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, i.v.) 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.(ABSTRACT TRUNCATED AT 250 WORDS)