Benzo[a]pyrene 7,8-dihydrodiol is more carcinogenic than benzo[a]pyrene in newborn mice

Kapitulnik, Jaime; Levin, Wayne; Conney, Allan H.; Yagi, Haruhiko; Jerina, Donald M.

doi:10.1038/266378a0

Cited by 183 publications

(41 citation statements)

References 14 publications

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“…These results show that in comparison with BP and the other three isomers of the BP-7,8-diol-9,10-epoxifdes, (+)-BP-7f3,8a-diol-9a,10a-epoxide 2 has exceptional tumorigenic activity in newborn mice. The number of pulmonary tumors per mouse observed in mice treated with 14 nmol of (+)-BP-7#,8ca-diol-9ai,10a-epoxide 2 was about the same as observed in other experiments with a 100-fold higher dose of BP (27). Many compounds induce pulmonary tumors in mice (37,38), but to our knowledge (+)-BP-7p,8a-diol-9a,lOa-epoxide 2 is the most potent compound ever tested for the induction of pulmonary tumors.…”

Section: Discussionsupporting

confidence: 83%

“…The BP-7,8-diol-9,10-epoxides derived from BP-7,8-dihydrodiol exist as a pair of diastereomers in which the 7-hydroxyl group is either cis (diol epoxide 1) or trans (diol epoxide 2) to the 9,10-epoxide. The latter metabolites possess high chemical (11,12) and mutagenic (6,(13)(14)(15) activity, are potent inducers of epidermal hyperplasia (16), and interact with nucleophilic sites on cellular DNA, RNA, and protein (4,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) (27,28). Although the diastereomeric BP-7,8-diol-9,10-epoxides are less carcinogenic than BP on mouse skin (29,30), dihydrodiol is a potent carcinogen with activity comparable to or somewhat greater than BP (29,31,32 (33).…”

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confidence: 99%

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Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Buening

Wislocki

Levin

et al. 1978

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

372

152

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The tumorigenicities of benzo[a]pyrene and each optical enantiomer of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides derived from trans-7,8-dihydroxy-7,8-dihydrobenzol[a]pyrene were tested by sequential intraperitoneal injection of mice with 1,2, and 4 nmol, or with 2, 4, and 8 nmol of each compound on the 1st, 8th, and 15th day of life, respectively. The experiment was terminated when the animals were 34--37 weeks old. (+)-7beta, 8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzol[a]pyrene [(+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2] had exceptional tumorigenicity, whereas benzo[a]-pyrene and the other three optically pure isomers of the benzo[a]pyrene 7,8-diol,9,10-epoxides had little or no activity. These results demonstrate differences in the carcinogenic activities of optically active isomers of a polycyclic hydrocarbon diol epoxide. Eleven percent of control mice had pulmonary tumors, whereas 71% and 100% of the mice treated with a total dose of 7 or 14 nmol of (+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2, respectively, had pulmonary tumors. Control mice had an average of 0.12 pulmonary tumors per mouse, whereas mice treated with a total dose of 7 or 14 nmol of (+)-BP-7beta,8alpha-diol-9alpha,10alpha-epoxide 2 had 1.72 and 7.67 pulmonary tumors per mouse, respectively. Mice treated with 14 nmol of (-)-BP-7alpha,8beta-diol-9beta,10beta-epoxide 2, (-)-BP-7beta,8alpha-diol-9beta,10beta-epoxide 1, or (+)-BP-7alpha,8beta-diol-9alpha,10alpha-epoxide 1 had 0.13, 0.25, and 0.34 pulmonary tumors per animal, respectively.

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Buening

Wislocki

Levin

et al. 1978

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

372

152

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“…This microsomal enzyme complex functions to metabolize a large number of xenobiotics having widely different structural components and spectrum of toxic actions. AHH is often used as an indicator of the capacity of biological systems to form reactive electrophilic metabolites which are frequently in the form of arene oxide intermediates (17) (18)(19)(20). Information on the rates of formation of specific active metabolites capable of eliciting biochemical lesions is needed to achieve a valid toxicokinetic evaluation.…”

Section: Microsomal Ontogeny Of Monoxygenases Aryl Hydrocarbon Hydroxmentioning

confidence: 99%

Metabolic activation/deactivation reactions during perinatal development.

Lucier¹,

Lui²,

Lamartiniere³

1979

Environ Health Perspect

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The role of metabolic activation/deactivation reactions during development is evaluated in relation to developmental pharmacology and toxicology. Enzyme systems evaluated include the mixed-function oxidases (aryl hydrocarbon hydroxylase and oxidative demethylation), epoxide hydration and conjugation (glutathione conjugation, sulfation, and glucuronidation). Placental transfer and milk secretion of chemicals are discussed in relation to maternal, placental, and fetal metabolism. Normal patterns of enzyme development can be modified in two ways: (1) enzyme induction and (2) enzyme imprinting. Postnatal induction of the mixed-function oxidases and glucuronyl-transferase following treatment of pregnant rats with TCDD is shown to be caused primarily by newborn exposure to TCDD in milk. Structure-activity relationship are defmed for the perinatal induction of hepatic enzymes by the pure PCBs. PCBs are divided into two classes: P-450 inducers and P-448 inducers. Imprinting or programming of hepatic metabolism is a function of the sexual differentiation of enzyme activity; male and female activities are similar in prepubertal animals, whereas pronounced sex differences are evident in adults. Treatment of newborn rats (days 2-6) with diethylstilbestrol or testosterone resulted in a feminization (decrease) of mixed-function oxidation and glucuronidation in adult males. No changes were seen in immature males or females or adult females. This effect appears to be irreversible and is under pituitary-hypothalamicgonadal control. In addition to the feminization of enzyme activity, neonatal exposure to hormonally active chemicals also feminizes the hepatic response to cadmium in resultant adult animals.

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“…It is converted to a highly reactive electrophilic metabolite, (ϩ)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo-[a]pyrene (B[a]P DE) (4), which can damage DNA by forming adducts, mainly at the exocyclic 2-and 6-amino groups of guanine and adenine, respectively (5). B[a]P and its diol epoxide metabolites (6)(7)(8) induce lung tumors in a newborn mouse model, and B[a]P DE-DNA adducts have been implicated in human lung cancer (9). B[c]Ph is another well studied PAH that is activated in the liver to carcinogenic diol epoxide metabolites (4).…”

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confidence: 99%

Structure of DNA polymerase β with a benzo[ c ]phenanthrene diol epoxide-adducted template exhibits mutagenic features

Batra

Shock

Prasad

et al. 2006

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

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We have determined the crystal structure of the human base excision repair enzyme DNA polymerase ␤ (Pol ␤) in complex with a 1-nt gapped DNA substrate containing a template N 2 -guanine adduct of the tumorigenic (؊)-benzo[c]phenanthrene 4R,3S-diol 2S,1R-epoxide in the gap. Nucleotide insertion opposite this adduct favors incorrect purine nucleotides over the correct dCMP and hence can be mutagenic. The structure reveals that the phenanthrene ring system is stacked with the base pair immediately 3 to the modified guanine, thereby occluding the normal binding site for the correct incoming nucleoside triphosphate. The modified guanine base is displaced downstream and prevents the polymerase from achieving the catalytically competent closed conformation. The incoming nucleotide binding pocket is distorted, and the adducted deoxyguanosine is in a syn conformation, exposing its Hoogsteen edge, which can hydrogen-bond with dATP or dGTP. In a reconstituted base excision repair system, repair of a deaminated cytosine (i.e., uracil) opposite the adducted guanine was dramatically decreased at the Pol ␤ insertion step, but not blocked. The efficiency of gap-filling dCMP insertion opposite the adduct was diminished by >6 orders of magnitude compared with an unadducted templating guanine. In contrast, significant misinsertion of purine nucleotides (but not dTMP) opposite the adducted guanine was observed. Pol ␤ also misinserts a purine nucleotide opposite the adduct with ungapped DNA and exhibits limited bypass DNA synthesis. These results indicate that Pol ␤-dependent base excision repair of uracil opposite, or replication through, this bulky DNA adduct can be mutagenic.DNA adduct ͉ DNA repair ͉ fidelity ͉ mutagenesis P olycyclic aromatic hydrocarbons (PAHs) such as benzo- , and the adduct derived from trans-opening of the epoxide ring by the exocyclic 2-amino group of guanine in DNA, which is the subject of the present investigation.Bulky PAH-derived lesions can persist in human tissues when cellular repair enzymes fail to correct these lesions (13). The presence of these lesions in the genome blocks replicative DNA polymerases. If these lesions are not repaired, they must be bypassed for replication to continue. Bypass DNA synthesis occurs when a translesional DNA polymerase is recruited to the site of DNA damage and inserts a nucleotide opposite the adduct. DNA synthesis can be error-free or error-prone. The resulting base pair is then extended by either the same DNA polymerase or an auxiliary polymerase. Because replication of these adducts is known to result in mutations (14-16), mutagenic bypass provides a mechanism for adduct-induced tumor initiation and progression.Several DNA repair mechanisms protect cells from the deleterious effects of DNA lesions. For example, bulky DNA adducts such as PAH adducts and the formamidopyrimidine adduct of aflatoxin are primarily repaired by nucleotide excision repair (17, 18), although some unstable B[a]P DE adducts might promote depurination and elicit the base excision repair (BER...

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Benzo[a]pyrene 7,8-dihydrodiol is more carcinogenic than benzo[a]pyrene in newborn mice

Cited by 183 publications

References 14 publications

Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Metabolic activation/deactivation reactions during perinatal development.

Structure of DNA polymerase β with a benzo[ c ]phenanthrene diol epoxide-adducted template exhibits mutagenic features

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