Tazuke Yuko, Maeda Kosaku, Wasa Masafumi, Satoko Nose, Fukuzawa Masahiro
Department of Pediatric Surgery, Jichi Children's Medical Center Tochigi/Jichi Medical University, Tochigi, Japan.
Pediatr Surg Int. 2011 Feb;27(2):151-8. doi: 10.1007/s00383-010-2798-8.
Glutamine prevents the intestinal mucosal injury induced by chemotherapy. However, the mechanism has not yet been elucidated. Proliferating cell nuclear antigen (PCNA) is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle, and PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair. We hypothesized that glutamine supplementation might stimulate the intestinal epithelial cell cycle interruption induced by chemotherapy. The effect of supplemental glutamine after cisplatin-induced intestinal mucosal injury on the expression of PCNA was investigated.
The male Wister rats were divided into three groups; a control group (control n = 5), which received standard rat diet; the Cis group (cisplatin 6 mg/kg i.p., n = 5), and the Cis + Gln group [cisplatin + Ala-Glutamine (0.5 g/day × 3 days p.o., n = 5)]. After 1, 3, and 7 days of chemotherapy, PCNA, and glutamine transporter (ASCT2) expression in the small intestine (jejunum and ileum) was investigated.
The expression of PCNA in the crypt of the small intestine (jejunum and ileum) decreased after chemotherapy, while the expression strongly increased by glutamine administration, even if it was after chemotherapy. On day 1, both the mRNA expression of the glutamine transporter (ASCT2) and PCNA expression in crypt cells were significantly increased by administration of glutamine (Cis + Gln group). The increased expression of ACST2 appeared earlier than in the Cis group. In the Cis + Gln group, the PCNA expression was normalized on day 3, and the expression was same as that in the control group on day 3.
Glutamine supplementation rapidly improved the expression of PCNA after cisplatin-induced intestinal mucosal injury. The effects of glutamine may be due to an anti-oxidant effect, but the amino acid might also attenuate the initial mucosal injury and improve intestinal cell turnover.
谷氨酰胺可预防化疗引起的肠黏膜损伤。然而，其机制尚未阐明。增殖细胞核抗原（PCNA）在细胞周期的DNA合成期表达于细胞核中，并且PCNA也参与称为复制后修复的DNA损伤耐受途径。我们推测补充谷氨酰胺可能会刺激化疗诱导的肠上皮细胞周期中断。研究了顺铂诱导肠黏膜损伤后补充谷氨酰胺对PCNA表达的影响。
雄性Wistar大鼠分为三组；对照组（对照n = 5），给予标准大鼠饮食；顺铂组（顺铂6 mg/kg腹腔注射，n = 5），以及顺铂 + 谷氨酰胺组[顺铂 + 丙氨酰 - 谷氨酰胺（0.5 g/天×3天口服，n = 5）]。化疗1、3和7天后，研究小肠（空肠和回肠）中PCNA和谷氨酰胺转运体（ASCT2）的表达。
化疗后小肠（空肠和回肠）隐窝中PCNA的表达降低，而即使在化疗后给予谷氨酰胺，其表达也强烈增加。在第1天，给予谷氨酰胺（顺铂 + 谷氨酰胺组）后，谷氨酰胺转运体（ASCT2）的mRNA表达和隐窝细胞中PCNA的表达均显著增加。ACST2表达的增加比顺铂组出现得更早。在顺铂 + 谷氨酰胺组中，PCNA表达在第3天恢复正常，且在第3天与对照组相同。
补充谷氨酰胺可在顺铂诱导肠黏膜损伤后迅速改善PCNA的表达。谷氨酰胺的作用可能归因于抗氧化作用，但该氨基酸也可能减轻初始黏膜损伤并改善肠细胞更新。
