Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen
Streptomycin alleviates irinotecan-induced delayed-onset diarrhea in rats by a mechanism other than inhibition of β-glucuronidase activity in intestinal lumen
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DOI：
10.1007/s00280-010-1310-4
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发表时间：
2011-01-01
影响因子：
3
通讯作者：
Yokokura, Teruo
中科院分区：
文献类型：
--
作者：
Kurita, Akinobu;Kado, Shoichi;Yokokura, Teruo
盐酸伊立替康（CPT-11）是癌症化疗的有效药物，但临床上有时会引起严重腹泻。 CPT-11主要被羧酸酯酶（CES）激活为SN-38，然后在肝脏中被UDP-葡萄糖醛酸基转移酶（UGT）解毒为SN-38葡萄糖醛酸苷（SN-38G）。 SN-38G 通过胆汁排泄，并通过肠内容物中的 β-葡萄糖醛酸酶 (β-GLU) 解偶联为 SN-38。为了阐明抗生素对 CPT-11 诱导的腹泻的缓解作用，我们使用三种腹泻模型，即重复给予 CPT-11（60 mg/kg/天，静脉注射，连续 4 天）的 Wistar 大鼠和单次给予 CPT-11（200和 20 mg/kg 静脉注射，分别）。 Gunn 大鼠患有 UGT1A 遗传性缺陷，无法将 SN-38 与 SN-38G 结合。因此，CPT-11 诱导的 Gunn 大鼠腹泻的发作不受 β-GLU 活性的影响。 SM 缓解了所有三种腹泻模型中的腹泻。 SM 对 Gunn 大鼠腹泻的缓解表明 SM 的作用是通过抑制 β-GLU 活性以外的机制发生的。 SM 降低肠道组织中 CPT-11 和/或 SN-38 的浓度，并减轻从回肠到结肠的上皮损伤。 SM 不抑制盲肠内容物中的 β-GLU 活性。 SM 还抑制肠道对 CPT-11 的吸收，降低肠上皮中的 CES 活性并增加 UGT 活性。这些结果表明，SM通过抑制肠腔对CPT-11的吸收以及肠上皮中CES和UGT活性的变化，减少CPT-11和SN-38对肠上皮的暴露，从而减轻迟发性腹泻。
Irinotecan hydrochloride (CPT-11) is a useful drug for cancer chemotherapy but sometimes induces severe diarrhea clinically. CPT-11 is mainly activated to SN-38 by carboxylesterase (CES) and then detoxified to SN-38 glucuronide (SN-38G) by UDP-glucuronosyltransferase (UGT) in the liver. SN-38G is excreted via bile and de-conjugated to SN-38 by beta-glucuronidase (beta-GLU) in the intestinal content. In order to clarify the alleviative effect of antibiotics on CPT-11-induced diarrhea, we examined whether penicillin G and streptomycin (SM) alleviate CPT-11-induced delayed-onset diarrhea using three diarrheal models, i.e., Wistar rats with repeated dosing of CPT-11 (60 mg/kg/day i.v. for 4 consecutive days) and Wistar and Gunn rats with a single dosing of CPT-11 (200 and 20 mg/kg i.v., respectively). Gunn rats have an inherited deficiency of UGT1A and cannot conjugate SN-38 to SN-38G. Therefore, onset of CPT-11-induced diarrhea in Gunn rats is not affected by beta-GLU activity. SM alleviated diarrhea in all three diarrheal models. The alleviation of diarrhea by SM in Gunn rats indicated that the effect of SM occurred by a mechanism other than the inhibition of beta-GLU activity. SM decreased CPT-11 and/or SN-38 concentrations in intestinal tissues and alleviated epithelial damage from the ileum to colon. SM did not inhibit beta-GLU activity in the cecal content. SM also inhibited the intestinal absorption of CPT-11 and decreased CES activity and increased UGT activity in the intestinal epithelium. These findings indicated that SM decreased the exposure of CPT-11 and SN-38 to the intestinal epithelium by inhibiting the absorption of CPT-11 from the intestinal lumen and the change of CES and UGT activities in the intestinal epithelium and alleviated delayed-onset diarrhea.