Cytochrome cellular mechanisms

MDR-ABC Transporters. Figure 3 Detoxification cellular mechanisms. X, toxic compound X-OH, oxidized toxic compound GS-X, conjugated toxic compound OATP, organic anion transporting proteins CYPs, cytochromes GSH, glutathion UDPGIcUA, Uridine 5-diphosphoglucuronic acid PAPs, 3-phosphoadenylylsulfate. 

Figure 20.5 Proposed model for the cellular mechanisms of gold(lll) porphyrin 1a induced apoptosis in HONE1 ceiis. Goid (III) porphyrin la directiy caused depietion of A P. ieading to the aiteration of Bci-2 famiiy proteins, AIF nucleus translocation, and cytochrome c release, which further activated caspase-9 and caspase-3, and subsequently caused PARP-1 cleavage. ROS were also generated. The altered cellular oxidative state affected cytotoxicity of gold(lll) porphyrin la by regulating mitochondrial permeabilization.

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

HCN is a systemic poison toxicity is due to inhibition of cytochrome oxidase, which prevents cellular utilization of oxygen. Inhibition of the terminal step of electron transport in cells of the brain results in loss of consciousness, respiratory arrest, and ultimately, death. Stimulation of the chemoreceptors of the carotid and aortic bodies produces a brief period of hyperpnea cardiac irregularities may also occur. The biochemical mechanisms of cyanide action are the same for all mammalian species. HCN is metabolized by the enzyme rhodanese which catalyzes the transfer of sulfur from thiosulfate to cyanide to yield the relatively nontoxic thiocyanate. 

A number of toxicological mechanisms have been proposed for hydrogen sulfide At extremely high concentrations it may exert a direct paralyzing effect on respiratory centers hydrogen sulfide is also known to inhibit cytochrome c oxidase, resulting in altered oxidative metabolism it can also disrupt critical disulfide bonds in essential cellular proteins. ... 

NO also has cytotoxic effects when synthesized in large quantities, eg, by activated macrophages. For example, NO inhibits metalloproteins involved in cellular respiration, such as the citric acid cycle enzyme aconitase and the electron transport chain protein cytochrome oxidase. Inhibition of the heme-containing cytochrome P450 enzymes by NO is a major pathogenic mechanism in inflammatory liver disease. 

The number of receptor sites and the position of the equilibrium (Eq. 1) as reflected in KT, will clearly influence the nature of the dose response, although the curve will always be of the familiar sigmoid type (Fig. 2.4). If the equilibrium lies far to the right (Eq. 1), the initial part of the curve may be short and steep. Thus, the shape of the dose-response curve depends on the type of toxic effect measured and the mechanism underlying it. For example, as already mentioned, cyanide binds very strongly to cytochrome a3 and curtails the function of the electron transport chain in the mitochondria and hence stops cellular respiration. As this is a function vital to the life of the cell, the dose-response curve for lethality is very steep for cyanide. The intensity of the response may also depend on the number of receptors available. In some cases, a proportion of receptors may have to be occupied before a response occurs. Thus, there is a threshold for toxicity. With carbon monoxide, for example, there are no toxic effects below a carboxyhemoglobin concentration of about 20%, although there may be... 

As molecules increase in complexity, the number of possibilities for mechanism of action also increase. For example, Structure 17.10 inhibits a specific kinase and specific cellular second messenger.111 In contrast, Structure 17.11 is specifically related to vitamin B2,112 while Structure 17.12, a steroid peroxide,113 is, in the imagination of this author, a molecule likely to impact steroid receptors and enzymes like cytochrome p450s involved in steroid metabolism. However, it is likely that the multiple functions observed for many complex natural products are a result of their interaction with multiple pathways and mechanisms. The environmental fates and... 

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