Protective mechanism of glutamine on the expression of proliferating cell nuclear antigen after cisplatin-induced intestinal mucosal injury

Abstract

Background: 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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.