Systems-Scale Analysis Reveals Pathways Involved in Cellular Response to Methamphetamine
Figure 3
METH exposure may promote oxidative stress through multiple mechanisms.
First, cytochrome P450s are up-regulated (upward-pointing red arrow) to potentially detoxify METH but in some cases also produce reactive oxygen species (ROS) byproducts. Second, METH, a weak base, is known to alkalinize dopamine (DA)-containing vesicles, promoting DA release into the cytosol. Cytosolic DA is rapidly degraded, resulting in ROS byproducts. Third, iron chelators are down-regulated (downward-pointed red arrow), potentially increasing the concentration of free iron, a known source of ROS. Fourth, degradation of the mitochondria, potentially resulting from (i) the ability of high cytosolic Ca2+ to promote the formation of permeability transition pores (PTP), (ii) increased membrane hydrolysis by Ca2+-dependent phospholipase A2 (PLA2) in the presence of increased Ca2+, (iii) the direct effects of ROS on mitochondrial integrity, and (iv) the potential effects of altered HK/porin ratio - HK detachment from mitochondria on PTP formation. This may cause the mitochondria to uncouple and result in ROS production. The cellular targets of oxidative stress, indicated by orange arrows, include membrane phospholipids; p53, a gene that regulates apoptosis; and DNA.