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PubMed1995

Benzo(a)pyrenediolepoxide-hemoglobin adducts and 3-hydroxy-benzo(a)pyrene urinary excretion profiles in rats subchronically exposed to benzo(a)pyrene.

The time profiles of benzo(a)pyrenediolepoxide (BaPDE)-hemoglobin (Hb) adduct formation and 3-hydroxybenzo(a)pyrene (3-OHBaP) urinary excretion were studied in male Sprague-Dawley rats exposed to daily benzo(a)pyrene (BaP) intraperitoneal doses of 1.25, 6.25, and 31.25 mumol/kg administered Tuesday to Friday for 4 consecutive weeks. Blood was withdrawn weekly, on Tuesdays, prior to dosing. Twenty-four-hour urine samples were collected on Mondays (following 72 h without treatment) and Thursdays. Analytes were quantified by high performance liquid chromatography (HPLC)/fluorescence. Exposure to BaP resulted in the accumulation of BaPDE-Hb adducts, reaching an average of 1.2 +/- 0.3, 8.3 +/- 1.9, and 38.2 +/- 6.1 pmol/g Hb for the 1.25, 6.25, and 31.25 mumol/kg per day doses after 4 weeks of treatment. The expected saw tooth excretion profile of 3-OHBaP was observed, with peaks on Thursdays and troughs on Mondays, and showed a progressive rise on both Mondays and Thursdays. Increase in Monday values with time suggested a possible increase in BaP body burden during exposure. To verify this aspect further, the urinary excretion kinetic of 3-OHBaP following acute intraperitoneal dosing (31.25 mumol/kg) was determined. Urine samples were collected at frequent timed intervals for up to 164 h post-dosing. Two-step elimination was observed, the second step having a half-life of 25 h, presumably linked to the slow release of BaP accumulated in fatty tissues upon repeated treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1989

Metabolism of benzo[a]pyrene and 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a pyrene in lung and liver of newborn mice.

Although the newborn mouse has been extensively used to test the tumorigenic activities of polynuclear aromatic hydrocarbons and their diol epoxide metabolites, no information is available on their metabolism in the newborn mouse in vivo. Therefore, we have investigated the metabolism and distribution of [3H]benzo[a]pyrene ([3H]BaP) and (+/-)-7 beta,8 alpha-[3H]dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene ([3H]BPDE) in liver and lung of mice given i.p. injections of these compounds on their 1st, 8th and 15th days of life. In lung, identified metabolites of [3H]BaP included diols, quinones, and phenols. Their levels were higher on the 1st day compared to the 8th and 15th days of life. The pattern of organic extractable metabolites detected in mouse liver was different from that in lung, being dominated by unidentified polar metabolites, the levels of which increased with age. Levels of [3H]BPDE in liver and lung were measured by trapping with 2-mercaptoethanol. It was demonstrated that [3H]BPDE rapidly reaches the lung after i.p. injections. The half-lives of [3H]BPDE in lung and liver were similar to those observed in vitro. The results are discussed with respect to the known tumorigenic activities of BaP and BPDE in newborn mice and in mouse skin.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1996

Chemopreventive activity of chlorophyllin against mouse skin carcinogenesis by benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide.

Chlorophyllin (CHL), the sodium and copper salt of chlorophyll, was tested for its chemopreventive activity against tumorigenesis induced by benzo[a]pyrene (B[a]P) and its ultimate electrophilic and carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide(BPDE). Administration of CHL (15 mg/kg body wt) by gavage to female ICR mice 30 min prior to a topical application of B[a]P or BPDE resulted in significant reduction in both incidence and multiplicity of skin tumors initiated by these carcinogens. CHL was rapidly distributed in the skin and other tissues of mice after oral administration. Taken together, these results suggest that CHL is a potential chemopreventive agent.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1983

Syncarcinogenic effect of the environmental pollutants cyclopenteno[cd]pyrene and benzo[a]pyrene in mouse skin.

