Evidence for membrane-mediated chromosomal damage by aflatoxin B1 in human lymphocytes

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Abstract
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 antilastogenic indicates the intermediacy of superoxide in DNA damage formation and supports the former mechanism.