The toxin increases the activity of an enzyme that regulates a cellular pumping mechanism that controls the movement of water and electrolytes between the intestine and the circulatory system.
Therefore, ML and HL very likely target the extra cytoplasmic region as a nonionic surfactant and thus does not need to enter the cell, thereby avoiding most cellular pump-based resistance mechanisms as previously proposed [ 30].
Another effect is the intracellular accumulation of glutamate, derived from the transamination of alpha-ketoglutarate; glutamate limits the function of ATP-dependent cellular pumps, inducing failure to maintain cellular electrolyte homeostasis.
Thus, the additional inhibition by 4-PB compared to verapamil is probably caused by the inhibition of additional or other cellular pumps than MDR1, which are not effected by verapamil.
Cellular pumps like ABCG2, MDR1 or MRP1 can export a broad spectrum of molecules, including chemotherapeutics out of the cells (Glavinas et al, 2004; Katragadda et al, 2005), preventing them from killing the tumour cell.
Factors contributing to RGC death may include local ischaemia hypoxia [ 9], excess glutamate [ 10], low functional cellular pumps and glutamate transporters [ 11], oxidative stress and free radical formation [ 12], inflammatory cytokines such as TNF (tumour necrosis factor) [ 13], abnormal immunity and secondary neurodegeneration caused by neuronal environmental changes [ 14].
The gene responsible (a cellular ion pump, CFTR) for cystic fibrosis has been modified and fixed in human stem cells.
The find, reported in today's Nature, suggests that these so-called hydrogenosomes may have evolved from the same ancestor as a more famous cellular energy pump, the mitochondria.
Further, the ability of human ABCB5 to confer multidrug resistance of cancer cells [ 9] may suggest that the zebrafish Abcb5 ortholog may act as a cellular efflux pump of toxicants.
