MOLYBDATE DEPLETES HEPATIC 3-PHOSPHOADENOSINE 5-PHOSPHOSULFATE AND IMPAIRS THE SULFATION OF ACETAMINOPHEN IN RATS

Molybdate (15 mmol/kg p.o.) decreased serum sulfate concentrations of rats 70% within 6 hr after administration. Parallel to this depletion, there was a dramatic decrease in hepatic sulfate and 3-phosphoadenosi ne 5-phosphosulfate (PAPS) concentrations (about 40 and 65%, respectiv ely). However, renal PAPS concentrations did not change significantly. Molybdate reduced serum, hepatic and renal sulfate as well as hepatic PAPS concentration in a dose-dependent manner up to the dose of 10 mm ol/kg. However, renal PAPS did not change. The results indicate that m olybdate reduced not only sulfate concentrations in serum and tissue, but also PAPS concentrations in liver. The effect of molybdate on the pharmacokinetics of acetaminophen (AA, 150 mg/kg i.v.) was also invest igated in order to determine whether molybdate-induced depletion of PA PS might be a useful tool for examining the importance of sulfation in the detoxication and toxication of xenobiotics. AA-sulfate concentrat ion in blood decreased 40 and 80% after administration of molybdate at doses of 2.5 and 15 mmol/kg, respectively. Molybdate also decreased t he excretion of AA-sulfate into bile and urine by about 60 and 80%, re spectively. However, molybdate did not alter the excretion of AA-glucu ronide and AA-glutathione/cysteine. The excretion of the parent AA inc reased 2-fold after molybdate administration (15 mmol/kg). In conclusi on, molybdate effectively lowers inorganic sulfate in serum and tissue s, and PAPS in the liver. Reduction of hepatic PAPS markedly decreases the sulfation of AA, suggesting that molybdate treatment could be use d to study the importance of sulfation in pharmacology and toxicology.