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PubMed1987

Metabolic activation to a mutagen of 3-hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, a secondary metabolite of benzo[a]pyrene.

3-Hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol) was isolated from arylsulfatase/beta-glucuronidase-treated bile of rats to which 3-hydroxybenzo[a]pyrene (3-OH-BP) has been administered. This triol was investigated for mutagenicity in Salmonella typhimurium (reversion to histidine prototrophy of strains TA 97, TA 98, TA 100 and TA 1537) and in V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine). When no exogenous metabolizing system was added the triol was inactive, while 3-OH-BP showed weak mutagenic effects with all four bacterial strains. In the presence of NADPH-fortified postmitochondrial supernatant fraction (S9 mix) of liver homogenate from Aroclor 1254-treated rats, the mutagenicity of 3-OH-BP was potentiated, and the triol was activated to a mutagen(s). In the presence of S9 mix, the triol was 5-18 times more mutagenic than 3-OH-BP in strains TA 97, TA 100 and TA 1537, but both compounds showed similar mutagenic potencies with strain TA 98. These strain differences strongly suggest that the mutagenicity of 3-OH-BP in the S9 mix-mediated test was not exclusively due to metabolites of 3-OH-BP-7,8-diol. Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol), like the triol, showed mutagenic effects only in the presence of S9 mix. Strain TA 1537 was reverted by the triol but not by the diol. In the other bacterial strains the diol was more mutagenic than the triol, the difference in potency being largest in strain TA 100 (2.5- to 10-fold, depending on the experimental conditions). In V79 cells, the diol was a potent mutagen, while the triol showed only very weak mutagenic effects. However the triol was more cytotoxic than the diol. High cytotoxicity of the triol was observed even in the absence of S9 mix. The results of the present study demonstrate that metabolites of 3-OH-BP-7,8-diol are biologically-active derivatives of benzo[a]pyrene. Comparison of the mutagenic effectiveness in different bacterial strains also reveals that metabolites of 3-OH-BP-7,8-diol and of BP-7,8-diol substantially differ in the kind of genetic alterations they evoke.

Animals↗
PubMed1978

Pyrene excimer fluorescence in rabbit skeletal alphaalphatropomyosin labeled with N-(1-pyrene)maleimide. A probe of sulfhydryl proximity and local chain separation.

Rabbit skeletal alphaalphatropomyosin was specificially labeled at cysteine 190 with the fluorescent reagent, N-(1-pyrene)maleimide. Spectroscopically different products were obtained by labeling at pH 6.0 (PyrI-alphaalphaTm) or pH 7.5 (PyrII-alphaalphaTm). PyrII-alphaalphaTm results from a secondary reaction between the N-(1-pyrene)succinimido moiety at cysteine 190 of PyrI-alphaalphaTm and a lysine group on the same chain, probably lysine 189. Pyrene excimer fluorescence was present in the native state but absent in the unfolded state of both products, thus verifying the proximity of the--SH groups and the chain register model for the structure of tropomyosin. Studies of the guanidinium chloride-dependent unfolding of PyrII-alphaalphaTm showed that loss of excimer fluorescence precedes unfolding, providing evidence for a region of preferential instability in the molecule near cysteine 190. This work suggests that N-(1-pyrene)maleimide could be used to probe both--SH proximity and local conformation in any protein if the presence of two or more proximal--SH groups is suspected.

Animals↗
PubMed1976

The conversion of benzo(alpha)pyrene 4,5-oxide into 4-hydroxybenzo(alpha)pyrene in the presence of polyriboguanylic acid.

Incubation of benzo[alpha] pyrene 4,5-oxide with poly(G) in neutral aqueous ethanol resulted in the formation of covalent adducts and in the production of free 4-hydroxybenzo[alpha]pyrene. This phenol, which was identified by its UV spectral properties and by its chromatographic characteristics, was also formed but at a much slower rate when the epoxide was incubated with DNA or with GMP. Phenol formation was not detected when benzo[alpha]-pyrene 4,5-oxide was incubated for prolonged periods in the presence of poly(A), poly(C) or poly(U) or in the absence of nucleic acid. Formation of 4-hydroxybenzo[alpha] pyrene from the epoxide in the presence of poly(G) was not accompanied by detectable base modifications or by breakage of phosphodiester linkages.

