Biotransformation of aflatoxin B-1 in human lung

In addition to being a potent hepatocarcinogen, aflatoxin B-1 (AFB(1)) is a pulmonary carcinogen in experimental animals, and epidemiological studies have shown an association between AFB(1) exposure and lung cancer in humans, This study investigated AFB(1) bioactivation and detoxification in human lung tissue obtained from patients undergoing clinically indicated lobectomy, [H-3]AFB(1) was bioactivated to a DNA binding metabolite by human whole lung cytosols in a time-, protein concentration-, and AFB(1) concentration-dependent manner. Cytosolic activation of [H-3]AFB(1) correlated with lipoxygenase (LOX) activity and was inhibited by the LOX inhibitor nordihydroguaiaretic acid (NDGA; 100 mu M), indicating that LOXs were largely responsible for the observed cytosolic activation of AFB(1), In whole lung microsomes, low levels of indomethacin inhibitable prostaglandin H synthase (PHS)-mediated [H-3]AFB(1)-DNA binding and cytochrome P-450 (P450)-mediated [H-3]AFB(1)-DNA binding were observed, Cytosolic glutathione S-transferase (GST)-catalyzed detoxification of AFB(1)-8,9-epoxide, produced by rabbit liver microsomes, was minimal at 1 and 10 mu M [H-3]AFB(1), With 100 mu M [H-3]AFB(1), [H-3]AFB(1)-8,9-epoxide conjugation with reduced glutathione was 0.34 +/- 0.26 pmol/mg/h (n = 10), In intact, isolated human lung cells, [H-3]AFB(1) binding to cellular DNA was higher in cell fractions enriched in macrophages than in either type II cell-enriched fractions or fractions containing unseparated cell types, Indomethacin produced a 63-100% decrease in [H-3]AFB(1)-DNA binding in macrophages from five of seven patients, while NDGA inhibited [H-3]AFB(1)-DNA adduct formation by 19, 40 and 56% in macrophages from three of seven patients, In alveolar type II cells, NDGA decreased [H-3]AFB(1)-DNA binding by 30-100% in cells from three patients and indomethacin had little effect, SKF525A, an isozyme non-selective P450 inhibitor, enhanced [H-3]AFB(1) binding to cellular DNA in unseparated cells, macrophages, and type II cells, suggesting that P450-mediated bioactivation of AFB(1) is not a major pathway by which AFB(1)-8,9-epoxide is formed in human lung cells, Overall, these studies suggest that P450 has a minor role in the bioactivation of AFB(1) in human lung, Rather, LOXs and PHS appear to be important bioactivation enzymes, Co-oxidative bioactivation of AFB(1), in combination with the low conjugating activity displayed by human lung cytosolic GSTs, likely contributes to human pulmonary susceptibility to AFB(1).