acetaminophen-induced alterations in sulfate and 3'-phosphoadenosine 5'-phosphosulfate homeostasis in rats with deficient dietary intake of sulfur

Z. Gregus, H. J. Kim, C. Madhu, Y. Liu, P. Rozman, C. D. Klaassen

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Abstract

Sulfation of drugs depends on the availability of 3'-phosphoadenosine 5'- phosphosulfate (PAPS), which requires inorganic sulfate for its synthesis. Therefore, decreased alimentary intake of inorganic sulfate or its precursor, cysteine, may compromise sulfation of xenobiotics. To test this hypothesis, separate groups of rats were maintained for 5 days on synthetic diets, which lacked sulfate, or cysteine, or both sulfate and cysteine. These dietary restrictions did not cause growth retardation or depletion of glutathione in liver. Under anesthesia, the animals were injected with acetaminophen (0.5 mmol/kg, iv) and elimination of acetaminophen from blood and excretion of acetaminophen metabolites in urine and bile was simultaneously quantified. Deficient intake of inorganic sulfate or cysteine alone did not significantly change elimination and biotransformation of acetaminophen. Combined nutritional deficiency of sulfate and cysteine, however, resulted in a 40% reduction in the excretion of acetaminophen-sulfate, quantitatively the most significant metabolite. Concomitantly, these animals eliminated acetaminophen from blood at a slower rate and converted more acetaminophen to its toxic intermediate, as indicated by increased excretion of acetaminophen-thioether conjugates. Serum and tissue sulfate concentrations were decreased to significantly lower levels in rats on sulfate and cysteine deficient diets, than in rats with a sufficient sulfur supply. Thus, reduced sulfation is apparently caused by diminished availability of inorganic sulfate for PAPS synthesis, even though hepatic and renal PAPS levels were not depleted more by acetaminophen in rats with deficient dietary supply of sulfate and cysteine than in rats with adequate sulfur intake. In addition, whereas acetaminophen-induced sulfate depletion was transient in control animals, it was prolonged in rats with deficient sulfate and cysteine intake, with serum, liver, and kidney inorganic sulfate concentrations remaining 60-80% below normal even at 8 hr after acetaminophen administration. Thus, diminished dietary intake of sulfur reduces detoxication and elimination of acetaminophen, with concomitant increase in its toxication. Because deficient sulfur intake aggravates sulfate depletion caused by a single dose of acetaminophen, unfavorable changes in acetaminophen metabolism (i.e., reduced sulfation and enhanced toxication) are even more likely after repeated doses of the drug.

Original languageEnglish
Pages (from-to)725-730
Number of pages6
JournalDrug Metabolism and Disposition
Volume22
Issue number5
Publication statusPublished - Jan 1 1994

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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