Benzopyrenes↗
PubMed1978

The effect of norharman on the metabolism of benzo[alpha]pyrene by rat-liver microsomes in vitro in relation to its enhancement of the mutagenicity of benzo[alpha]pyrene.

The effect of norharman on the metabolism of benzo[alpha]pyrene by rat-liver microsomes was studied. Separation of the metabolites into hydrophilic and hydrophobic fractions showed that norharman inhibited the conversion of hydrophobic metabolites to hydrophilic ones. Analysis of the hydrophobic metabolites by high-pressure liquid chromatography showed that norharman also inhibited the disappearance of benzo[alpha]pyrene itself. However, large amounts of hydrophobic metabolites, such as phenol, quinones and diols, were formed in the presence of norharman, and formation of the strong mutagen 7,8-dihydroxybenzo[alpha]pyrene was increased 10-fold by norharman. The increase in formation of this compound may be one of the chief reasons why norharman enhances the mutagenicity of benzo[alpha]pyrene on Salmonella typhimurium.

Alkaloids↗
PubMed1978

Regio- and stereoselectivity of various forms of purified cytochrome P-450 in the metabolism of benzo[a]pyrene and (-) trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene as shown by product formation and binding to DNA.

Highly purified cytochromes P-450(LM2) and P-450(LM4) and partially purified P-450(LM1), P-450(LM3b), and P-450(LM7) from rabbit liver microsomes exhibit different catalytic activities in the metabolism of benzo[a]pyrene (BzP) and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)trans-7,8-diol] in a reconstituted enzyme system. The two highly purified cytochromes also exhibit differences in the activation of BzP and (-)trans-7,8-diol to intermediates that bind to DNA, as well as in the stereoselective conversion of (-)trans-7,8-diol to the highly mutagenic and carcinogenic diol-epoxides r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (diol-epoxide I) and r - 7,t - 8 - dihydroxy - c - 9,10 - oxy - 7,8,9,10 - tetrahydrobenzo[a]pyrene (diol-epoxide II). P-450(LM2) is more active than P-450(LM4) in the metabolism of BzP and in its conversion to products that bind to DNA. In contrast, P-450(LM4) is more active than P-450(LM2) in the metabolism of (-)trans-7,8-diol and in its conversion to products that bind to DNA. The ratio of activity (percent substrate metabolized) with BzP relative to that with (-)trans-7,8-diol is 21 for P-450(LM2) and 0.3 for P-450(LM4); P-450(LM1), P-450(LM3b), and P-450(LM7) gave intermediate ratios. Marked stereoselectivity in the oxygenation of the (-)trans-7,8-diol to the highly mutagenic and putatively carcinogenic diol-epoxides I and II was observed with P-450(LM4), whereas the other preparations showed less selectivity. The ratio of diolepoxide I to diol-epoxide II ranges from 0.3 for P-450(LM7) to 11 for P-450(LM4). The substrate specificity and regio- and stereo-selectivity of the different forms of cytochrome P-450 may regulate the balance between activation and detoxification pathways of BzP and therefore determine the susceptibility of individual tissues, strains, and species to the carcinogenic action of BzP.

Animals↗
PubMed1987

Reactivity with DNA of three pyrenofuran analogues of benzo(a)pyrene and benzo(e)pyrene.

Three pyrenofurans, the pyreno[1,2-b]furan (FP1), the pyreno[2,1-b] furan (FP2) and the pyreno[4,5-b]furan (FP3) have been synthesized as analogues of the mutagenic and carcinogenic benzo(a)pyrene (FP1 and FP2) and of its non-carcinogenic isomer benzo(e)pyrene (FP3). For each of the pyrenofurans, the reactivity with DNA has been tested in presence of liver microsomes of rats induced with 3-methylcholanthrene. Fluorescence spectroscopy showed that only FP2 and FP3 which possess a "bay region" react with DNA. In both cases, metabolites bound to DNA have a fluorescence emission comparable to that of the "bay region" dihydrodiols obtained after the "in vitro" metabolism of initial molecules. FP2 is shown to react similarly to benzo(a)pyrene whereas the reactivity of FP3 is different from that of benzo(e)pyrene, in spite of their structural similarities. This is probably due to reasons of three-dimensional space configuration. The peculiar reactivity of FP3 is predicted by calculations of the bond order values.