Benzo[a]pyrene (BP) and cyclopenteno[cd]pyrene (CPEP) are widespread environmental pollutants. CPEP is a relatively potent carcinogen in mouse skin with an activity second only to BP among environmental aromatic hydrocarbons. We have studied the combined application of BP and CPEP on mouse skin to determine their possible synergistic carcinogenic effect. Nine-week-old female Swiss mice in groups of 30 were treated on the back with high (H), medium (M) and low (L) doses, respectively, of 20 (H), 6.6 (M) or 2.2 (L) nmol BP or 200 (H), 66.6 (M) or 22.2 (L) nmol CPEP in 50 microliters acetone twice weekly for 48 weeks. Other groups received BP-H + CPEP-H, BP-M + CPEP-M, BP-L + CPEP-L, BP-H + CPEP-L, BP-M + CPEP-L, BP-L + CPEP-H, or BP-L + CPEP-M. A significant, 3- to 7-fold syncarcinogenic effect occurred when BP-M + CPEP-M were administered together. A smaller, but significant, synergistic effect (1.2- to 3.8-fold) was also observed when BP-M + CPEP-L or BP-L + CPEP-M was applied. Because of the syncarcinogenic effect of BP and CPEP, their abundance in engine emissions and ambient air samples may present a major source of carcinogenic risk.

Animals↗
PubMed1988

Dose-response relationships of the tumorigenicity of cyclopenta[cd]pyrene, benzo[a]pyrene and 6-nitrochrysene in a newborn mouse lung adenoma bioassay.

Cyclopenta[cd]pyrene (CPP) was a potent tumorigen when tested over a 5-fold dose range in the newborn mouse assay. A 20-fold increase in lung tumor multiplicity and a nearly 8-fold increase in tumor incidence was observed at the lowest total dose tested (1.55 mumol) with the dose-response relationship indicating a saturation of tumor multiplicity at approximately 7 tumors/animal. No liver nodules or lymphatic system tumors were noted. Analysis of dose-response data for benzo[a]-pyrene (BaP) and 6-nitrochrysene (6-NC) showed that tumor multiplicity for BaP also saturated at approximately 7 tumors/animal, whereas no similar saturation was found for 6-NC at up to 40 tumors/animal. Progression of lung adenomas to adenocarcinomas, as measured by the incidence of mice bearing malignant tumors, was essentially a linear function of dose. To facilitate comparison and maximize quantitative data obtainable from the newborn mouse assay-parameters were defined for tumor incidence (ED50), tumor multiplicity (TM1.0) and tumor malignancy (malignancy index). Values for the ED50 and TM1.0 were similar for the same compound and a tumorigenic potency series of 6-NC greater than BaP greater than CPP was obtained corresponding to a ratio of approximately 1:10-25:76.5-135, respectively. The malignancy index, however, indicated increased adenocarcinoma induction in the order CPP greater than 6-NC greater than BaP as expressed by the ratio 1:1.4:8.3, respectively.

Adenoma↗
PubMed1988

Differences in the DNA adducts formed in cultured rabbit and rat dermal fibroblasts by benzo(a)pyrene and (-)benzo(a)pyrene-7,8-diol.

Benzo(a)pyrene (BaP) is highly carcinogenic in rats but is without effect in rabbits when administered s.c. The possibility that BaP-DNA adducts could be responsible for this species difference was investigated by comparing BaP-deoxyribonucleoside adducts formed in dermal fibroblast cultures from Wistar rats and New Zealand rabbits. Treatment with [G-3H]BaP (1.2 microM) for 6, 24, and 48 h produced an essentially qualitative species-specific difference. Over 95% of the DNA adducts in the rabbit dermal cell cultures were derived from anti-BaPDE; the major BaP adduct formed (90%) was (+)-anti-BaPDE-deoxyguanosine. This adduct was formed at very low levels in the rat dermal fibroblasts (7%). These cells contained a large proportion of (+/-)-r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene (syn-BaPDE)-DNA adducts (45%) and over 48% of other, unidentified, BaP-DNA adducts. Cells treated with (-)-BaP-7,8-diol (1.2 microM) produced almost exclusively (greater than 99%) (+)-anti-BaPDE-deoxyguanosine in rabbit cells, while the rat cells did not form this product. These results suggest that adducts other than anti-BaPDE-deoxyguanosine may be involved in rat s.c. BaP carcinogenesis; the preferential formation of (+)-anti-BaPDE-deoxyguanosine by rabbit dermal fibroblasts does not directly correlate with the resistance of rabbit dermis to tumor formation.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1988

