Oguro T, Gregus Z, Madhu C, Liu L, Klaassen C D
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City.
J Pharmacol Exp Ther. 1994 Sep;270(3):1145-51.
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.
钼酸盐（口服剂量为15 mmol/kg）给药后6小时内使大鼠血清硫酸盐浓度降低了70%。与这种消耗同时发生的是，肝脏硫酸盐和3-磷酸腺苷5-磷酸硫酸酯（PAPS）浓度显著下降（分别约为40%和65%）。然而，肾脏PAPS浓度没有明显变化。钼酸盐以剂量依赖的方式降低血清、肝脏和肾脏中的硫酸盐以及肝脏中的PAPS浓度，直至剂量达到10 mmol/kg。然而，肾脏PAPS没有变化。结果表明，钼酸盐不仅降低了血清和组织中的硫酸盐浓度，还降低了肝脏中的PAPS浓度。为了确定钼酸盐诱导的PAPS消耗是否可能是一种用于研究硫酸化在异源生物解毒和中毒中的重要性的有用工具，还研究了钼酸盐对乙酰氨基酚（AA，静脉注射剂量为150 mg/kg）药代动力学的影响。分别给予2.5和15 mmol/kg剂量的钼酸盐后，血液中AA-硫酸盐浓度分别下降了40%和80%。钼酸盐还分别使AA-硫酸盐向胆汁和尿液中的排泄减少了约60%和80%。然而，钼酸盐没有改变AA-葡萄糖醛酸苷和AA-谷胱甘肽/半胱氨酸的排泄。给予钼酸盐（15 mmol/kg）后，母体AA的排泄增加了2倍。总之，钼酸盐有效地降低了血清和组织中的无机硫酸盐以及肝脏中的PAPS。肝脏PAPS的减少显著降低了AA的硫酸化，表明钼酸盐处理可用于研究硫酸化在药理学和毒理学中的重要性。
