Formation and tumorigenicity of benzo[b]fluoranthene metabolites in mouse epidermis

Geddie, J. Edgar; Amin, Shantu; Huie, Keith; Hecht, Stephen S.

doi:10.1093/carcin/8.11.1579

Cited by 23 publications

(17 citation statements)

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“…Our analysis of the pattern of DNA adducts from rats treated with BbF suggests that none of the adducts are related to the bay-region diol epoxide of BbF (trans-9,10dihydro-9,10-dihydroxy-BbF-11,12-oxide). These results are in concert with those found by analyzing DNA from mouse epidermis treated with BbF (27). Although BbF is a strong mouse skin tumor initiator, the major mouse skin DNA adducts of BbF are not related to the bay-region diol epoxide.…”

Section: Discussionsupporting

confidence: 80%

Quantitative and temporal relationships between DNA adduct formation in target and surrogate tissues: implications for biomonitoring.

Nesnow

Ross

Nelson

et al. 1993

Environ Health Perspect

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DNA-carcinogen adducts offer a potential dosimeter for environmental genotoxicants reaching the exposed individual. Because the target tissues for many chemical carcinogens are not readily accessible for monitoring adducts in humans, peripheral blood lymphocytes (PBLs) have served as surrogate sources of exposed DNA. Both benzo[a]pyrene (BaP) and benzo[b]fluoranthene (BbF) are widely distributed in the environment as components of complex mixtures, such as automobile exhaust, cigarette smoke, foods, water, and urban air. Thus, human exposure to these chemicals is widespread, and they probably contribute to overall human lung cancer risk. The interpretation of the results of such studies would be enhanced by an understanding of the pharmacokinetics of specific DNA adduct formation and persistence in both target and surrogate tissues. Polycyclic aromatic hydrocarbons (PAHs) were administered to male Sprague-Dawley rats IP at 100 mg PAH/kg body weight. Lung, liver, and PBL tissues were harvested 1, 3, 7, 14, 28, and 56 days after treatment. DNA was extracted from each tissue and 32P-postlabeling analysis of DNA adducts with nuclease P1 enhancement was conducted. In all three tissues, BaP-DNA adducts exhibit a similar pattern, reaching a maximum at 3-4 days, followed by a decrease to 56 days. For BbF, the maximum DNA adduct levels in each tissue were between 5 and 14 days after injection. By 56 days after administration, the total adducts remaining in all tissues were measurable. Correlation analyses of the amount of DNA adducts in lung or liver compared to those found in the PBL of the same animals suggest a range of correlations (R2 = 0.67-0.83).(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 80%

Quantitative and temporal relationships between DNA adduct formation in target and surrogate tissues: implications for biomonitoring.

Nesnow

Ross

Nelson

et al. 1993

Environ Health Perspect

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“…These results are in concert with those found by analyzing DNA from mouse epidermis treated with BbF (27). Although BbF is a strong mouse skin tumor initiator, the major mouse skin DNA adducts of BbF are not related to the bay-region diol epoxide.…”

Section: Discussionsupporting

confidence: 80%

Quantitative and Temporal Relationships between DNA Adduct Formation in Target and Surrogate Tissues: Implications for Biomonitoring

