Hjelle J J, Hazelton G A, Klaassen C D
Drug Metab Dispos. 1985 Jan-Feb;13(1):35-41.
The purpose of this investigation was to determine the effects of acute administration of acetaminophen on adenosine 3'-phosphate 5'-phosphosulfate (PAPS) and UDP-glucuronic acid concentrations in fed male rats. Acetaminophen produced a dosage-dependent decline in rat hepatic PAPS concentrations which was significant after dosages of 150, 300, or 600 mg/kg, ip. The time course of the decline in PAPS values after 600 mg acetaminophen/kg showed that PAPS concentrations reached a nadir 1 hr after dosing (40% of control values). Serum sulfate concentrations were also decreased by large dosages of acetaminophen (32 and 15% of control 2 hr after 150 and 600 mg/kg, respectively) and a significant, positive correlation between serum sulfate and hepatic PAPS concentrations was noted. In addition, hepatic cysteine and glutathione concentrations were lowered by high dosages of acetaminophen. Hepatic UDP-glucuronic acid concentrations were greatly decreased for 2 hr after a dosage of 600 mg acetaminophen/kg (15, 23, and 42% of control 0.5, 1.0, and 2.0 hr after dosing, respectively) whereas 150 mg/kg produced a less pronounced and more transient decrease. These findings demonstrate that both PAPS and UDP-glucuronic acid concentrations in liver are decreased after administration of acetaminophen and imply that capacity-limited sulfation and glucuronidation of acetaminophen are due to a decrease in co-substrate availability.
本研究的目的是确定对喂食状态下的雄性大鼠急性给予对乙酰氨基酚后，其对3'-磷酸腺苷5'-磷酸硫酸酯（PAPS）和UDP-葡萄糖醛酸浓度的影响。对乙酰氨基酚使大鼠肝脏PAPS浓度呈剂量依赖性下降，腹腔注射150、300或600mg/kg剂量后下降显著。给予600mg对乙酰氨基酚/kg后PAPS值下降的时间进程表明，给药后1小时PAPS浓度降至最低点（为对照值的40%）。大剂量对乙酰氨基酚也会降低血清硫酸盐浓度（150和600mg/kg给药后2小时分别为对照值的32%和15%），并且观察到血清硫酸盐与肝脏PAPS浓度之间存在显著的正相关。此外，高剂量对乙酰氨基酚会降低肝脏半胱氨酸和谷胱甘肽浓度。给予600mg对乙酰氨基酚/kg后2小时内，肝脏UDP-葡萄糖醛酸浓度大幅下降（给药后0.5、1.0和2.0小时分别为对照值的15%、23%和42%），而150mg/kg产生的下降不太明显且更短暂。这些发现表明，给予对乙酰氨基酚后肝脏中的PAPS和UDP-葡萄糖醛酸浓度均会下降，这意味着对乙酰氨基酚的硫酸化和葡萄糖醛酸化能力受限是由于共底物可用性降低所致。
