Evidence for membrane-mediated chromosomal damage by aflatoxin B1 in human lymphocytes.
The hepatocarcinogen aflatoxin B1 (AFB1) was found to be a potent clastogen for phytohemagglutinin stimulated human lymphocytes. It also induced sister chromatid exchanges. These types of chromosomal damage were induced at very low levels of covalent AFB1 - DNA adducts suggesting that AFB1 operates in part by indirect action because of its membrane-active character. The membrane-active character of AFB1 is documented by the following results: (i) AFB1 stimulated the excretion of hydroxy- and/or hydroperoxy-arachidonic acid (AA) and free AA into the culture medium; (ii) the phospholipase A2 inhibitor p-bromophenacylbromide was anticlastogenic ; (iii) the inhibitors of the oxidative metabolism of AA indomethacin, flufenamic acid, 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid and BN 1015 were anticlastogenic . These results are compatible with the induction of DNA damage by indirect action or the formation of covalent adducts via metabolic activation by cooxygenation . The observation that CuZn superoxide dismutase was anticlastogenic indicates the intermediacy of superoxide in DNA damage formation and supports the former mechanism.
D016604:Aflatoxin B1; D000348:Aflatoxins / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002396:Catechols / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002869:Chromosome Aberrations; D003434:Crossing Over, Genetic / Q000187:drug effects*; D005439:Flufenamic Acid / Q000494:pharmacology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D008353:Mannitol / Q000494:pharmacology; D009637:Masoprocol; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D000348:Aflatoxins; D000975:Antioxidants; D001095:Arachidonic Acids; D002273:Carcinogens; D002396:Catechols; D008353:Mannitol; D005439:Flufenamic Acid; D009637:Masoprocol; D016604:Aflatoxin B1; D007213:Indomethacin