Animals↗
PubMed2005

Solid-matrix fluorescence quenching of benzo[e]pyrene and (+/-)-anti-dibenzo[a, l]pyrene diolepoxide-DNA adducts.

The solid-matrix fluorescence (SMF) quenching of benzo[e]pyrene and (+/-)-anti-dibenzo[a, l]pyrene-11,12-diol-13,14-epoxide ((+/-)-antiDB[a, l]PDE)-DNA adducts with thallium nitrate (TlNO(3)) and sodium iodide (NaI) was examined and several SMF quenching models were developed. The SMF quenching data for B[e]P with either TlNO(3) or NaI fit a two-independent-binding-site model. However, the SMF quenching of (+/-)-anti-DB[a, l]PDE-DNA adducts with TlNO(3) fits a sphere of action model, but quenching with NaI was modeled with the two-independent-binding-site model. The data were compared with earlier SMF quenching data for 7,8,9,10-tetrahydroxytetrahydro-benzo[a]pyrene (tetrol I-1) and (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide ((+/-)-anti-BPDE)DNA adducts. The interpretation of the SMF quenching data for the (+/-)-anti-DB[a, l]PDE-DNA adducts was distinctively different than the interpretation of the SMF quenching data for the (+/-)-antiBPDE-DNA adducts. This initial study shows that SMF quenching has the potential to characterize polycyclic aromatic hydrocarbonDNA adducts with different numbers of aromatic rings. In addition, the data indicated that external and intercalated DNA adducts interacted with heavy-atom salts in dissimilar fashions. The new SMF methodology developed is useful for the characterization of both polycyclic aromatic hydrocarbon-DNA adducts and metabolites from polycyclic aromatic hydrocarbons.

Benzopyrenes↗
PubMed1975

The benzo(alpha)pyrene deoxyribonucleoside products isolated from DNA after metabolism of benzo(alpha)pyrene by rat liver microsomes in the presence of DNA.

Rat liver microsomes (induced by 3-methylcholanthrene) were used to catalyze the binding of tritium-labeled benzo(alpha)pyrene to DNA. Enzymic degradation of this DNA to deoxyribonucleosides, followed by separation of the products by Sephadex LH20 column chromatography, revealed two major products. One of these was shown to be the same as that obtained from DNA with benzo(alpha)pyrene bound following treatment of mouse embryo cells in culture with the carcinogen. Neither product resembled those obtained from DNA that had been caused to react with benzo(alpha)pyrene 4,5-oxide (K-region eposide). The aryl hydrocarbon hydroxylase activity of the microsome preparations was determined and related to the extent of microsome-catalyzed hydrocarbon binding. Inhibitors of the enzyme epoxide hydrase increased this binding but caused the loss of one of the two major products. On the basis of the results obtained, a model is proposed of the mechanism of benzo(alpha)pyrene metabolism and DNA binding.

Aryl Hydrocarbon Hydroxylases↗
PubMed1978

Tumorigenicity studies with diol-epoxides of benzo(a)pyrene which indicate that (+/-)-trans-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene is an ultimate carcinogen in newborn mice.

The tumorigenic activities of benzo(a)pyrene(BP), (+/-)-trans-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 1), (+/-)-trans-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 2), (+/-)-trans-7,8,-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP 7,8-dihydrodiol), and the tetraols derived from the hydrolysis of diol-epoxide 2 were evaluated in newborn mice. The mice were given injections sequentially of 4, 8, and 16 nmoles of each compound on the first, eighth, and fifteenth days of life, and the animals were killed when they were 28 weeks old. Diol-epoxide 1 was highly toxic in newborn mice, and most of the animals treated with this compound died before weaning. Diol-epoxide 2 and BP 7,8-dihydrodiol were, respectively, about 40- and 15-fold more active than BP in causing pulmonary adenomas. Vehicle-treated control animals had an average of 0.13 lung adenoma/mouse, whereas animals treated with BP, BP 7,8-dihydrodiol, or diol-epoxide 2 had, respectively, 0.24, 1.77 and 4.42 pulmonary adenomas/mouse. Diol-epoxide 1 and the tetraols derived from diol-epoxide 2 did not induce pulmonary adenomas. The inactivity of diol-epoxide 1 under the conditions of our study should be interpreted with caution because of the high toxicity of this compound. The results of our study provide evidence that BP 7,8-dihydrodiol is a proximate carcinogenic metabolite and that diol-epoxide 2 is an ultimate carcinogenic metabolite of BP in the newborn mouse.

