Gregus Z, White C, Howell S, Klaassen C D
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66103.
Biochem Pharmacol. 1988 Nov 15;37(22):4307-12. doi: 10.1016/0006-2952(88)90611-9.
Sulfation of organic compounds requires activation of inorganic sulfate via formation of adenosine 3'-phosphate 5'-phosphosulfate (PAPS). Inorganic sulfate can be formed by sulfoxidation of cysteine, which can be derived from GSH. Thus, a decrease in hepatic GSH may impair formation of inorganic sulfate, the synthesis of PAPS, and the sulfation of chemicals. This hypothesis was tested by investigating the effect of GSH depletion on the levels of inorganic sulfate in serum and of PAPS in liver, and on the capacity to form the sulfate conjugate of harmol in rats. Phorone (2 mmol/kg, i.p.) decreased hepatic GSH (97%), serum inorganic sulfate (63%), and hepatic PAPS (48%). Diethyl maleate and vinylidene chloride (6 mmol/kg, each, i.p.) were less effective than phorone in decreasing GSH in liver and inorganic sulfate in serum, and they did not alter hepatic PAPS levels. Three hours after phorone treatment, the nadir of hepatic PAPS concentration, harmol was injected in order to assess sulfation in vivo. After administration of harmol (100 and 300 mumol/kg, i.v.), less harmol sulfate and more harmol glucuronide were found in the serum of phorone-treated rats as compared to control rats. At the higher dosage of harmol, phorone reduced the biliary excretion of harmol sulfate while increasing the biliary excretion of harmol glucuronide. These results indicate that severe GSH depletion decreases PAPS formation and sulfation of chemicals. However, an increase in glucuronidation may compensate for the impaired sulfation.
有机化合物的硫酸化作用需要通过形成3'-磷酸腺苷5'-磷酸硫酸酯（PAPS）来激活无机硫酸盐。无机硫酸盐可由半胱氨酸的硫氧化作用形成，而半胱氨酸可来源于谷胱甘肽（GSH）。因此，肝脏中GSH的减少可能会损害无机硫酸盐的形成、PAPS的合成以及化学物质的硫酸化作用。通过研究GSH耗竭对大鼠血清中无机硫酸盐水平、肝脏中PAPS水平以及对去甲骆驼蓬碱形成硫酸酯共轭物能力的影响，对这一假说进行了验证。佛尔酮（2 mmol/kg，腹腔注射）可使肝脏GSH减少97%、血清无机硫酸盐减少63%、肝脏PAPS减少48%。马来酸二乙酯和偏二氯乙烯（各6 mmol/kg，腹腔注射）在降低肝脏GSH和血清无机硫酸盐方面的效果不如佛尔酮，且它们并未改变肝脏PAPS水平。在佛尔酮处理3小时后，即肝脏PAPS浓度达到最低点时，注射去甲骆驼蓬碱以评估体内的硫酸化作用。与对照大鼠相比，在给去甲骆驼蓬碱（100和300 μmol/kg，静脉注射）后，佛尔酮处理的大鼠血清中去甲骆驼蓬碱硫酸盐较少，而去甲骆驼蓬碱葡萄糖醛酸苷较多。在较高剂量的去甲骆驼蓬碱时，佛尔酮减少了去甲骆驼蓬碱硫酸盐的胆汁排泄，同时增加了去甲骆驼蓬碱葡萄糖醛酸苷的胆汁排泄。这些结果表明，严重的GSH耗竭会减少PAPS的形成和化学物质的硫酸化作用。然而，葡萄糖醛酸化作用的增加可能会弥补受损的硫酸化作用。
