Biotransformation of aflatoxin B1 in human lung

Carcinogenesis
P J DonnellyT E Massey

Abstract

In addition to being a potent hepatocarcinogen, aflatoxin B1 (AFB1) is a pulmonary carcinogen in experimental animals, and epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. This study investigated AFB1 bioactivation and detoxification in human lung tissue obtained from patients undergoing clinically indicated lobectomy. [3H]AFB1 was bioactivated to a DNA binding metabolite by human whole lung cytosols in a time-, protein concentration-, and AFB1 concentration-dependent manner. Cytosolic activation of [3H]AFB1 correlated with lipoxygenase (LOX) activity and was inhibited by the LOX inhibitor nordihydroguaiaretic acid (NDGA; 100 microM), indicating that LOXs were largely responsible for the observed cytosolic activation of AFB1. In whole lung microsomes, low levels of indomethacin inhibitable prostaglandin H synthase (PHS)-mediated [3H]AFB1-DNA binding and cytochrome P-450 (P450)-mediated [3H]AFB1-DNA binding were observed. Cytosolic glutathione S-transferase (GST)-catalyzed detoxification of AFB1-8,9-epoxide, produced by rabbit liver microsomes, was minimal at 1 and 10 microM [3H]AFB1. With 100 microM [3H]AFB1, [3H]AFB1-8,9-epoxide conjugation with reduced glutathione was 0.34 +/-...Continue Reading

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