Hypoxia oxidative metabolism

Toxic effects caused by cyanide binding of ferric iron in mitochondrial cytochrome oxidase, affecting cellular ability to utilize 02 in oxidative phosphorylation, causing tissue hypoxia, anaerobic metabolism and lactic acidosis... 

Lactic acidosis generally results from a greatly increased NADH/NAD ratio in tissues (Fig.22.15). The increased NADH concentration prevents pyruvate oxidation in the TCA cycle and directs pyruvate to lactate. To compensate for the decreased ATP production from oxidative metabolism, PFK-1, and, therefore, the entire glycolytic pathway is activated. For example, consumption of high amounts of alcohol, which is rapidly oxidized in the liver and increases NADH levels, can result in a lactic acidosis. Hypoxia in any tissue increases lactate production as cells attempt to compensate for a lack of O2 for oxidative phosphorylation. 

The following O2-linked metaboHtes have been implicated as potential chemical mediators in the metabolic hypothesis adenosine (from ATP hydrolysis ATP ADP —> AMP — adenosine), H+, and lactate (from lactic acid generated by glycolysis). Their levels are increased when there is a reduction in O2 supply relative to demand (i.e., tissue hypoxia). The production of more CO2 as a result of increased tissue activity (leading to increased oxidative metabolism) leads to vasodilation through increased H+ concentration. Increased potassium ion and interstitial fluid osmolarity (i.e., more osmoticaUy active particles) transiently cause vasodilation under physiological conditions associated with increased tissue activity. 

Unhke that of the adult, fetal metabolism is geared toward tissue accretion and maturation in preparation for birth (109) however, like the adult, there is an absolute requirement for oxidative metabolism to achieve these ends. The fetus, especially in early to midgestation, has a much lower metabohc rate than its adult counterpart (Fig. 4) and yet, unlike the adult, the fetus is capable of withstanding prolonged periods of profound hypoxia and anoxia. 

Hypoxia is one of the signatures of cyanide poisoning. In CN poisoning, as in ischemia, oxidative metabolism is blocked and acidosis is enhanced. Acidosis decreases contractility and metabolism while sparing ATP supplies. 

The mechanism for the production of O2" in ischaemic tissue appears to involve changes in purine metabolism within ischaemic cells. Sublethal hypoxia decelerates mitochondrial oxidative phosphorylation, rendering the production of ATP dependent upon the... 

Along with mese genetic features, a low growm rate and a low blood supply (conditions often present m sohd mmors) can affect sensitivity to ionizing radiation wim me following mechanisms (Brown, 1999) reduction of me rate of cells m me most sensitive phases of me cell cycle low efficiency of ROS formation wimm me irradiated mmor due to hypoxia clonal selection of cancer cells highly resistant to oxidative stress/apoptosis and wim efficient anaerobic metabolism. 

Oxygen is normally readily available to all reasonably well-perfused tissues, but deep inside organs such as the liver, especially the centrilobular area (see chap. 6), there will be a reduction in the oxygen concentration. This is clearly important when both oxidative and reductive pathways are available for a particular substrate. Therefore, as conditions in a particular tissue become more anaerobic, reductive pathways will become more important. This is well illustrated by the metabolism of halo thane where, in the rat, hypoxia will increase reductive metabolism and hepa to toxicity (see chap. 7). Glutathione is an extremely important cofactor, involved in both protection and conjugation. It may be depleted by both of these processes, or under certain circumstances, such as hereditary glucose-6-phosphate deficiency in man, supply may be reduced (see chap. 5). This will clearly influence toxicity, and there are a number of examples discussed in chapter 7 in which it is important. 

Prilocaine is an amide-type LA with a rapid onset and an intermediate duration of action associated with a low toxicity. However, metabolism to ortho-toluidine can cause oxidation of the ferric form of hemoglobin to the ferrous form, creating methemoglobin. In most cases the methemoglobuniemia is benign, but sometimes tissue hypoxia is observed (Eriksson, 1966). 

Figure 6 Percentage of oxygen used for the oxidation of protein (upper half) and the quantity of protein involved in anaerobic metabolism during short-term hypoxia (lower half).

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