Adenoma↗
PubMed1991

Micronuclei in mouse skin cells following in vivo exposure to benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, chrysene, pyrene and urethane.

Detection of micronuclei (MN) in skin cells from HRA/Skh hairless mice treated with chemical or physical agents may prove informative in qualitative and quantitative studies of skin carcinogenesis. MN induction and cell survival were estimated in cytokinesis-blocked keratinocytes, cultured for 4 days in vitro, after a single topical dose of various organic compounds. Treatment with 2.56 micrograms (10 nmol) 7,12-dimethylbenz[a] anthracene (DMBA) resulted in maximal MN induction in cells removed from skin 12-24 hr after topical administration (79-88 MN/1,000 cells compared with 10-16 MN/1,000 cells in acetone-treated controls). Even in cells removed only 1 hr after DMBA treatment, a significant increase in MN was evident. However, to allow sufficient time for metabolic activation, a sampling time for of 24 hr was adopted for all test substances. Dose-dependent increases in MN were observed with DMBA, benzo[a]pyrene, chrysene, and urethane. Increased numbers of micronucleated cells were detected at the lowest doses administered in the present study (0.128, 0.5, 50, and 50 micrograms, respectively). Although reduced cell recovery occurred following exposure of mice to acetone, pyrene, and other chemicals, there was no evidence that cytotoxicity contributed to MN scored in keratinocytes. Moreover, the probable noncarcinogen, pyrene, failed to induce MN at doses from 2.5 micrograms to 2.5 mg/mouse. These results show that it is possible to assess chemical exposure in skin by measuring cell survival and skin genotoxicity by measuring MN induction in cultured keratinocytes. The available data suggest that MN induction may be a useful indicator of the carcinogenic potential of chemicals applied to the skin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Polycyclic aromatic hydrocarbon (PAH) metabolizing enzyme activities in human lung, and their inducibility by exposure to naphthalene, phenanthrene, pyrene, chrysene, and benzo(a)pyrene as shown in the rat lung and liver.

In order to survey changes and activities in the polycyclic aromatic hydrocarbon (PAH)-metabolizing enzymes implicated in lung cancer susceptibility studies, we investigated enzyme induction by 2-5-ring-sized 'biomarker' PAHs in rat liver and lung, and the activities in five human lung specimens. Naphthalene, phenanthrene, pyrene, chrysene, and benzo[a]pyrene (BaP) were administered to rats for 3 days (25-128 mg/kg/day) and the responses compared with those of model inducers. PAH treatment increased the CYP1A-catalyzed activity of pyrene 1-hydroxylation and 7-ethoxyresorufin O-deethylation in rat liver by up to 28- and 279-fold, and in rat lung by up to 22- and 51-fold, respectively. 1-Naphthol (hUGT1A6), 1-hydroxypyrene (hUGT1A6/1A9), and entacapone (hUGT1A9) are markers of PAH-glucuronidating human uridine diphosphate-glucuronosyltransferases (UGT). These activities increased up to 6.4-fold in rat liver and up to 1.9-fold in rat lung. NADPH:quinone oxidoreductase 1 (NQO1) and glutathione S-transferase activities increased up to 5.3- and 1.6-fold (liver), and up to 4.4- and 1.4-fold (lung), respectively. CYP1A showed the best liver-to-lung relationship (R (2 )=( )0.90). The inducing efficiency by PAHs differed extensively: control 60-fold), many times greater than the experimental (inducible/constitutive) variation in the rat. Kinetics of 1-hydroxypyrene glucuronidation showed two low-K (m) forms both in rat and human lung. Since the 2-4-ring PAHs (major constituents) were poor enzyme inducers, it appears that the PAH-metabolizing pathways are mainly induced by BaP-type minor constituents. Gene-environmental interactions which magnify polymorphic variability in pulmonary bioactivation/detoxification capacity probably play a key role in individual susceptibility to (or protection against) chemically induced lung cancer. Hence, human exposure to PAH mixtures with high content of BaP-type hydrocarbons confers a potentially higher health risk than PAH mixtures with low content of procarcinogens.

