Functional Study On Human Carcinogenic Metabolizing Enzymes And Their Genetic Variants

Section I Functional Characterization of CYP2A13 on AFB1 MetabolismThe worldwide human exposure to aflatoxin B₁ (AFB₁), particularly in developing countries, remains to be a serious public health concern. Although AFB₁ is best known as a hepatocarcinogen, epidemiological studies have shown a positive association between human lung cancer occurrence and inhalation exposure to AFB₁. Cytochrome P450 (CYP)-catalyzed metabolic activation is required for AFB₁ to exert its carcinogenicity. Previous studies have identified CYP1 A2 and CYP3A4 as the major enzymes for AFB₁ activation in human liver. However, the key CYP enzymes in human lung that can efficiently activate AFB₁ in situ are unknown. In the present study, we demonstrate that CYP2A13, an enzyme predominantly expressed in human respiratory tract, has a significant activity in metabolizing AFB₁ to its carcinogenic/toxic AFB₁-8, 9-epoxide and AFM₁-8, 9-epoxide at both low (15 μM) and high (150 μM) substrate concentrations. Under the same conditions, there was no detectable AFB₁ epoxide formation by CYP2A6, which was reported to be also involved in the metabolic activation of AFB₁. Consistent with the activity data, there was an approximately 1000-fold difference in LC50 values of AFB₁ (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing...