7-Sulfooxymethyl-12-methylbenz[a]anthracene Is an Exceptionally Reactive Electrophilic Mutagen and Ultimate Carcinogen

Flesher, James W.; Horn, Jamie; Lehner, Andreas F.

doi:10.1006/bbrc.1997.6049

Cited by 26 publications

(14 citation statements)

References 22 publications

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“…Additionally, the meso-region theory proposes the formation of meso-hydroxymethyl metabolites, which subsequently generate benzylic-DNA adducts (61)(62)(63)(64)(65). In case of 7-12-DMBA, involvement of the 12-CH 2 OH and 7-CH 2 OH have been invoked in adduct formation via this pathway, with hydroxylation suggested as the rate-limiting step (72).…”

Section: (2)mentioning

confidence: 99%

Carbocations from Oxidized Metabolites of Benzo[a]anthracene: A Computational Study of Their Methylated and Fluorinated Derivatives and Guanine Adducts

Borosky

Laali

2006

Chem. Res. Toxicol.

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Structure-reactivity relationships and substituent effects on carbocation stability in benzo [a] anthracene (BA) derivatives have been studied computationally at the B3LYP/6-31G* and MP2/6-31G** levels. Bay-region carbocations are formed by O-protonation of the 1,2-epoxides in barrierless processes. This process is energetically more favored as compared to carbocation generation via zwitterion formation/O-protonation, via single electron oxidation to generate a radical cation, or via benzylic hydroxylation. Relative carbocation stabilities were determined in the gas phase and in water as solvent (PCM method). Charge delocalization mode in the BA carbocation framework was deduced from NPA-derived changes in charges, and substitution by methyl or fluorine was studied at different positions selected on basis of the carbocation charge density. A bayregion methyl group produces structural distortion with consequent deviation from planarity of the aromatic system, which destabilizes the epoxide, favoring ring opening. Whereas fluorine substitution at sites bearing significant positive charge leads to carbocation stabilization by fluorine p-π back-bonding, a fluorine atom at a ring position which presented negative charge density leads to inductive destabilization. Methylated derivatives are less sensitive to substituent effects as compared to the fluorinated analogues. Although the solvent decreases the exothermicity of the epoxide ring opening reactions due to greater stabilization of the reactants, it provokes no changes in relative reactivities. Relative energies in the resulting bay-region carbocations are examined taking into account the available biological activity data on these compounds. In selected cases, quenching of bay-region carbocations was investigated by analyzing relative energies (in the gas phase and in water) and geometries of their guanine adducts formed via covalent bond formation with the exocyclic amino group and with the N-7.

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Section: (2)mentioning

confidence: 99%

Carbocations from Oxidized Metabolites of Benzo[a]anthracene: A Computational Study of Their Methylated and Fluorinated Derivatives and Guanine Adducts

Borosky

Laali

2006

Chem. Res. Toxicol.

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“…However, there is evidence that the carcinogen 7-hydroxymethyl-12-methylbenz[a]anthracene is activated to a DNA reactive sulfate ester and a strong aralkylating electrophilic mutagen and ultimate carcinogen (22). Furthermore, even if the observations of Surh et al could disprove the sulfotransferase activation pathway for 7-hydroxy-methyl-12-methylbenz[a]anthracene, the observations still could not disprove the theory that the carcinogenic properties of picene and DBA depend on the existence of an L-region, but are independent of the existence of a bay-region.…”

Section: Resultsmentioning

confidence: 99%

Role of the Bay- and L-Regions in the Metabolic Activation and Carcinogenicity of Picene and Dibenz[ a,h ]anthracene

Flesher

Horn

Lehner

2002

Polycyclic Aromatic Compounds

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Early carcinogenicity tests found no evidence of activity for picene but found considerable initiating and carcinogenic activity for DBA. More recent investigation suggests that both pentacyclics are complete carcinogens when administered as single s.c. injections in NMRI mice, despite findings that picene acts as neither an initiating nor promoting agent. To investigate this contradiction, the complete carcinogenicity of both isomers was compared by s.c. injection in female Sprague-Dawley rats. The results demonstrated that 1 µmol of DBA administered three times weekly for 20 doses, induced sarcomas in all test animals by 33 weeks (100%). Similar treatment with picene did not induce sarcoma in any test animals by 37 weeks (0%). These present results agree with the earlier studies. It follows then that the metabolic activation and carcinogenicity of DBA and picene are dependent on the presence of an L-region, but are independent of the presence of a bay-region.

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“…7-Methylbenz [a]anthracene and 12-methylbenz [a]anthracene are also carcinogenic in mice and rats (see Dipple et al, 1984). 7-Hydroxymethyl-12-methylbenz [a]anthracene and 7-sulfooxymethyl-12-methylbenz [a]anthracene were tumorigenic when injected subcutaneously into rats (Flesher et al, 1997b). However, it was considered improbable that DMBA would act via metabolic activation to 7-sulfooxymethyl-12-methylbenz- [a]anthracene to induce hepatomas in male B6C3F 1 mice and lung adenomas in A/J mice, to initiate mouse skin tumours, to induce injection-site sarcomas in rats or to initiate preneoplastic enzyme-altered foci in rat liver.…”

Section: Mechanism Via Meso-region Biomethylation and Benzylic Oxidationmentioning

confidence: 99%

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

Hellou¹,

Beach²,

Leonard³

et al. 2012

Polycyclic Aromatic Compounds

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7-Sulfooxymethyl-12-methylbenz[a]anthracene Is an Exceptionally Reactive Electrophilic Mutagen and Ultimate Carcinogen

Cited by 26 publications

References 22 publications

Carbocations from Oxidized Metabolites of Benzo[a]anthracene: A Computational Study of Their Methylated and Fluorinated Derivatives and Guanine Adducts

Carbocations from Oxidized Metabolites of Benzo[a]anthracene: A Computational Study of Their Methylated and Fluorinated Derivatives and Guanine Adducts

Role of the Bay- and L-Regions in the Metabolic Activation and Carcinogenicity of Picene and Dibenz[ a,h ]anthracene

Integrating Field Analyses with Laboratory Exposures to Assess Ecosystems Health

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