Polyamines and the Intestinal Tract

Abstract

Owing to their high turnover, the intestinal mucosal cells have a particularly high requirement for polyamines. Therefore, they are an excellent charcol for the study of polyamine function in rapid physiological growth and differentiation. After a cursory introduction to the major aspects of polyamine metabolism, regulation, and mode of action, we discuss the contribution of the polyamines to the maintenance of normal gut function, the maturation of the intestinal mucosa, and its repair after injuries. Repletion of cellular polyamine pools with (D,L)-2-(difluoromethyl)ornithine has considerably improved our understanding of how the polyamines are involved in the regulation of normal and neoplastic growth. Unfortunately, the attempts to exploit polyamine metabolism as a cancer therapeutic target have not yet been successful. However, the selective inactivation of ornithine decarboxylase appears to be a promising chemopreventive method in familial adenomatous polyposis. Presumably, it relies on the fact that ornithine decarboxylase is a critical regulator of the proliferative response of the protooncogene c-myc, but not of its apoptotic response.

Polyamines regulate E-cadherin transcription through c-Myc modulating intestinal epithelial barrier function

“…5 and 6 not only confirm our previous observations (20) showing that decreased levels of E-cadherin were associated with an increase in basal levels of epithelial paracellular permeability but also provide new evidence indicating that reduction in E-cadherin levels by polyamine depletion or E-cadherin silencing remarkably potentiated H 2 O 2 -induced epithelial barrier dysfunction. This finding is of physiological significance, because normal IECs contain high levels of polyamines and their cellular levels are changed rapidly in response to various physiological and pathological stimuli (16,46,54). On the other hand, E-cadherin mediates strong cell-cell adhesion and has functional role in forming and regulating the epithelial barrier.…”

“…Polyamines play a critical role in the maintenance of intestinal epithelial integrity (46,54), but the exact mechanisms underlying polyamines at cellular and molecular levels remain unclear. We (10,19,20) recently demonstrated that polyamines regulate the intestinal epithelial barrier function and that polyamine depletion increases epithelial paracellular permeability at least partially by repressing expression of ZO-1 and E-cadherin.…”

“…The natural polyamines (putrescine, spermidine, and spermine) are ubiquitous polycationic molecules found in all eukaryotic cells and play distinct regulatory roles in intestinal epithelial cells (IECs) (7,16,46,54). Polyamines regulate expression of various genes involved in epithelial cell division (28,38,52,55), repair (41,51), and apoptosis (27,57,59), whereas polyamine deficiency inhibits mucosal growth and delays healing after injury.…”

Polyamines of Plant Origin - An Important Dietary Consideration for Human Health

“…Interestingly, there was no significant difference in the intracellular polyamine metabolism between any of the treatment groups, indicating that intracellular de novo synthesis of polyamines was not activated to compensate for a deficiency in exogenous polyamines (Löser et al, 1999). Conversely, oral administration of polyamines to neonatal mice resulted in precocious maturation of the gut, as evidenced by increased villus and crypt length, changes of the activities of brush-border membrane hydrolases (Dorhout et al, 1997, as cited by Seiler and Raul, 2007), as well as precocious development of the intestinal immune system after spermine administration (ter Steege et al, 1997, as cited by Seiler and Raul, 2007). Importantly, the action of polyamines in gut development has been demonstrated using a human model, albeit in vitro.…”

“…Caco-2 cells, derived from a colorectal adenocarcinoma, are commonly used for studies of the gastric mucosa, because they spontaneously express characteristics of enterocyte differentiation upon confluence, including the formation of tight junctions. Depletion of the putrescine and spermidine pools with the specific inhibitor α-difluoromethylornithine (DFMO), prevented the growth of microvilli and differentiation of Caco-2 cells (Herold et al, 1993, andDuranton et al, 1998, as cited by Seiler and Raul, 2007). Whilst polyamines are clearly required for gut development and maturation in the young, these studies also suggest implications of polyamines for gut integrity with ageing, because the continual renewal process in the gut is characterized by active proliferation of stem cells localized near the base of the crypts, progression of these cells up the crypt-villus axis with cessation of proliferation and subsequent differentiation and apoptosis (Zou et al, 2008).…”