Boatman R J, English J C, Perry L G, Fiorica L A
Health and Environment Laboratories, Eastman Kodak Company, Rochester, New York 14652-6272, USA.
Chem Res Toxicol. 2000 Sep;13(9):861-72. doi: 10.1021/tx000038p.
The current studies were conducted to investigate the degree and type of protein binding of hydroquinone (HQ) in the rat following single oral or intraperitoneal (ip) or repeated oral administrations. Male or female F-344 rats or male SD rats received a single dose of HQ at 0, 25, 50, or 100 mg/kg by either gavage or ip injection (SD rats only). In addition, male or female F-344 or male SD rats received HQ by gavage for 6 weeks (5 days/week) at 0, 25, or 50 mg/kg/day. Sulfhydryl-bound HQ was quantitated in protein from blood, kidneys, livers, or spleens 24 h after treatment using an alkaline permethylation procedure. The amount of total protein-S adducts increased with increasing dose in all the tissues that were assayed. Female rats had higher levels of adducts in blood, livers, and kidneys than did male rats when they were treated orally. Male F-344 rats treated orally had elevated levels of adducts in these same tissues compared to SD rats treated orally. For all genders and strains of rats and for all treatment regimens, mono-adducts predominated in livers (>72% of total). In the kidneys, tri- and tetrasubstituted adducts predominated with the summation accounting for >60% of the total. Ip administration of HQ resulted in significantly elevated levels of adducts in all the tissues that were examined, with the greatest increases seen for protein from blood and spleens. Levels of protein-S adducts of HQ in rat kidney following a single gavage administration correlated well with previously published differences in acute HQ nephrotoxicity in rats (female F-344 rat > male F-344 rat > male SD rat). Elevated levels of HQ protein-S adducts following repeated gavage administration did not correlate to measurable clinical signs of nephrotoxicity. Evidence is presented suggesting a possible role for the prostaglandin H synthase complex in the metabolic activation of HQ. In addition, protein arylation alone cannot account for the greater sensitivity of male F-344 rats toward chronic administration of HQ. The sensitivity of male F-344 rats to HQ is likely due to other factors, including the incidence and severity of chronic progressive nephropathy.
开展了当前这些研究，以调查大鼠单次口服、腹腔注射或重复口服对苯二酚（HQ）后其蛋白质结合的程度和类型。雄性或雌性F-344大鼠或雄性SD大鼠通过灌胃或腹腔注射（仅SD大鼠）接受0、25、50或100mg/kg的单次HQ剂量。此外，雄性或雌性F-344大鼠或雄性SD大鼠以0、25或50mg/kg/天的剂量通过灌胃接受HQ 6周（每周5天）。在处理后24小时，使用碱性全甲基化程序对血液、肾脏、肝脏或脾脏中的蛋白质中与巯基结合的HQ进行定量。在所检测的所有组织中，总蛋白-S加合物的量随剂量增加而增加。口服给药时，雌性大鼠血液、肝脏和肾脏中的加合物水平高于雄性大鼠。与口服给药的SD大鼠相比，口服给药的雄性F-344大鼠在这些相同组织中的加合物水平升高。对于所有性别和品系的大鼠以及所有治疗方案，肝脏中主要是单加合物（占总量的>72%）。在肾脏中，三取代和四取代加合物占主导，其总和占总量的>60%。腹腔注射HQ导致所检查的所有组织中的加合物水平显著升高，血液和脾脏中的蛋白质加合物增加最为明显。大鼠单次灌胃给药后肾脏中HQ的蛋白-S加合物水平与先前发表的大鼠急性HQ肾毒性差异（雌性F-344大鼠>雄性F-344大鼠>雄性SD大鼠）密切相关。重复灌胃给药后HQ蛋白-S加合物水平升高与可测量的肾毒性临床体征无关。有证据表明前列腺素H合酶复合物在HQ的代谢活化中可能起作用。此外，仅蛋白质芳基化不能解释雄性F-344大鼠对长期给予HQ的更高敏感性。雄性F-344大鼠对HQ的敏感性可能归因于其他因素，包括慢性进行性肾病的发生率和严重程度。
