To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:345
Formation, Pro-mutagenic DNA Adducts leads to Tumorigenesis, Hepatocellular carcinoma
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma (HCC)||non-adjacent||Moderate||Moderate||Agnes Aggy (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
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).
Evidence Supporting this KER
While there is no specific information for AFB1, it is widely recognized that pro-mutagenic adducts formed by AFB1 metabolites may be repaired/removed or may result in mutations. The fidelity of the repair processes and probability of mis-repair determine whether mutations arise in tumor-critical genes. The altered hepatic foci (AHF) are believed to result from mutations expressed in cells that demonstrate reduced apoptosis and increased proliferation, likely linked to the mutations. (Alekseyev et al., 2004; Zhang et al., 2003; Giri et al., 2002; Bailey et al., 1996; Lin et al., 2014). The further development of AHF to HCC is believed to be a continuum of these same processes over time. These are discussed in a previous section and include effects on apoptosis, inflammation, the development of a tumor microenvironment, interference with the anti-oxidant response, and likely others.
Uncertainties and Inconsistencies
The direct KER relationships between adducts and mutations (MIE→KE#2) and from mutations to AHF (KE#2→KE#3) and from AHF to HCC (KE#3→AO) determine this indirect relationship. Unfortunately, there is a paucity of data to support quantification of a relationship between adducts and HCC; neither are there data to address an AFB1-related dose-response for both KEs.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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).
Alekseyev YO, Hamm ML, Essigmann JM (2004) Aflatoxin B1 formamidopyrimidine adducts are preferentially repaired by the nucleotide excision repair pathway in vivo. Carcinogenesis 25: 1045-1051. Bailey EA, Iyer RS, Stone MP, Harris TM, Essigmann JM (1996) Mutational properties of the primary aflatoxin B1-DNA adduct. Proc Natl Acad Sci U S A 93: 1535-1539.
Bechtel DH (1989) Molecular dosimetry of hepatic aflatoxin B1-DNA adducts: linear correlation with hepatic cancer risk. Regul Toxicol Pharmacol 10: 74-81
Cullen JM, Marion PL, Sherman GJ, Hong X, Newbold JE (1990) Hepatic neoplasms in aflatoxin B1-treated, congenital duck hepatitis B virus-infected, and virus-free pekin ducks. Cancer Res 50: 4072-4080.
Johnson NM, Egner PA, Baxter VK, Sporn MB, Wible RS, et al (2014) Complete protection against aflatoxin B1-induced liver cancer with triterpenoid: DNA adduct dosimetry, molecular signature and genotoxicity threshold. Cancer Prev Res (Phila).
Jubert C, Mata J, Bench G, Dashwood R, Pereira C, et al (2009) Effects of chlorophyll and chlorophyllin on low-dose aflatoxin B(1) pharmacokinetics in human volunteers. Cancer Prev Res (Phila) 2: 1015-1022.
Giri I, Johnston DS, Stone MP (2002) Mispairing of the 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1 adduct with deoxyadenosine results in extrusion of the mismatched dA toward the major groove. Biochemistry 41: 5462-5472.
Gursoy-Yuzugullu O, Yuzugullu H, Yilmaz M, Ozturk M (2011) Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation. Liver Int 31: 561-571.
Kensler TW, Egner PA, Dolan PM, Groopman JD, Roebuck BD (1987) Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones. Cancer Res 47: 4271-4277.
Kensler TW, Egner PA, Wang JB, Zhu YR, Zhang BC, et al (2004) Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas. Gastroenterology 127: S310-S318.
Kensler TW, Roebuck BD, Wogan GN, Groopman JD (2011) Aflatoxin: a 50-year odyssey of mechanistic and translational toxicology. Toxicol Sci 120 Suppl 1: S28-S48.
Kimura M, Lehmann K, Gopalan-Kriczky P, Lotlikar PD (2004) Effect of diet on aflatoxin B1-DNA binding and aflatoxin B1-induced glutathione S-transferase placental form positive hepatic foci in the rat. Exp Mol Med 36: 351-357.
Kirby GM, Stalker M, Metcalfe C, Kocal T, Ferguson H, Hayes MA (1990) Expression of immunoreactive glutathione S-transferases in hepatic neoplasms induced by aflatoxin B1 or 1,2-dimethylbenzanthracene in rainbow trout (Oncorhynchus mykiss). Carcinogenesis 11: 2255-2257.
Lin YC, Li L, Makarova AV, Burgers PM, Stone MP, Lloyd RS (2014) Molecular basis of aflatoxin-induced mutagenesis--role of the aflatoxin B1-formamidopyrimidine adduct. Carcinogenesis .
Maxuitenko YY, MacMillan DL, Kensler TW, Roebuck BD (1993) Evaluation of the post-initiation effects of oltipraz on aflatoxin B1-induced preneoplastic foci in a rat model of hepatic tumorigenesis. Carcinogenesis 14: 2423-2425.
Pottenger LH, Andrews LS, Bachman AN, Boogaard PJ, Cadet J, et al (2014) An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride. Crit Rev Toxicol 44: 348-391.
Roebuck BD, Liu YL, Rogers AE, Groopman JD, Kensler TW (1991) Protection against aflatoxin B1-induced hepatocarcinogenesis in F344 rats by 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz): predictive role for short-term molecular dosimetry. Cancer Res 51: 5501-5506.
Sudakin DL (2003) Dietary aflatoxin exposure and chemoprevention of cancer: a clinical review. J Toxicol Clin Toxicol 41: 195-204.
Xu YH, Campbell HA, Sattler GL, Hendrich S, Maronpot R, et al (1990) Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. Cancer Res 50: 472-479.
Xu YH, Maronpot R, Pitot HC (1990) Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. Carcinogenesis 11: 267-272.
Zhang YJ, Chen Y, Ahsan H, Lunn RM, Lee PH, et al (2003) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma. Int J Cancer 103: 440-444.