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-phosphoadenosine 5-phosphosulfate (PAPS) concentrations (about 40 and 65%, respectively). 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 mmol/kg. However, renal PAPS did not change. The results indicate that molybdate 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 investigated in order to determine whether molybdate-induced depletion of PAPS might be a useful tool for examining the importance of sulfation in the detoxication and toxication of xenobiotics. AA-sulfate concentration in blood decreased 40 and 80% after administration of molybdate at doses of 2.5 and 15 mmol/kg, respectively. Molybdate also decreased the excretion of AA-sulfate into bile and urine by about 60 and 80%, respectively. However, molybdate did not alter the excretion of AA-glucuronide and AA-glutathione/cysteine. The excretion of the parent AA increased 2-fold after molybdate administration (15 mmol/kg). In conclusion, molybdate effectively lowers inorganic sulfate in serum and tissues, and PAPS in the liver. Reduction of hepatic PAPS markedly decreases the sulfation of AA, suggesting that molybdate treatment could be used to study the importance of sulfation in pharmacology and toxicology.
Oguro
T
T
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City.
Gregus
Z
Z
Madhu
C
C
Liu
L
L
Klaassen
C D
CD
D000082:Acetaminophen / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008982:Molybdenum / Q000494:pharmacology*; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000378:metabolism*
D013431:Sulfates; C044659:molybdate; D000082:Acetaminophen; D010724:Phosphoadenosine Phosphosulfate; D008982:Molybdenum