Biotransformation of aflatoxin B sub(1) in human lung

In addition to being a potent hepatocarcinogen, aflatoxin B sub(1) (AFB sub(1)) is a pulmonary carcinogen in experimental animals, and epidemiological studies have shown an association between AFB sub(1) exposure and lung cancer in humans. This study investigated AFB sub(1) bioactivation and detoxification in human lung tissue obtained from patients undergoing clinically indicated lobectomy. [ super(3)H]AFB sub(1) was bioactivated to a DNA binding metabolite by human whole lung cytosols in a time-, protein concentration-, and AFB sub(1) concentration-dependent manner. Cytosolic activation of [ super(3)H]AFB sub(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 sub(1). In whole lung microsomes, low levels of indomethacin inhibitable prostaglandin H synthase (PHS)-mediated [ super(3)H]AFB sub(1)-DNA binding and cytochrome P-450 (P450)-mediated [ super(3)H]AFB sub(1)-DNA binding were observed. Cytosolic glutathione S-transferase (GST)-catalyzed detoxification of AFB sub(1)-8,9-epoxide, produced by rabbit liver microsomes, was minimal at 1 and 10 mu M [ super(3)H]AFB sub(1). With 100 mu M [ super(3)H]AFB sub(1), [ super(3)H]AFB sub(1)-8,9-epoxide conjugation with reduced glutathione was 0.34 plus or minus 0.26 pmol/mg/h (n = 10). In intact, isolated human lung cells, [ super(3)H]AFB sub(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 [ super(3)H]AFB sub(1)-DNA binding in macrophages from five of seven patients, while NDGA inhibited [ super(3)H]AFB sub(1)-DNA adduct formation by 19, 40 and 56% in macrophages from three of seven patients. In alveolar type II cells, NDGA decreased [ super(3)H]AFB sub(1)-DNA binding by 30-100% in cells from three patients and indomethacin had little effect. SKF525A, an isozyme non-selective P450 inhibitor, enhanced [ super(3)H]AFB sub(1) binding to cellular DNA in unseparated cells, macrophages, and type II cells, suggesting that P450-mediated bioactivation of AFB sub(1) is not a major pathway by which AFB sub(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 sub(1) in human lung. Rather, LOXs and PHS appear to be