Synchronous fluorescence spectrophotometry of benzo[a]pyrene diol epoxide-DNA adducts: a tool for detection of in-vitro and in-vivo DNA damage by exposure to benzo[a]pyrene.

We have applied synchronous fluorescence spectrophotometry (SFS) to study benzo[a]pyrene diol epoxide (BPDE)-DNA adducts in biological samples. Adducts are measured as benzo[a]pyrene (BP) tetrols after acid hydrolysis, and give a peak at 374 nm of emission with a 34-nm wavelength difference. In vitro and in animal studies, there is a positive correlation between the amount of adducts and the BP dose. In cell culture studies, the amount of adducts is increased by increasing both the dose of BP and the time of culture with BP. In preliminary human studies, BPDE-DNA has been found by SFS in placental DNA from some but not all smoking mothers and in blood cell DNA from some individuals in occupationally exposed groups.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1981

Synergistic, additive, and antagonistic mutagenic responses to binary mixtures of benzo(a)pyrene and benzo(e)pyrene as detected by strains TA98 and TA100 in the Salmonella/microsome assay.

Binary mixtures of benzo(a)pyrene (B(a)P) and benzo(e)pyrene (B(e)P) produce synergistic mutagenic (comutagenic) responses in Salmonella typhimurium strain TA98 (a frameshift detector). The optimum enhancement (25 X) was found at B(a)P concentration of 0.3 microgram/plate and B(e)P concentration of 1.5 microgram/plate. The response of strain TA100 (mostly a base-substitution detector) is opposite that of TA98, showing antagonism and additivity in similar concentration ranges.

Benzo(a)pyrene↗
PubMed1994

The role of 12 cDNA-expressed human, rodent, and rabbit cytochromes P450 in the metabolism of benzo[a]pyrene and benzo[a]pyrene trans-7,8-dihydrodiol.

The potent carcinogen benzo[a]pyrene (B[a]P) and its metabolite B[a]P trans-7,8-dihydrodiol (7,8-diol) require metabolic activation by the microsomal cytochrome P450s (P450s) to exert several adverse biological effects, including binding to DNA, toxicity, mutagenicity, and carcinogenicity. In the study reported here, we defined the role of each of 12 individual cDNA-expressed cytochrome P450s in the metabolism of B[a]P and 7,8-diol. Human P450s 1A1 and 1A2 were expressed in the absence or presence of epoxide hydrolase (EH) in a human lymphoblastoid cell line, and six human and five rodent and rabbit P450s were expressed from cDNA with vaccinia virus vectors in the hepatoma cell line Hep G2. B[a]P metabolism resulted in nine metabolites (three diols, three quinones, and three phenols), which were separated, identified, and quantitated by high-pressure liquid chromatography. In the human lymphoblastoid cells, human 1A1 metabolized B[a]P at a rate 4.5 times greater than that for 1A2. EH was shown to be directly involved in B[a]P activation, since increasing the amount of EH resulted in less 7-hydroxybenzo[a]pyrene and more 7,8-diol formation. Of the human P450s expressed with the vaccinia virus vectors in Hep G2 cells, 1A2 and 2C9 showed the highest activity and 2B6 showed moderate activity for B[a]P metabolism. Mouse 1A1 had activity 40 times higher than any human, rabbit, or rodent P450s, indicating the potential pitfalls of extrapolating P450 activity across species. Metabolism of the 7,8-diol resulted in six metabolites (four tetrols and two triols). In the lymphoblastoid cells, human 1A1 was shown to be 4.2 times more active than 1A2 for 7,8-diol metabolism. Among human P450s expressed from vaccinia virus, 1A2, 2E1, and 2C9 gave the highest activity, and 2C8 and 3A4 showed moderate activity for 7,8-diol metabolism to the diol epoxides. Again, mouse 1A1 was much more active than any other P450. These studies, in which we determined the capacity of individual P450 in the metabolism and activation of B[a]P and 7,8-diol, may thus lead to a better understanding of how P450s control the detoxification and activation of polycyclic aromatic hydrocarbons.

