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.