Kaneda N, Kurita A, Hosokawa Y, Yokokura T, Awazu S
Yakult Central Institute for Microbiological Research, Kunitachi, Tokyo, Japan.
Cancer Res. 1997 Dec 1;57(23):5305-8.
7-Ethyl-10-hydroxycamptothecin (SN-38) is the active metabolite of an anticancer drug, irinotecan (CPT-11). Severe late diarrhea is the dose-limiting toxic effect of CPT-11. This diarrhea has been examined regarding biliary excretion and deconjugation of SN-38 glucuronide by the enzyme beta-glucuronidase (beta-GL) in intestinal microflora. Prompted by the enzymological and structural similarity of CPT-11 to organophosphorus and carbamate insecticides, we studied the effect of CPT-11 on blood beta-GL activity in rats. The i.v. injection of CPT-11 in rats significantly elevated their plasma beta-GL activity (with phenolphthalein glucuronide as a substrate) at doses of 10 and 40 mg/kg, with peak activity observed 2-3 h after administration. SN-38 lactone and carboxylate had no effect on the plasma beta-GL level. The enhancement of the activity was also observed in serum using SN-38 glucuronide as a substrate. The serum beta-GL levels showed a close correlation between these substrates. The enhancement of plasma (serum) beta-GL activity is suggested to be a result of the release of beta-GL from liver microsomes. Serum and microsomal carboxylesterase were not significantly affected by CPT-11 administration.
7-乙基-10-羟基喜树碱（SN-38）是抗癌药物伊立替康（CPT-11）的活性代谢产物。严重的迟发性腹泻是CPT-11的剂量限制性毒性作用。关于肠道微生物群中β-葡萄糖醛酸酶（β-GL）对SN-38葡萄糖醛酸苷的胆汁排泄和去结合作用，已对这种腹泻进行了研究。受CPT-11与有机磷和氨基甲酸酯类杀虫剂在酶学和结构上的相似性启发，我们研究了CPT-11对大鼠血液中β-GL活性的影响。以酚酞葡萄糖醛酸苷为底物，给大鼠静脉注射10和40mg/kg剂量的CPT-11后，其血浆β-GL活性显著升高，给药后2-3小时观察到活性峰值。SN-38内酯和羧酸盐对血浆β-GL水平无影响。以SN-38葡萄糖醛酸苷为底物时，在血清中也观察到活性增强。血清β-GL水平在这些底物之间显示出密切相关性。血浆（血清）β-GL活性增强被认为是肝脏微粒体中β-GL释放的结果。CPT-11给药对血清和微粒体羧酸酯酶无显著影响。