Animals↗
PubMedDate not supplied

Stereoselective metabolism of benzo[a]pyrene and 7-methylbenzo[a]pyrene by liver microsomes from sprague-Dawley rats pretreated with polychlorinated biphenyls.

The dihydrodiols formed from the metabolism of benzo[a]pyrene (BaP) and 7-methylbenzo[a]pyrene (7-MBaP) by liver microsomes from male Sprague-Dawley rats treated with polychlorinated biphenyls (PCBs, Aroclor 1254) have been examined by circular dichroism (CD) spectropolarimetry. Comparisons with optically pure enantiomers obtained via high performance liquid chromatography (HPLC) resolution of diastereomeric di-(-)-menthoxyacetates indicated that the trans-4,5-, 7,8- and 9,10-dihydrodiols formed from BaP metabolism are predominantly R,R-enantiomers with optical purities greater than 98%. The major enantiomers of the metabolically formed 7-MBaP-trans-4,5- and 9,10-dihydrodiols and 7-hydroxymethyl-BaP-trans-9,10-dihydrodiol have Cotton effects very similar to those of BaP-4R,5R- and 9R,10R-dihydrodiols, respectively. These 7-MBaP-trans-4,5- and 9,10-dihydrodiol metabolites therefore contain predominantly the R,R-enantiomers. The optical purity of metabolically formed 7-MBaP-trans-4,5-dihydrodiol was determined to be 30.8% enriched in (-)-enantiomer. The optical purity of the 9,10-dihydrodiol was not determined due to the lack of synthetic standards. The major trans-7,8-dihydrodiol enantiomer formed from 7-MBaP metabolism is a (+)-enantiomer (optical purity 60.4%) which has Cotton effects opposite in sign to that of the (-)-7R,8R-dihydrodiol formed from BaP metabolism. The results indicate that a methyl substituent on a polycyclic aromatic hydrocarbon may alter the stereoselective properties of the microsomal drug-metabolizing enzyme systems toward the substrate molecule.

Animals↗
PubMed1986

Excretion of benzo[a]pyrene-Gua adduct in the urine of benzo[a]pyrene-treated rats.

A benzo[a]pyrene(BP)-Gua adduct was extracted in the urine of rats treated with BP. Some (0.15%) of the administered dose of BP was excreted as BP-Gua within 48 h. A double labelling experiment demonstrated that the excreted product contained both a BP and a Gua moiety. Partially hepatectomized rats treated with [14C]Gua during the regenerative phase were injected with [3H]BP and the urine collected and processed by chromatographic procedures. The adduct had similar chromatographic properties to the adduct released from human PLC/5 cells treated with 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and co-chromatographed with 7-BPDE-Gua released from BPDE-adducted DNA under aqueous conditions. Detection and quantitation of BP-Gua offers an alternative, non-invasive method of monitoring individuals exposed to carcinogenic polycyclic aromatic hydrocarbons (PAHs).

Animals↗
PubMed1989

Benzo[a]pyrene-DNA-adducts and monooxygenase activities in mice treated with benzo[a]pyrene, cigarette smoke or cigarette smoke condensate.

