Formation, Pro-mutagenic DNA Adducts leads to Tumorigenesis, Hepatocellular carcinoma

Formation of the pro-mutagenic DNA adduct, N7-AFB1-G (or its conversion product, N7-AFB1-FAPy) is the first step in the initiation of a process that may finish in development of hepatocellular carcinoma (HCC). These steps (pro-mutagenic adduct formation and HCC) are indirectly linked through insufficient/mis-repair of DNA and induction of a mutation in a critical gene and clonal expansion/cell proliferation with formation of altered hepatic foci (AHF).

One might obtain a quantitative understanding of this linkage from studies with AFB1 that reported dose-response data for both AFB1-induced adduct levels and HCC tumor incidence. However, no such data were identified. As mentioned above, some chemoprevention studies report reduced levels of AFB1-induced adducts (or increased urinary elimination of AFB1-induced adducts) but they only used single dose levels, so there are no dose-response data. Most initiation-promotion studies used a highly artificial system with chemical initiation with an alkylating agent and promotion with phenobarbital, TCDD, or some other compound, coupled with partial hepatectomy to further stimulate rapid cell proliferation (Xu et al., 1990a, 1990b). Chemoprotection studies such as Johnson et al. (2014) indicate that a strong relationship likely exists between AFB1-induced adducts and tumors, but insufficient data exist for quantification or definitive dose-response determination.

HCC has been observed essentially universally in AFB1-treated mammals, birds, and fish examined (Pottenger et al., 2014; Kensler et al., 2011; Kimura et al., 2004; Cullen et al., 1990; Kirby et al., 1990).