Kinds of mutations induced by aflatoxin B<sub>1</sub> in a shuttle vector replicating in human cells transiently expressing cytochrome P450IA2 cDNA

Trottier, Yvon; Waithe, William I.; Anderson, Alan

doi:10.1002/mc.2940060209

Cited by 44 publications

(19 citation statements)

References 45 publications

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“…The predominant mutation of AFB1-N7-Gua (Fig. 3) was the G -*> T transversion (-75% of all mutations), similar to that observed previously with metabolically activated AFB1 in E. coli induced for the SOS response and containing the mucAB mutagenesis-enhancing gene products (13) and in mammalian systems (16,22). A possible premutagenic lesion responsible for this mutation is the AP site that results from the facile depurination of AFB1-N7-Gua.…”

Section: Discussionsupporting

confidence: 84%

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Mutational properties of the primary aflatoxin B1-DNA adduct.

Bailey

Iyer

Stone

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

159

143

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The mutagenic activity of the major DNA adduct formed by the liver carcinogen aflatoxin B1 (AFB1) was investigated in vivo. An oligonucleotide containing a single 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB1-N7-Gua) adduct was inserted into the single-stranded genome of bacteriophage M13. Replication in SOS-induced Escherichia coli yielded a mutation frequency for AFBI-N7-Gua of 4%. The predominant mutation was G --T, identical to the principal mutation in human liver tumors believed to be induced by aflatoxin. The G -> T mutations of AFB,-N7-Gua, unlike those of the AFBI-N7-Gua-derived apurinic site, were much more strongly dependent on MucAB than UmuDC, a pattern matching that in intact cells treated with the toxin. It is concluded that the AFB,-N7-Gua adduct, and not the apurinic site, has genetic requirements for mutagenesis that best explain mutations in aflatoxin-treated cells. While most mutations were targeted to the site of the lesion, a significant fraction (13%) occurred at the base 5' to the modified guanine. In contrast, the apurinic site-containing genome gave rise only to targeted mutations. The mutational asymmetry observed for AFB1-N7-Gua is consistent with structural models indicating that the aflatoxin moiety of the aflatoxin guanine adduct is covalently intercalated on the 5' face ofthe guanine residue. These results suggest a molecular mechanism that could explain an important step in the carcinogenicity of aflatoxin B1.The fungal metabolite aflatoxin B1 (AFB1) contaminates the food supply in eastern Asia and sub-Saharan Africa, where it is associated with an increased incidence of hepatocellular carcinoma (HCC) (1). AFB1 requires metabolic conversion to its exo-8,9-epoxide (2, 3) in order to cause damage to DNA (4), the event that presumably initiates the genetic changes resulting in HCC (5). The AFB1 epoxide reacts with guanine to form a population of adducts (6), the principal of which both in vitro (3, 7-9) and in vivo (8,(10)(11)(12)) is 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFBl-N7-Gua). The positively charged imidazole ring of this adduct promotes depurination, resulting in apurinic (AP) site formation. Alternatively, under slightly basic conditions the imidazole ring of AFB1-N7-Gua opens to form the chemically and biologically stable AFB1 formamidopyrimidine (AFBI-FAPY) (1). The initial AFB,-N7-Gua adduct, the AFB1-FAPY, and the AP site, individually or collectively, represent the likely chemical precursors to the genetic effects of AFB1.The nature of mutations induced by electrophilic derivatives of AFB1 has been studied in several forward mutation assays.Upon examining AFB1 mutagenesis in the endogenous Escherichia coli lacI gene, Foster et al. (13) (20,21). The same mutations are observed in human hepatocytes grown in culture (22).The genetic studies cited above indicate that several mutations occur in DNA globally modified by AFB1, but the predominant mutation induced or selected in vivo appears to be the GC -> TA transversion. At least three DNA lesio...

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Section: Discussionsupporting

confidence: 84%

“…Both GC --TA and GC --AT mutations are induced with equal efficiency in other systems by metabolically activated AFB1 (14) and AFB1 8,9-dichloride (15) (16,17). In the c-Ki-ras oncogene of rat hepatocellular carcinomas, GC -> AT transitions in codon 12 are observed (18,19 (20,21).…”

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confidence: 99%

Mutational properties of the primary aflatoxin B1-DNA adduct.