Synchronous fluorescence spectrophotometry (SFS), developed to study benzo[a]pyrene-7,8-diol-9,10-epoxide(BPDE)-DNA, was used to measure the in vivo formation of DNA-adducts in genetically responsive C57BL/6 (B6) and non-responsive DBA/2 (D2) mice. Treatment with cigarette smoke by inhalation for 3-16 days, or i.p. injection of cigarette smoke condensate or neutral fraction did not lead to detectable levels of BPDE-DNA-adducts in either lungs or liver, although aryl hydrocarbon hydroxylase (AHH) activity, an indicator of benzo[a]pyrene (BP) metabolism, was clearly induced in lungs of B6 mouse. A dose-dependent amount of BPDE-DNA-adducts in lung and somewhat less in liver was found after i.p. injection with BP (20-80 mg/kg). Mice treated with vehicle or 4 mg/kg of BP were negative for adducts by SFS. In B6 mice AHH was induced both in lungs and livers while there was no AHH induction in D2 mice although the levels of BPDE-DNA-adducts were somewhat higher than in B6 mice. Thus, no clear correlation seems to exist between AHH activity and the formation of BPDE-DNA-adducts. Also, according to our results SFS can be used to quantitate adduct-formation in in vivo animal studies.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

Metabolism of benzo[a]pyrene and (-)-trans-benzo[a]pyrene-7,8-dihydrodiol by freshly isolated hepatocytes of brown bullheads.

The metabolism of [3H]benzo[a]pyrene (BP) and (-)-trans-[14C]7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) was studied in freshly isolated hepatocytes of the wild benthic fish, brown bullhead (Ictalurus nebulosus). Bullhead hepatocytes incubated with 40 microM [3H]BP for 1 h metabolized BP to water soluble metabolites which were separated on silica gel t.l.c. plates to reveal conjugates with glucuronic acid, glutathione, and sulfate (51%, 14% and 4% of total metabolites, respectively). Additional metabolites that were extractable with ethyl acetate were separated by reversed phase HPLC to reveal only two major metabolites: BP-9,10-dihydrodiol and BP-7,8-diol (13% and 2.6% of total metabolites, respectively). Hepatocytes isolated from individual fish displayed an 11-fold variability in the rates at which they metabolized BP (756 +/- 167 pmol x mg dry wt-1 x h-1), which correlated negatively (r = -0.7, P less than 0.01) with an 18-fold variability in the glycogen content of the cells. Hepatocytes isolated from the same fish, in parallel incubations under the same optimum conditions, metabolized BP-7,8-diol 4.5-fold faster than they metabolized BP. The variability in the rate of BP-7,8-diol metabolism was about 7-fold. Major metabolites included glutathione conjugates, glucuronides and sulfates (35%, 25% and 30% of total metabolites, respectively). These conjugates, like those formed from BP, were degradable with gamma-glutamyltransferase, beta-glucuronidase and arylsulfatase, respectively. Ethyl acetate extractable metabolites were predominantly isomeric benzo-ring tetrahydrotetrols (9% of total metabolites). In summary, this study indicates that during short-term incubations bull-head hepatocytes metabolize BP and BP-7,8-diol primarily to conjugated derivatives. The usefulness of thin-layer chromatography for the convenient determination of the rate of BP-7,8-diol metabolism is demonstrated.

Animals↗
PubMed1987

Modulation of the cytotoxicity and mutagenicity of benzo[a]pyrene and benzo[a]pyrene 7,8-diol by glutathione and glutathione S-transferases in mammalian cells (CHO/HGPRT assay).

Biologically reactive metabolites of benzo[a]pyrene (BP) and benzo[a]-pyrene 7,8-diol (BP-diol), formed by the mixed-function oxidase (MFO) system, are substrates for conjugation and detoxication by glutathione (GSH) when catalyzed by glutathione S-transferases (GSHT). We have investigated the detoxication of BP- and BP-diol-induced cytotoxicity and mutagenicity with GSH by supplementing the S9 mix used in the Chinese hamster ovary cells/hypoxanthine-guanine phosphoribosyltransferase (CHO/HGPRT) assay with GSH (6.5 mM) or GSH plus GSHT. The addition of GSH to the S9 mix resulted in a reduction of BP- and BP-diol induced cytotoxicity. GSH plus GSHT eliminated BP-induced cytotoxicity and reduced the mutagenicity of BP. GSH inhibited the mutagenicity at low (essentially non-lethal) concentrations of BP-diol, but did not do so at toxic concentrations. GSH plus GSHT inhibited the cytotoxicity and mutagenicity of BP-diol at concentrations not affected by GSH alone. These studies indicate that biochemical mechanisms of detoxication can affect the biological activity of a carcinogen, such as BP or BP-diol as profoundly as bioactivation by the MFO system.

