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PubMed1999

Mono- and Diglucuronide formation from benzo[a]pyrene and chrysene diphenols by AHH-1 cell-expressed UDP-glucuronosyltransferase UGT1A7.

Polycyclic aromatic hydrocarbon (PAH)-type compounds induce at least two rat UDP-glucuronosyltransferase isoforms, UGT1A6 and UGT1A7. Among the glucuronidation reactions of PAH metabolites studied, mono- and diglucuronide formation of benzo[a]pyrene and chrysene-3,6-diphenol showed the highest induction factors in rat liver microsomes. Availability of AHH-1 cells stably expressing UGT1A7 allowed us to study whether this PAH-inducible isoform could catalyze benzo[a]pyrene and chrysene-3,6-diphenol glucuronidation. It was found that UGT1A7 indeed catalyzed mono- and diglucuronide formation of both benzo[a]pyrene and chrysene 3,6-diphenols. V79 cell-expressed rat UGT1A6 also catalyzed these reactions, except for chrysene diphenol diglucronide formation (Bock et al., Mol Pharmacol 42: 613-618, 1992). Enzyme kinetic studies of the glucuronidation of 6-hydroxychrysene (used as a stable PAH phenol) indicated that UGT1A7 conjugated this compound with a lower apparent Km value (0.1 microM) than UGT1A6 (10 microM). The results suggest that the two PAH-inducible UGTs may cooperate in conjugating PAH metabolites, but that UGT1A7 is more efficient.

Benzo(a)pyrene↗
PubMed2002

Ozonation of chrysene: evaluation of byproduct mixtures and identification of toxic constituent.

The effects of chrysene and the ozonated byproducts on in vitro gap junctional intercellular communication (GJIC) were evaluated using the scrape loading/dye transfer (SL/DT) technique. A 1 mM solution of chrysene was ozonated at dosages of 1.75, 3, 4.25, and 5 mol O3/mol chrysene (Chr). The early ozonation mixture, 1.75 mol O3/mol Chr, exhibited greater inhibition to GJIC than chrysene and irreversible damage to cells leading to cell death. To determine the compounds potentially responsible for the increase in toxicity, the byproducts formed upon treatment with 1.44 mol O3/mol Chr were separated into 14 fractions using RP-HPLC. The major compounds identified in the fractions were 2-(2'-formyl) phenyl-1-naphthaldehyde, 2-(2'formyl) phenyl-1-naphthoic acid, and 2-2-carboxyphenyl-1-naphthoic acid. 2-(2'-Formyl) phenyl-1-naphthaldehyde was determined to be the compound causing GJIC inhibition in sample fractions and byproduct mixtures.

Animals↗
PubMed1981

Embryotoxic effects of benzo[a]pyrene, chrysene, and 7,12-dimethylbenz[a]anthracene in petroleum hydrocarbon mixtures in mallard ducks.

Studies with different avian species have revealed that surface applications of microliter amounts of some crude and fuel oils that coat less than 10% of the egg surface result in considerable reduction in hatching with teratogenicity and stunted growth. Other studies have shown that the embryotoxicity is dependent on the aromatic hydrocarbon content, further suggesting that the toxicity is due to causes other than asphyxia. In the present study the effects of three polycyclic aromatic hydrocarbons identified in petroleum were examined on mallard (Anas platyrhynchos) embryo development. Addition of benzo[a]pyrene (BaP), chrysene, or 7,12-dimethylbenz[a]anthracene (DMBA) to a synthetic petroleum hydrocarbon mixture of known composition and relatively low embryotoxicity resulted in embryotoxicity that was enhanced or equal to that of crude oil when 10 microliter was applied externally to eggs at 72 h of development. The order of ability to enhance embryotoxicity was DMBA greater than BaP greater than chrysene. The temporal pattern of embryonic death was similar to that reported after exposure to crude oil, with additional mortality occurring after outgrowth of the chorioallantois. Retarded growth, as reflected by embryonic body weight, crown-rump length, and bill length, was accompanied by teratogenicity. Abnormal embryos exhibited extreme stunting; eye, brain, and bill defects; and incomplete ossification. Gas chromatographic-mass spectral analysis of externally treated eggs showed the passage of aromatic hydrocarbons including chrysene through the shell and shell membranes to the developing embryos. These findings suggest that the presence of polycyclic aromatic hydrocarbons in petroleum, including BaP, chrysene, and DMBA, significantly enhances the overall embryotoxicity in avian species.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

p53 controls global nucleotide excision repair of low levels of structurally diverse benzo(g)chrysene-DNA adducts in human fibroblasts.

