Isoprostanes

Isoprostanes represent a new class of prostaglandin-like compounds produced in vivo in humans and animals by non-enzymic free-radical-mediated oxidation of membrane-bound polyunsaturated fatty acids. An isomer of PGF2a in which the two alkyl substituents on the five-membered ring were arranged cis rather than trans was detected in human urine and was the first of these compounds to be characterized. This compound was initially termed 8-iso-PGF2a, or 8-epi-PGF2a, though as many more variants in the isoprostane series were discovered it is now termed iPF2a-III (Figure 3.21). The last figure refers to the compound being of type III, with eight types being differentiated by the nature of the non-carboxylic chain. Compounds may be formed from linolenic acid and y-linolenic acid, as well as from arachidonic, eicosapentaenoic, and dihomo-y-linolenic acids. Structural characteristics of the four classes of isoprostanes derived from arachidonic acid are shown in Figure 3.22; the letter code as in prostaglandin nomenclature is used to define the ring substitution pattern. The four types of isoprostane shown in Figure 3.22 can be viewed as arising by a free radical mechanism which resembles the enzyme-mediated formation of prostaglandins shown in Figure 3.17. The varying side-chain substituents arise by utilizing different double bonds from the several available in the cyclization mechanism, and incorporating an oxygen atom from molecular oxygen at different positions. Many variants are produced because chemical processes rather than enzyme-controlled processes are employed. Free-radical-derived isomers of leukotrienes and thromboxanes have also been reported.

CO2H

CO2H

CO2H

CO2H

HO OH

HO OH

CO2H

CO2H

O arachidonic acid

arachidonic acid —

)-rW=VVCO2

CO2H

HO OH

Type III

arachidonic acid —

HO OH

Type III

CO2H HO OH

Type V

Figure 3.22

arachidonic acid

HO Type IV

CO2H HO OH

Type V

HO Type IV

HO Type VI

Figure 3.22

Interest in these isoprostanoid derivatives stems partly from the finding that certain compounds possess biological activity, probably via interaction with receptors for prostaglandins. For example, iPF2a-III is a potent vasoconstrictor and also aggregates platelets, whilst 8,12-/so-iPF2a-III (Figure 3.21) possesses activity similar to PGF2a. Another potential application relates to their origin via free radical peroxidation of unsaturated fatty acids. Free radicals are implicated in inflammatory and degenerative diseases such as atherosclerosis, cancer, and Alzheimer's disease. Isoprostane analysis of urine or serum may thus allow non-invasive monitoring of oxidative damage as a insight into these disease states.

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