Animals↗
PubMed1990

Formation of hemoglobin-benzo[a]pyrene adducts in human erythrocytes incubated with benzo[a]pyrene and hamster embryo cells.

Evidence is accumulating that the levels of covalent carcinogen-macromolecule adducts, including adducts with hemoglobin, reflect biologically effective levels of carcinogen exposure. The purposes of the present study were (a) to establish a cellular system for obtaining adducts between intracellular human hemoglobin and metabolites of polycyclic aromatic hydrocarbons (PAH), and (b) to evaluate techniques for chromatographic characterization of the adducts. We showed that hemoglobin-benzo[a]pyrene adducts were formed when human erythrocytes were treated with [3H]benzo[a]pyrene (BP) in the presence of hamster embryo fibroblasts, which are known to be effective for BP metabolism. After lysis of the erythrocytes, noncovalently bound BP and its metabolites were effectively removed from hemoglobin under mild conditions by using hydrophobic interaction and size-exclusion liquid chromatography. Three to five distinct adducts were resolved by reversed-phase and ion-exchange liquid chromatography. As determined by a two-step, reversed-phase liquid chromatographic procedure, trypsin treatment of globin from the cellular system yielded at least three of the four 7,8,9,10-tetrahydro-7,8,9,10-tetrahydroxy BP tetrols known to arise from mammalian metabolism of BP. This observation is consistent with both (a) the recently described formation of labile carboxyl esters via reaction of BP-7,8-dihydrodiol-9,10-epoxide (BPDE) with hemoglobin and (b) the known formation of both anti- and syn-BPDE in hamster embryo fibroblasts. In addition, high-performance liquid chromatographic analysis demonstrated the presence of other products presumed to be BP-peptide adducts because of their susceptibility to thermolysin treatment.

Animals↗
PubMed1992

Chinese medicinal herbs modulate mutagenesis, DNA binding and metabolism of benzo[a]pyrene 7,8-dihydrodiol and benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide.

Oldenlandia diffusa(OD) and Scutellaria barbata (SB) have been used in traditional Chinese medicine for treating liver, lung and rectal tumors. In this study, the effects of aqueous extracts of these two herbs on benzo[a]pyrene 7,8-dihydrodiol. (BaP 7,8-DHD) and benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE)-induced mutagenesis using Salmonella typhimurium TA100 as the bacterial tester strain and rat liver 9000 x g supernatant (S9) as the metabolic activation system were assessed. We also determined the effects of these two herbs on BaP 7,8-DHD and BPDE binding to calf thymus DNA. Organosoluble metabolites of BaP 7,8-DHD and water-soluble conjugates of BaP 7,8-DHD and BPDE were analyzed by high-performance liquid chromatography (HPLC) and alumina column liquid chromatography. Mutagenesis assays revealed that these two herbs produced a significant concentration-dependent inhibition of histidine-independent (His+) revertants induced by BaP 7,8-DHD and BPDE. OD and SB also inhibited BPDE-induced mutagenesis in a concentration-dependent manner in the absence of S9. SB had a greater inhibitory effect than OD. SB significantly inhibited BaP 7,8-DHD and BPDE binding to DNA while OD significantly enhanced DNA binding of both compounds. OD and SB inhibited the formation of organosoluble metabolites of BaP 7,8-DHD and decreased the formation of water-soluble conjugates of BaP 7,8-DHD and BPDE. However, the fraction of the total radioactivity in the water-soluble conjugates present as sulfate and glutathione was increased by OD and SB. Glucuronide fraction was decreased. The results of this study affirm our previous work suggesting that these two Chinese medicinal herbs possess antimutagenic properties and further suggest that they act as blocking agents through a scavenging mechanism.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1992

The co-carcinogen benzo[e]pyrene increases the binding of a low dose of the carcinogen benzo[a]pyrene to DNA in Sencar mouse epidermis.