Bailey

Iyer

Stone

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

159

143

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“…AFB1 and BPDE are well-studied genotoxic carcinogens that are known to cause point mutations (Foster et al, 1983;Trottier et al, 1992b;Levy et al, 1992;Yang et al, 1987;Wei et al, 1991Wei et al, , 1993. Although CPBA is a known DNA-damaging agent (Jacobsen and Humayun, 1986;Rosenthal et al, 1990), its mutagenic properties seem not to have been reported previously.…”

Section: Discussionmentioning

confidence: 99%

The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid

Courtemanche

Anderson

1999

Oncogene

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The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modi®ed by the chemical mutagens (+)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, a¯atoxin B 1 and meta-chloroperoxybenzoic acid Chantal Courtemanche 1,2 and Alan Anderson* ,1,2 1 Centre de recherche en canceÂrologie de l'UniversiteÂ Laval, Pavillon L'HoÃtel-Dieu de QueÂbec, Centre hospitalier universitaire de QueÂbec, QueÂbec G1R 2J6 Canada; and 2 DeÂpartement de biologie, UniversiteÂ Laval, QueÂbec G1K 7P4 Canada p53 has been postulated to be the guardian of the genome. However, results supporting the prediction that point mutation frequencies are elevated in p53-de®cient cells either have not been forthcoming or have been equivocal. To analyse the e ect of p53 on point mutation frequency, we used the supF gene of the pYZ289 shuttle vector as a mutagenic target. pYZ289 was treated in vitro by ultraviolet irradiation, a¯atoxin B 1 , (+)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and meta-chloroperoxybenzoic acid and then transfected into p53-de®cient cells with or without a p53 expression vector. p53 reduced the mutant frequency up to ®vefold when pYZ289 was treated with a¯atoxin B 1 , (+)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene or meta-chloroperoxybenzoic acid but not when it was ultraviolet-irradiated. The p53-dependent mutation frequency reduction was higher at a higher level of premutational lesions for a¯atoxin B 1 and (+)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and at a lower level of lesions for meta-chloroperoxybenzoic acid. This suggests that the chemical mutagens produce, in a dose-dependent fashion, two kinds of DNA damage, one subject to p53-dependent mutation frequency reduction and the other not. These results indicate that p53 can reduce the point mutation frequency in a shuttle vector treated by chemical mutagens and suggest that p53 can act as guardian of the genome for at least some kinds of point mutations.

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“…1 Dietary exposure to aflatoxins has liver by microsomal oxidase to reactive AFB 1 (8,9-epoxide) that is covalently linked to DNA, inducing mutation of the p53 gene at codon 249 (p53 mt 249), a critical factor in the development of hepatocarcinoma. [5][6][7][8] Aflatoxins also cross the placenta and high concentrations have been found in cord blood, 3,9 thereby affecting the fetus and newborn. It has been reported to be a risk factor for jaundice in the newborn.…”

Section: Introductionmentioning

confidence: 99%

Morbidity in neonates of mothers who have ingested aflatoxins

Abdulrazzaq

Osman

Yousif

et al. 2004

Annals of Tropical Paediatrics

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This study was undertaken to assess whether aflatoxin M(1) concentrations in newborn infants correlated with those of their mothers and to determine whether the presence of aflatoxin M(1) in cord blood was associated with an increase in morbidity in the newborn. There was a strong correlation (r =0.797, p <0.0001) between mothers' and cord blood levels of aflatoxin. There was also a strong negative correlation between aflatoxin levels and birthweight (r =-0.565, p <0.001) but there was no association between aflatoxin M(1) concentration in maternal or cord blood and rates of jaundice or infection.

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Kinds of mutations induced by aflatoxin B₁ in a shuttle vector replicating in human cells transiently expressing cytochrome P450IA2 cDNA

Cited by 44 publications

References 45 publications

Mutational properties of the primary aflatoxin B1-DNA adduct.

Mutational properties of the primary aflatoxin B1-DNA adduct.

The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid

Morbidity in neonates of mothers who have ingested aflatoxins

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Kinds of mutations induced by aflatoxin B1 in a shuttle vector replicating in human cells transiently expressing cytochrome P450IA2 cDNA

Cited by 44 publications

References 45 publications

Mutational properties of the primary aflatoxin B1-DNA adduct.

Mutational properties of the primary aflatoxin B1-DNA adduct.

The p53 tumor suppressor protein reduces point mutation frequency of a shuttle vector modified by the chemical mutagens (±)7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, aflatoxin B1 and meta-chloroperoxybenzoic acid

Morbidity in neonates of mothers who have ingested aflatoxins

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Kinds of mutations induced by aflatoxin B₁ in a shuttle vector replicating in human cells transiently expressing cytochrome P450IA2 cDNA