Animals↗
PubMed1981

Carcinogenicity of the environmental pollutants cyclopenteno-[cd]pyrene and cyclopentano[cd]pyrene in mouse skin.

Cyclopenteno[cd]pyrene (CPEP) is a widespread environmental pollutant. This hydrocarbon and its 3,4-dihydro derivative, cyclopentano[cd]pyrene (CPAP), were tested on skin in a two-stage initiation-promotion experiment in CD-1 mice and by repeated application in Swiss mice. The biological effect of CPEP and CPAP was compared to that of benzo[a]-pyrene (BP). Nine-week-old female CD-1 mice in groups of 30 were treated every other day over a 20-day period at mini-dose levels of 0.18, 0.06 and 0.02 mumol of CPEP or CPAP in acetone. One group was treated with BP at the low mini-dose level. Initiation was followed by twice weekly application of tetradecanoyl phorbol acetate for 40 weeks. In the second experiments, nine-week-old female Swiss mice in groups of 30 were treated at dose levels of 1.8, 0.6 and 0.2 mumol CPEP or CPAP in acetone twice weekly for 30 weeks. One group was treated with BP at the low dose. CPAP was virtually inactive in both studies. In the initiation-promotion experiment CPEP was inactive at the low dose level, whereas BP exhibited significant tumorigenicity. At the medium and high doses CPEP showed weak, but statistically insignificant, tumorigenic activity. Repeated application of CPEP at the high, medium and low doses resulted in tumor incidences of 23, 37 and 57%, respectively. This reverse dose-response may be due to the relatively high cytotoxicity of CPEP, BP, which was compared to CPEP at the low dose, elicited tumors in 100% of the mice. Most of the CPEP-induced neoplasms were malignant and some metastasized to lungs and lymph nodes. The inactivity of CPAP suggests the carcinogenicity of CPEP is probably due to formation of the ultimate metabolite CPEP 3,4-oxide. In view of the abundance of CPEP in environmental and occupational pollutants, its moderately potent carcinogenicity may represent a potential health hazard.

Animals↗
PubMed1985

Effect of ellagic acid and hydroxylated flavonoids on the tumorigenicity of benzo[a]pyrene and (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene on mouse skin and in the newborn mouse.

Ellagic acid, quercetin and robinetin were tested for their ability to antagonize the tumor-initiating activity of benzo[a]pyrene (B[a]P) and (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), the ultimate carcinogenic metabolite of benzo[a]-pyrene. Ellagic acid, robinetin or quercetin (2500 nmol) had no tumor-initiating activity on mouse skin, but the topical application of 2500 nmol of ellagic acid 5 min before a tumor-initiating dose of 200 nmol of B[a]P 7,8-diol-9,10-epoxide-2 caused a 59-66% inhibition in the number of skin tumors per mouse that were observed after 15-20 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Similar treatment with 2500 nmol of robinetin or quercetin caused a statistically insignificant 16-24% inhibition in the tumor-initiating activity of 200 nmol of B[a]P 7,8-diol-9,10-epoxide-2 applied 5 min later. Treatment of mice with 2500 nmol of ellagic acid 5 min before the application of 50 nmol of B[a]P inhibited the mean number of skin tumors per mouse by 28-33% after 15-20 weeks of promotion, but these decreases were not statistically significant. Robinetin and quercetin had little or no effect on the tumor-initiating activity of B[a]P on mouse skin. Treatment of preweanling mice with 1/7, 2/7 and 4/7 of the total dose of ellagic acid (300 nmol), robinetin (1400 nmol), myricetin (1400 nmol) or quercetin (1400 nmol) i.p. on their first, eighth and fifteenth day of life, respectively, did not cause the formation of tumors in animals that were killed 9-11 months later. Similar treatment of preweanling mice with the above doses of the phenolic compounds 10 min before the i.p. injection of a total dose of 30 nmol of B[a]P 7,8-diol-9,10-epoxide-2 during the animal's first 15 days of life caused a 44-75% inhibition in the number of diol-epoxide-induced pulmonary tumors per mouse. Similar treatment with these plant phenols had little or no effect on B[a]P-induced pulmonary tumors.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1986