The mechanism of the co-carcinogenic activity of benzo[e]pyrene (BeP) was investigated by determining the effects of BeP on the binding of the carcinogen benzo[a]pyrene (BaP) to DNA in Sencar mouse epidermis. The dose of BaP used was 20 nmol/mouse, a dose which is not carcinogenic in a single application but is carcinogenic after multiple treatments such as those in the BaP-BeP co-carcinogenesis experiments described by Van Duuren and Goldschmidt (J. Natl. Cancer Inst., 56, 1237, 1976). After 3 h of exposure to [3H]BaP and BeP at BaP:BeP dose ratios of 1:3 and 1:10, [3H]BaP-DNA adducts in both BeP-treated groups were lower than in an acetone-BaP control group. After 12 and 24 h of exposure, the BaP-BeP (1:10) group contained 19% and 33% higher [3H]BaP-DNA adduct levels than the control. In the BaP-BeP (1:3) group, the amount of [3H]BaP-DNA adduct levels was higher than the control after 12 h. BeP co-treatment with either [3H]BaP-7,8-dihydrodiol or anti-[3H]BaPDE had no effect on the amount of BaPDE-DNA adducts present. These results demonstrate that the co-carcinogen BeP increases the amount of a low dose of BaP that binds to mouse epidermal DNA and indicate that the increase in BaP-DNA adducts results from increased metabolism of BaP to the proximate carcinogen BaP-7,8-dihydrodiol.

Animals↗
PubMed1993

Exceptional tumor-initiating activity of 4-fluorobenzo[j]-fluoranthene on mouse skin: comparison with benzo[j]-fluoranthene, 10-fluoro-benzo[j]fluoranthene, benzo[a]pyrene, dibenzo[a,l]pyrene and 7,12-dimethylbenz[a]anthracene.

Exceptional tumorigenic potency was observed with 4-fluorobenzo[j]fuoranthene (4-fluoroB[j]F) relative to benzo[j]fluoranthene (B[j]F) and 10-fluorobenzo[j]fluoranthene (10-fluoroB[j]F) in a mouse skin initiation promotion bioassay. Comparison of the tumorigenic response obtained at total initiating doses of 50, 100, and 1000 nmol firmly established the greater tumorigenic potency of 4-fluoroB[j]F. B[j]F produced a significant tumorigenic response only at total initiating doses of 100 and 1000 nmol per mouse. 10-FluoroB[j]F produced a significant tumorigenic response only at the highest initiating dose, 1000 nmol per mouse. In contrast, 4-fluoroB[j]F produced a significant tumorigenic response at all three doses. At a total initiating dose of 50 nmol, a 90% incidence of tumor-bearing mice with an average of 3.05 tumors per mouse was observed with 4-fluoroB[j]F. A second initiation promotion bioassay was performed to establish the tumorigenic potency of 4-fluoroB[j]F relative to benzo[a]-pyrene (B[a]P), 7,12-dimethylbenz[a]anthracene (DMBA), and dibenzo[a,l]pyrene (DB[a,l]P). 4-FluoroB[j]F did exhibit significant tumor-initiating activity at doses of 10 and 25 nmol per mouse, inducing a 45 and 60% incidence of tumor-bearing mice with an average of 0.75 and 1.65 tumors per mouse, respectively. While B[a]P was not tumorigenic at these doses, DMBA and DB[a,l]P exhibited significant tumorigenic activity at doses of 1, 4, 10, and 25 nmol per mouse. DB[a,l]P induced a 95% incidence of tumor-bearing mice with an average of 5.0 tumors per mouse at a total initiator dose of 1 nmol. DMBA at this dose produced an 85% incidence of tumor-bearing mice with an average of 1.30 tumors per mouse. The results of these initiation promotion bioassays clearly demonstrate that 4-fluoroB[j]F is significantly more active than B[j]F, 10-fluoroB[j]F and B[a]P and less active than either DMBA or DB[a,l]P as a tumor initiator on mouse skin.

9,10-Dimethyl-1,2-benzanthracene↗