Prooxidant action, oxygen

As described in the preceding paragraphs, oxidation products of carotenoids can be formed in vitro as a result of their antioxidant or prooxidant actions or after their autoxidation by molecular oxygen. They can also be found in nature, possibly as metabolites of carotenoids. Frequently encountered products are the monoepoxide in 5,6- or 5, 6 -positions and the diepoxide in 5,6 5, 6 positions or rearrangement products creating furanoid cycles in the 5,8 or 5, 8 positions and 5,8 5, 8 positions, respectively. Products like apo-carotenals and apo-carotenones issued from oxidative cleavages are also common oxidation products of carotenoids also found in nature. When the fission occurs on a cyclic bond, the C-40 carbon skeleton is retained and the products are called seco-carotenoids. 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

At high concentrations, ascorbate can reduce molecular oxygen to superoxide, being oxidized to monodehydroascorbate. Both Fe " and Cu " ions are reduced by ascorbate, again yielding monodehydroascorbate the resultant Fe " and Cu are reoxidized by reaction with hydrogen peroxide to yield hydroxide ions and hydroxyl radicals. Thus, as well as its antioxidant role, ascorbate has prooxidant action the net result will depend on the relative rates of formation of superoxide and hydroxyl radicals by autooxidation and metal-catalyzed reactions of ascorbate, and the trapping of these radicals by ascorbate. 

Mitochondrial oxidative stress and mitochondrial GSH defense affects transcription factor activation. Oxidant stress in mitochondria not only can promote the loss of mitochondrial GSH and mitochondrial functions, but also can promote extramito-chondrial activation of NF-kB and therefore may affect nuclear gene expression. Mitochondria are targets of cytokines leading to the overproduction of reactive oxygen species induced by ceramide, a lipid intermediate of cytokine action and closely associated with apoptosis. Chronic ethanol intake depletes liver mitochondrial glutathione due to an ethanol-induced defect in the transport of GSH from cytosol into the mitochondrial matirix. This sensitizes liver cells to the prooxidant effects of cytokines and prooxidants generated by the oxidative metabolism of ethanol. 

As mentioned above many tumor promoters induce a cellular prooxidant state. Because poly(ADP) ribosylation of chromosomal proteins could play a role in active oxygen-induced modulation of gene expression by PMA we studied the effect of antioxidants. As shown in Fig. 2 for human fibroblasts 3229 the extracellular addition of moderate concentrations of CuZn-superoxide dismutase and catalase suppressed the PMA-induced accumulation of poly(ADPR) by 80-100%. Heated catalase was inactive. The low molecular weight antioxidant butylated-hydroxytoluene also suppressed the increase in poly(ADPR). These results suggest that active oxygen produced in a superoxide driven Fenton reaction represents an intermediate in the mechanism of action of PMA. The fact that the same antioxidants had no effect on poly(ADPR) synthesis induced by MNNG further emphasizes the fundamental difference between the two agents. 

There are various factors in the effectiveness of the antioxidant action. Among these are the presence of oxygenated functional groups in the stmcture of the pigment," the conditions of the medium where the pigment acts," " and the nature of the prooxidant substance." Any of these factors may cause a self-oxidizing effect in place of the expected antioxidant beneficial one. Nevertheless, different in vitro and in vivo studies have concluded that the antioxidant action of pigments such as p-carotene and lycopene is effective. 

---