In vivo formation and persistence of DNA adducts in mouse and rat skin exposed to (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

The in vivo DNA adduct formation of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BPD) and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) were compared and the persistence and disappearance of the adducts in both mouse and rat epidermis determined. BPD (100 nmol/mouse in 150 microliter acetone and 200 nmol/rat in 300 microliter acetone) and anti-BPDE (77 nmol/mouse in 150 microliter tetrahydrofuran and 154 nmol/rat in 300 microliter tetrahydrofuran) were topically applied to 50-day-old male Swiss mice and 35-day-old Wistar rats. To improve the identification of the DNA adducts formed, an acid hydrolysis technique was used to convert the BPD- and anti-BPDE-deoxyribonucleoside adducts formed in mouse and rat skin to BP tetrols. The modified deoxyribonucleosides and BP tetrols obtained by hydrolysis of adducts were isolated by reverse-phase h.p.l.c. At approximately similar doses per unit area of treated skin, the initial total binding of these compounds to epidermal DNA and the level of modified deoxyribonucleosides was approximately 6-fold lower in rat skin epidermis than in mouse skin epidermis. Similar ratios of (+/-)-anti-BPDE-deoxyguanosine (dGuo) to (+/-)-syn-BPDE-dGuo adducts (5.7 and 6.1, determined by h.p.l.c. analysis of BP tetrols obtained by hydrolysis of modified dGuo) were found in both mouse and rat epidermis a short time (6 h) after topical application of (+/-)-trans-BPD. Three hours after topical application of (+/-)-anti-BPDE, the ratios of BP-7,10/8,9-tetrol to 7/8,9,10-tetrol were 9:1 in mouse epidermal DNA and 6:1 in rat epidermal DNA. One and three weeks after application of these two compounds, only (+)-anti-BPDE-dGuo was detected in mouse epidermis; 2 and 0.2% of the initial (+)-anti-BPDE-dGuo level was found to persist in the epidermal DNA from BPD- and anti-BPDE-treated mice respectively. No DNA adducts were detected in rat epidermis 3 weeks after BPD and anti-BPDE treatment. Thus, 3 weeks after topical application of BPD and anti-BPDE to mouse and rat skin, the DNA adducts completely disappeared from rat epidermis while they persisted in mouse epidermis. The results suggest that: the persistence of (+)-anti-BPDE-dGuo may be related to carcinogenesis in mouse epidermis by BPD and anti-BPDE; the complete disappearance of the anti-BPDE-dGuo adduct may also account in part for the relative resistance of tissue from this species to the carcinogenic action of benzo[a]pyrene.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2002

Relationship of exposure to coke-oven emissions and urinary metabolites of benzo(a)pyrene and pyrene in coke-oven workers.

Coke-oven workers are occupationally exposed to a high concentration of polycyclic aromatic hydrocarbons (PAH). r-7,t-8,9,c-10-Tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (trans-anti-BaP-tetraol) and 1-hydroxypyrene (1-OHP) are urinary metabolites of benzo(a)pyrene and pyrene, respectively. In this study, we investigated the relationship among individual air exposure to benzene soluble fraction (BSF) of total particulates, as a surrogate marker of ambient PAH exposures, and urinary trans-anti-BaP-tetraol and 1-OHP concentrations in coke-oven workers at a steel plant in Taiwan. Fifty-seven subjects, including 41 male workers who work in one coke-oven plant and 16 men (referents) from an administrative area, were studied. The mean trans-anti-BaP-tetraol and 1-OHP concentrations (mean +/- SD) were 0.4 +/- 0.3 nmol/mol creatinine and 9.7 +/- 21.6 micromol/mol creatinine, respectively, in coke-oven workers. These levels were significantly higher than those in referents (0.03 +/- 0.03 nmol/mole creatinine, P < 0.001 and 0.4 +/- 0.2 micromol/mol creatinine, P < 0.01, respectively). Urinary trans-anti-BaP-tetraol concentrations were significantly and positively correlated with individual average BSF and urinary 1-OHP concentrations. That is, the higher the urinary trans-anti-BaP-tetraol concentrations, the more ambient BSF exposure and urinary 1-OHP concentrations (Spearman correlation coefficients r = 0.68 and 0.70, respectively; P < 0.0001; n = 57). These findings suggest that urinary 1-OHP and trans-anti-BaP-tetraol might be considered as potential biomarkers for the assessment of uptake of known PAH carcinogens in the air.