Nesnow¹,

Ross²,

Nelson³

et al. 1993

Environmental Health Perspectives

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DNA-carcinogen adducts offer a potential dosimeter for environmental genotoxicants reaching the exposed individual. Because the target tissues for many chemical carcinogens are not readily accessible for monitoring adducts in humans, peripheral blood lymphocytes (PBLs) have served as surrogate sources of exposed DNA. Both benzo[a]pyrene (BaP) and benzo [b]fluoranthene (BbF) are widely distributed in the environment as components of complex mixtures, such as automobile exhaust, cigarette smoke, foods, water, and urban air. Thus, human exposure to these chemicals is widespread, and they probably contribute to overall human lung cancer risk. The interpretation of the results of such studies would be enhanced by an understanding of the pharmacokinetics of specific DNA adduct formation and persistence in both target and surrogate tissues. Polycyclic aromatic hydrocarbons (PAHs) were administered to male Sprague-Dawley rats IP at 100 mg PAH/ kg body weight. Lung, liver, and PBL tissues were harvested 1,3, 7,14, 28, and 56 days after treatment. DNA was extracted from each tissue and 32P-postlabeling analysis of DNA adducts with nuclease P1 enhancement was conducted. In all three tissues, BaP-DNA adducts exhibit a similar pattern, reaching a maximum at 34 days, followed by a decrease to 56 days. For BbF, the maximum DNA adduct levels in each tissue were between 5 and 14 days after injection. By 56 days after administration, the total adducts remaining in all tissues were measurable. Correlation analyses ofthe amount of DNA adducts in lung or liver compared to those found in the PBL of the same animals suggest a range of correlations (R2 = 0.67-0.83). For BaP, DNA adducts in both liver and lung may be predicted by PBL DNA adduct levels. For BbF, adduct levels in PBLs directly reflect adduct levels in the liver and are less predictive of lung adduct levels. The collateral pharmacokinetics for DNA adduct persistence in lung, liver, and PBLs suggest that PBL adduct-based dosimetry may reflect patterns of adduction in other less accessible tissues. Thus, PBL DNA adducts may prove to be useful dosimeters for the delivered dose of DNA.

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“…In contrast, metabolism in the naphthalene region of the molecule results exclusively in dihydrodiol formation. Similar observations were made in the metabolism of benzo [5] fluoranthene, in which a fivemembered ring insulates the benzene and phenanthrene portions of the molecule (17). Phenols are the major metabolites in the benzene portion, whereas dihydrodiols are the major metabolites in the phenanthrene portion.…”

Section: Resultssupporting

confidence: 72%

Rat liver metabolism of benzo[b]naphtho[2,1-d]thiophene

Murphy¹,

Amin²,

Coletta³

et al. 1992

Chem. Res. Toxicol.

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Thioarenes, sulfur-containing polycyclic aromatic hydrocarbons, have been detected in a number of environmental sources. The metabolism of one thioarene, benzo[b]naphtho[2,1,d]thiophene ([2,1]BNT), by F344 rat liver 9000g supernatant (S-9) was studied. [2,1]BNT which is structurally analogous and has similar carcinogenic potency to chrysene, was metabolized to six ethyl acetate-extractable metabolites when incubated with S-9 from Aroclor 1254-treated F344 rats. Each metabolite was collected from reverse-phase HPLC, and their identities were determined by analysis of MS and NMR data. In order of elution from HPLC they are as follows: (1) trans-1,2-dihydroxy-1,2-dihydrobenzo[b]naphtho[2,1-d]thiophene, (2) benzo[b]naphtho[2,1-d]-thiophene sulfone, (3) benzo[b]naphtho[2,1-d]thiophene sulfoxide, (4) trans-3,4-dihydroxy-3,4-dihydrobenzo[b]naphtho[2,1-d]thiophene, (5) 8- or 9-hydroxybenzo[b]naphtho[2,1-d]thiophene, and (6) 7-hydroxybenzo[b]naphtho[2,1-d]thiophene. In addition, the identities of metabolites 1, 2, 3, and 4 were confirmed by comparison to standards. The syntheses of the sulfone and sulfoxide of [2,1]BNT are reported here. The syntheses of the dihydrodiols were reported previously. Metabolite 5, a hydroxy[2,1]BNT, was the major metabolite formed by liver S-9 from untreated F344 rats. Microsomal preparations from these rats also produced significant amounts of the dihydrodiols, 1 and 4, and the sulfoxide, 3. Microsomes prepared from Wistar rats produced dihydrodiols and the sulfone and sulfoxide of [2,1]BNT. Therefore, [2,1]BNT is metabolized by both ring oxidation and sulfur oxidation in these two strains of rats.

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Formation and tumorigenicity of benzo[b]fluoranthene metabolites in mouse epidermis

Cited by 23 publications

References 0 publications

Quantitative and temporal relationships between DNA adduct formation in target and surrogate tissues: implications for biomonitoring.

Quantitative and temporal relationships between DNA adduct formation in target and surrogate tissues: implications for biomonitoring.

Quantitative and Temporal Relationships between DNA Adduct Formation in Target and Surrogate Tissues: Implications for Biomonitoring

Rat liver metabolism of benzo[b]naphtho[2,1-d]thiophene

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