Kharasch E D, Hoffman G M, Thorning D, Hankins D C, Kilty C G
Department of Anesthesiology, University of Washington, Seattle 98195, USA.
Anesthesiology. 1998 Jun;88(6):1624-33. doi: 10.1097/00000542-199806000-00027.
The sevoflurane degradation product compound A is nephrotoxic in rats and undergoes metabolism to glutathione and cysteine S-conjugates, with further metabolism by renal cysteine conjugate beta-lyase to reactive intermediates. Evidence suggests that toxicity is mediated by renal uptake of compound A S-conjugates and metabolism by beta-lyase. Previously, inhibitors of the beta-lyase pathway (aminooxyacetic acid and probenecid) diminished the nephrotoxicity of intraperitoneal compound A. This investigation determined inhibitor effects on the toxicity of inhaled compound A.
Fischer 344 rats underwent 3 h of nose-only exposure to compound A (0-220 ppm in initial dose-response experiments and 100-109 ppm in subsequent inhibitor experiments). The inhibitors (and targets) were probenecid (renal organic anion transport mediating S-conjugate uptake), acivicin (gamma-glutamyl transferase), aminooxyacetic acid (renal beta-lyase), and aminobenzotriazole (cytochrome P450). Urine was collected for 24 h, and the animals were killed. Nephrotoxicity was assessed by histology and biochemical markers (serum BUN and creatinine; urine volume; and excretion of protein, glucose, and alpha-glutathione-S-transferase, a predominantly proximal tubular cell protein).
Compound A caused dose-related proximal tubular cell necrosis, diuresis, proteinuria, glucosuria, and increased alpha-glutathione-S-transferase excretion. The threshold for toxicity was 98-109 ppm (294-327 ppm-h). Probenecid diminished (P < 0.05) compound A-induced glucosuria and excretion of alpha-glutathione-S-transferase and completely prevented necrosis. Aminooxyacetic acid diminished compound A-dependent proteinuria and glucosuria but did not decrease necrosis. Acivicin increased nephrotoxicity of compound A, and aminobenzotriazole had no consistent effect on nephrotoxicity of compound A.
Nephrotoxicity of inhaled compound A in rats was associated with renal uptake of compound A S-conjugates and cysteine conjugates metabolism by renal beta-lyase. Manipulation of the beta-lyase pathway elicited similar results, whether compound A was administered by inhalation or intraperitoneal injection. Route of administration does not apparently influence nephrotoxicity of compound A in rats.
七氟醚降解产物化合物A对大鼠具有肾毒性，可代谢生成谷胱甘肽和半胱氨酸S-共轭物，并经肾半胱氨酸共轭β-裂解酶进一步代谢生成反应性中间体。有证据表明，毒性是由化合物A S-共轭物的肾摄取及β-裂解酶的代谢介导的。此前，β-裂解酶途径的抑制剂（氨氧乙酸和丙磺舒）可减轻腹腔注射化合物A的肾毒性。本研究确定了抑制剂对吸入性化合物A毒性的影响。
将Fischer 344大鼠进行仅经鼻暴露于化合物A 3小时（初始剂量反应实验中为0 - 220 ppm，后续抑制剂实验中为100 - 109 ppm）。抑制剂（及其作用靶点）包括丙磺舒（介导S-共轭物摄取的肾有机阴离子转运体）、阿西维辛（γ-谷氨酰转移酶）、氨氧乙酸（肾β-裂解酶）和氨基苯并三唑（细胞色素P450）。收集24小时尿液后处死动物。通过组织学和生化指标（血清尿素氮和肌酐；尿量；蛋白质、葡萄糖和α-谷胱甘肽-S-转移酶的排泄，α-谷胱甘肽-S-转移酶是一种主要存在于近端肾小管细胞的蛋白质）评估肾毒性。
化合物A导致剂量相关的近端肾小管细胞坏死、利尿、蛋白尿、糖尿以及α-谷胱甘肽-S-转移酶排泄增加。毒性阈值为98 - 109 ppm（294 - 327 ppm - h）。丙磺舒减轻了（P < 0.05）化合物A诱导的糖尿和α-谷胱甘肽-S-转移酶排泄，并完全预防了坏死。氨氧乙酸减轻了化合物A所致的蛋白尿和糖尿，但未减轻坏死。阿西维辛增加了化合物A的肾毒性，氨基苯并三唑对化合物A的肾毒性无一致影响。
大鼠吸入性化合物A的肾毒性与化合物A S-共轭物的肾摄取及肾β-裂解酶对半胱氨酸共轭物的代谢有关。无论化合物A是通过吸入还是腹腔注射给药，对β-裂解酶途径的调控都产生了相似的结果。给药途径显然不影响化合物A对大鼠的肾毒性。