Adult↗
PubMed1983

Binding of benzo(a)pyrene and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo(a)pyrene to histones.

AKR-2B mouse embryo cells were incubated for 24 hr with [3H]benzo(a)pyrene, and the histones were isolated and analyzed using one- and two-dimensional gel electrophoresis and autoradiography. The results revealed that (a) histones H1, H2A, and H3 incorporated significant amounts of label whereas little or no label was associated with histones H2B and H4 and (b) electrophoresis of the histones in the Triton:acid:urea gel system caused labeled histones to have a slower migration than did the corresponding unlabeled histones. Additional studies such as incubation of (+/-)-7 beta,8 alpha-[3H]dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene with nuclei resulted in radioactive labeling of histones H1, H2A, H2B, and H3 and of high-mobility-group proteins HMG1 and HMG2. The low levels of label associated with histone H4 in the whole-cell and nuclear studies were further investigated by incubating isolated histones with (+/-)-7 beta,8 alpha-[3H]dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Under these conditions, negligible amounts of radioactivity were associated with H4, while significant labeling of H1, H2A, H2B, and H3 and other nuclear proteins was observed. The results suggest that factors other than the presence of suitable nucleophilic acceptor sites on the histones may be necessary for carcinogen binding.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1995

Differential mutagenicity and cytotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol and (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide in genetically engineered human fibroblasts.

DNA repair-deficient (xeroderma pigmentosum group A (XPA)) and DNA repair-proficient (normal) human skin fibroblasts were genetically engineered by transformation with a controllable human cytochrome P450 (CYP)1A1 expression vector. Induction of CYP1A1 enabled these cells to metabolize (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol (BPD) into a potent cytotoxicant and mutagen. The XPA cells were more susceptible than the normal cells to the cytotoxic effects of both CYP1A1-metabolized BPD and exogenously supplied (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10- epoxide (BPDE). Furthermore, the differential cytotoxicity between XPA and normal cells induced by CYP1A1-metabolized BPD was 8.4-fold greater than that induced by exogenously supplied BPDE. The two cell lines had similar CYP1A1 activities, suggesting that a difference in metabolic potential was not the cause of the differential response to BPD. At comparable cytotoxicity in both XPA and normal cells, BPD treatment induced more mutants and more DNA adducts than BPDE treatment did. At similar levels of DNA adducts in XPA cells, the levels of cytotoxicity induced by CYP1A1-metabolized BPD and exogenously supplied BPDE were similar, but CYP1A1-metabolized BPD induced a threefold higher hypoxanthine phosphoribosyltransferase mutation frequency. In contrast, at similar levels of adducts in CYP1A1-expressing normal cells, BPD induced less cytotoxicity and a lower mutation frequency. DNA adducts were identified and quantified by 32P-postlabeling analyses. The principal adduct formed by both CYP1A1-metabolized BPD and exogenously supplied BPDE was 10-beta-(deoxyguanosin-N2-yl)-7 beta,8 alpha,9 alpha-trihydroxy-7,8,9,10- tetrahydrobenzo[a]pyrene, indicating that the differential effects of BPD- and BPDE-induced adducts were not due to a difference in the types of adducts formed. The results of these studies suggest that CYP1A1-metabolized BPD may form adducts preferentially in transcriptionally active genes or that the intracellular concentration of BPDE may influence the balance between cytotoxicity and mutagenicity (or both).

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