lly GC base pairs. DOX can form DNA adducts, binds to DNA and topoisomerases and inhibits DNA replication and transcription. It promotes DNA double-strand breaks (DSBs) and the DNA damage prompts various responses, including cell cycle arrest and apoptosis, primarily via activation of p53 pathway but also independent of it, with beneficial, if tumor cells, or otherwise detrimental consequences. While toxic to the tumor cell, DOX is also toxic to all other cell types. The cardiotoxicity of the drug is the main and the most severe adverse effect, and the cardiomyopathies associated with DOX can eventually lead to heart failure. The formation of reactive oxygen species (ROS), impaired iron homeostasis and mitochondrial dysfunction are thought to underlie the cardiotoxicity of DOX. Although more than 50% of DOX is eliminated unchanged, the drug undergoes several types of transformation such as two- and one-electron reduction and to a smaller extent deglycosidation. Free radical generation is a feature of DOX metabolism. The drug can interact with iron and generate hydroxyl radical and with the iron-responsive elements (IRE) regions of mRNAs, it can impact on the function of iron regulatory proteins (IRPs) and disturb iron homeostasis. In addition, DOX localizes to mitochondria, forms adducts with mitochondrial DNA, interacts with cardiolipin - an essential component of inner mitochondrial membrane, and is capable of impacting on a number of proteins/enzymes important for mitochondrial function. Doxorubicin is also administered as a pegylated liposomal product.

The uptake of DOX is mediated by Slc22a16, while several transporters are involved in the elimination of the drug. Those include Abcb1, Abcc2 and Abcc3, Abcg2 and Ralbp1. As mentioned, there are several routes of DOX processing. The most common one is the two-electron reduction, followed by the one-electron reduction. The Cbr1 and Cbr3, and the Akr1a1 and Akr1c3 carry out the two-electron reduction. Xdh and Nqo1 and the endothelial nitric oxide synthase Nos3, carry out the one-electron reduction. The deglycosidation of DOX accounts for only ~1-2% of processing and the enzymes involved are still to be characterized. Both the one-electron and the deglycosidation reactions generate ROS. In the one-electron reduction the quinone moiety generates a semiquinone radical that regenerates the parent quinone by reducing molecular oxygen to ROS. It is believed that further processing of metabolites via glucuronidation, sulfation or methylation is necessary before they can be eliminated. To see the ontology report for annotations, GViewer and download, click here

...(less)