Aflatoxin B1Activation in Human Lung

Abstract

Inhalation exposure to the carcinogen aflatoxin B1(AFB1) in certain occupations is considerable. Because circumstantial epidemiological evidence suggests that AFB1inhalation may cause primary lung cancer, we investigated AFB1activation by human lung microsomes. Microsomes were incubated with [3H]AFB1(124 μm), and activation to the AFB1-8,9-epoxide was measured as the AFB1–glutathione (AFB1–GSH) conjugate by HPLC. The formation of AFB1–GSH was in the range of 0.05–0.073 fmol/mg protein/min. The role of cytochrome P450 (CYP) 3A in this activation was investigated by oxidation of nifedipine (a prototype substrate for CYP 3A), by immunoinhibition, and by immunoblot analysis. Nifedipine oxidation varied from 0.2 to 19.2 pmol/mg protein/min in microsomes from different subjects, but did not correlate with AFB1activation. Anti-human polyclonal CYP 3A4 IgG inhibited AFB1activation. CYP 3A isoforms were immunoestimated to be in the range of 0.01–1.90 pmol/mg protein. Neither CYP 1A2 nor associated activity was detected in the lung microsomes. These data indicate that human lung microsomes activate AFB1to form theexo-AFB1-8,9-epoxide and that CYP(s) of the 3A subfamily may be responsible for this activity. The relatively low amount of AFB1activation in human lung compared to that in human liver can be explained by the scarcity of CYP-containing cells in the lung.In situAFB1activation and resultant carcinogenic risk are distinctly possible in occupational settings where inhalation of AFB1-contaminated dusts occurs.