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Essay / Iron Metabolism - 833
This section will focus on the details of what is known about how doxorubicin treatment and type 2 diabetes mellitus (T2DM) causes cellular iron dysregulation and an increase in oxidative stress. In-depth information on iron metabolism, doxorubicin and T2DM and their relationship to iron regulation will be described. Regulation of iron storage will be proposed as an additional mechanism by which metformin may ameliorate doxorubicin-induced oxidative stress and T2D. Iron MetabolismIron plays an essential role in virtually all organisms, from bacteria to humans. In addition to binding oxygen to heme, it participates in many other cellular events, including DNA synthesis and the transfer of electrons in the electron transport chain. Although it is the most abundant element on earth (97), iron has very low bioavailability. Iron is therefore highly conserved in organisms; humans do not have a pathway for iron excretion, but rather regulate iron at the level of absorption. Once absorbed, iron continues to be regulated because it is also very reactive with oxygen. Figure 1 shows the Haber-Weiss and Fenton reactions, which readily occur under physiological conditions with free iron and oxygen or hydrogen peroxide to produce free radicals. These free radicals will cause damage to the cell and contribute to oxidative stress (67, 97). Iron absorption, transport and storage are therefore highly regulated and disruption of iron metabolism has been implicated in several diseases. The mechanism of iron absorption and transport is well known and is briefly described here. Nonheme and heme iron are absorbed into the enterocyte via DMT1 and heme carrier protein 1, respectively (5, 67, 97). Once inside the enterocyte, iron can be stored in the middle of the paper, the iron-sulfur clusters dissociate, causing a conformational change, and aconitase becomes IRP-1(3). This has possible implications for the relationship between iron homeostasis, oxidative stress, and metabolism, which will be discussed in more detail later. In summary, iron is an important and highly reactive element involved in several cellular processes. Iron uptake occurs via DMT1 and heme carrier protein 1, is transported to cells via transferrin, and is endocytosed upon binding of TfR1. Once inside the cell, iron is transferred to the mitochondria, stored in ferritin, or released into the labile iron pool. The transport of iron out of the cell occurs via ferroportin, of which hepcidin is a powerful inhibitor. Iron homeostasis may be disrupted, increasing cellular oxidative stress and contributing to the etiology of different diseases.. (5, 30, 67, 97).