SULFATION OF ACETAMINOPHEN AND ACETAMINOPHEN-INDUCED ALTERATIONS IN SULFATE AND 3'-PHOSPHOADENOSINE 5'-PHOSPHOSULFATE HOMEOSTASIS IN RATS WITH DEFICIENT DIETARY-INTAKE OF SULFUR

Sulfation of drugs depends on the availability of 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which requires inorganic sulfate for its syn thesis. 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 da ys on synthetic diets, which lacked sulfate, or cysteine, or both sulf ate and cysteine. These dietary restrictions did not cause growth reta rdation or depletion of glutathione in liver. Under anesthesia, the an imals were injected with acetaminophen (0.5 mmol/kg, iv) and eliminati on of acetaminophen from blood and excretion of acetaminophen metaboli tes in urine and bile was simultaneously quantified. Deficient intake of inorganic sulfate or cysteine alone did not significantly change el imination and biotransformation of acetaminophen. Combined nutritional deficiency of sulfate and cysteine, however, resulted in a 40% reduct ion in the excretion of acetaminophen-sulfate, quantitatively the most significant metabolite. Concomitantly, these animals eliminated aceta minophen from blood at a slower rate and converted more acetaminophen to its toxic intermediate, as indicated by increased excretion of acet aminophen-thioether conjugates. Serum and tissue sulfate concentration s 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 availabil ity of inorganic sulfate for PAPS synthesis, even though hepatic and r enal PAPS levels were not depleted more by acetaminophen in rats with deficient dietary supply of sulfate and cysteine than in rats with ade quate sulfur intake. In addition, whereas acetaminophen-induced sulfat e depletion was transient in control animals, it was prolonged in rats with deficient sulfate and cysteine intake, with serum, liver, and ki dney inorganic sulfate concentrations remaining 60-80% below normal ev en at 8 hr after acetaminophen administration. Thus, diminished dietar y intake of sulfur reduces detoxication and elimination of acetaminoph en, with concomitant increase in its toxication. Because deficient sul fur intake aggravates sulfate depletion caused by a single dose of ace taminophen, unfavorable changes in acetaminophen metabolism (i.e., red uced sulfation and enhanced toxication) are even more likely after rep eated doses of the drug.