Hydroxynonenal, a component of clastogenic factors?
Exposure of human lymphocyte cultures to superoxide generated by the xanthine-xanthine oxidase (X-XO) system, resulted in formation of a clastogenic factor (CF), as expected from previous work. We speculated that arachidonic acid (AA), the major polyunsaturated fatty acid of biological membranes, was oxidized via the cyclooxygenase-lipoxygenase pathways or nonenzymatically by oxygen free radicals in the culture medium to products with clastogenic properties. In the present study, we analyzed CF for AA-derived products and tested corresponding commercial standards for their clastogenic properties. The results show that prostaglandins, thromboxane, and H(P)ETEs were not increased in supernatants from X-XO treated cultures compared to untreated cultures. Synthetic H(P)ETEs added to the medium of lymphocyte cultures were only slightly or not clastogenic. In contrast hereto, the degradation product 4-hydroxynonenal was found in 50% of CF samples, while it was absent in all 43 control samples. The kinetics of detectability in the culture medium was similar to that of CF. Also, the clastogenic effect of synthetic 4-hydroxynonenal at concentrations as low as 0.1 microM suggested that this aldehyde, known for its genotoxic effects, was a clastogenic component of CF. The indirect action mechanisms of 4-hydroxynonenal via inactivation of functional SH groups in DNA polymerases, may explain why chromatid-type damage is predominant in lymphocytes exposed to CF in the Go-G1 phase of the cell cycle. This particularly was already stressed 20 years ago in the first observations of radiation-induced CF. However, 4-hydroxynonenal is not the only clastogenic component of CF.(ABSTRACT TRUNCATED AT 250 WORDS)
Emerit
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Laboratory of Genetics, CNRS, University Paris VI, France.
Khan
S H
SH
Esterbauer
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D000447:Aldehydes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000139:chemically induced; D025063:Chromosome Disorders; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D008214:Lymphocytes / Q000737:chemistry / Q000378:metabolism; D009153:Mutagens / Q000737:chemistry* / Q000378:metabolism; D013931:Thromboxanes / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D000447:Aldehydes; D001095:Arachidonic Acids; D007042:Hypoxanthines; D009153:Mutagens; D013931:Thromboxanes; D016718:Arachidonic Acid; D019271:Hypoxanthine; D014969:Xanthine Oxidase; C027576:4-hydroxy-2-nonenal