Benzo(g)chrysene is a widespread environmental contaminant and potent carcinogen. We have measured the formation and nucleotide excision repair of covalent DNA adducts formed by the DNA-reactive metabolite of this compound in human fibroblasts, in which expression of the p53 tumor suppressor gene could be controlled by a tetracycline-inducible promoter. Cells were exposed for 1 h to 0.01, 0.1, or 1.2 microM (+/-)-anti-benzo(g)chrysene diol-epoxide, and DNA adducts were assessed at various post-treatment times by subjecting isolated DNA to (32)P-postlabeling analysis. Four major DNA adducts were detected, corresponding to the reaction of either the (+)- or (-)-anti-benzo(g)chrysene diol-epoxide stereoisomer with adenine or guanine. Treatment with 1.2 microM resulted in a level of 1100 total adducts/10(8) nucleotides for both p53-proficient and -deficient cells; removal of adducts was not observed in either case. In cells treated with 0.1 microM, the maximum level of total adducts at 24 h was 150/10(8) nucleotides in p53-proficient cells and 210 adducts/10(8) nucleotides in p53-deficient cells. A concentration of 0.01 microM resulted in a maximum of 20 adducts/10(8) nucleotides in p53-proficient cells at 4 h, but 40 adducts/10(8) nucleotides persisted in p53-deficient cells at 24 h. Whereas there were clear differences in the time course of adduct levels in p53-proficient compared with p53-deficient cells treated with 0.1 microM or 0.01 microM, these levels did not decrease extensively over 3 days. This is likely because of the stabilization of the diol-epoxide in cells, and consequent exposure and formation of adducts for many hours after the initial treatment. Furthermore, despite minor quantitative differences, all 4 of the adducts behaved similarly with respect to the effect of p53 expression on their removal. p53 appears to minimize the appearance of benzo(g)chrysene adducts in human cells by up-regulating global nucleotide excision repair and reducing the maximum adduct levels achieved. The fact that this p53-dependent effect is noted at levels of DNA adducts that are commonly found in human tissues (i.e., <100 adducts/10(8) nucleotides) because of environmental factors such as smoking is particularly significant with respect to human carcinogenesis related to environmental exposure.

Carcinogens, Environmental↗
PubMed1995

Cyclodextrin modified micellar electrokinetic chromatography for the chiral direct resolution of (+), (-)-trans-1,2-dihydrodiol metabolite of chrysene in vitro activated by rat liver microsome S9 fraction.

A gamma-cyclodextrin (gamma-CD) modified electrokinetic micellar capillary chromatography (MEKC) method was used for the enantiomer separation of a racemic trans-1,2-dihydro-1,2-dihydroxy-chrysene (chry-trans-1,2-diOH) mixture. The chiral resolution was strongly influenced by several important parameters: surfactant concentration and addition of organic modifier to the background electrolyte (BGE). An optimized electrophoretic system was used, consisting of the following conditions: 25 mM phosphate buffer, pH 7.8, 50 mM sodium dodecyl sulfate, 20 mM gamma-CD, 7.4% v/v 2-propanol as BGE; the applied voltage, 18 kV, corresponded to 37 microA at a constant temperature of 25 degrees C. This electrophoretic method was applied for monitoring the chry-trans-1,2-diOH enantiomer formation in a real sample, obtained from in vitro metabolic activation of chrysene by phenobarbital-beta-naphthoflavone-induced rat microsomes. The (+) and (-) enantiomers were identified by the racemate and the single enantiomer standard addition method and by spectra comparison with the synthetic compound. Under the experimental conditions used for chrysene activation, the (+) optical isomer was the prevailing form. The CD-MEKC system showed high reproducibility and selectivity, allowing a fast and interference-free analysis even of the in vitro metabolic sample extract, without any pretreatment.

Animals↗
PubMed1979

The formation of dihydrodiols in the chemical or enzymic oxidation of dibenz[a,c]anthracene, dibenz[a,h]-anthracene and chrysene.

The formation of trans-dihydrodiols from dibenz[a,c]anthracene, dibenz[a,h]anthracene and chrysene by chemical oxidation in an ascorbic acid-ferrous sulphate-EDTA system and by rat-liver microsomal fractions has been studied using a combination of thin-layer (TLC) and high pressure liquid chromatography (HPLC) to separate the mixtures of isomeric dihydrodiols. The 1,2- and 3,4-dihydrodiols of dibenz[a,c]anthracene, the 1,2-,3,4- and 5,6-dihydrodiols of dibenz[a,h]anthracene and the 1,2-, 3,4- and 5,6-dihydrodiols of chrysene were formed in chemical oxidations. These dihydrodiols were also formed when the three parent hydrocarbons were metabolized by rat-liver microsomal fractions and, in addition, dibenz[a,c]anthracene yielded the 10,11-dihydrodiol. The 1,2- and 3,4-dihydrodiols of dibenz[a,c]anthracene have not been reported previously either as metabolites of the hydrocarbon or as products of chemical syntheses and the 5,6-dihydrodiol of chrysene was not detected in earlier metabolic studies.

Animals↗
PubMed1994

Fjord-region diol-epoxides of benzo[c]chrysene are potent inducers of micronuclei in murine bone marrow.

Vicinal diol-epoxides are the best established carcinogenic metabolites of polycyclic aromatic hydrocarbons. Numerous studies have demonstrated their high genotoxic activity in various in vitro test systems. However, in vivo mutagenicity data are not available. The fjord-region diol-epoxides of benzo[c]chrysene combine high mutagenic activity in vitro with high hydrolytic stability. They were tested for the induction of micronuclei in the bone marrow following intraperitoneal administration to NMRI mice. The anti diastereomer of the diol-epoxide enhanced the frequency of micronucleated polychromatic erythrocytes strongly (7-19-fold above the value in untreated controls) over a very wide dose range (2.5-300 mumol/kg body weight). The syn diastereomer demonstrated similar effects, but required about 5 times higher doses. The corresponding proximate mutagen, benzo[c]chrysene-trans-9,10-dihydrodiol, was only moderately active, whereas the positive control substance, benzo[a]pyrene-trans-7,8-dihydrodiol, was strongly active. The study indicates that intraperitoneally administered diol-epoxides of benzo[c]chrysene may reach the bone marrow. Therefore, it will be possible to study the influence of metabolic modulation, e.g. by enzyme induction, on the effects of these ultimate mutagens and their metabolic precursors in vivo.

Animals↗
PubMed1987

Formation of DNA adducts in mouse skin treated with metabolites of chrysene.

Analysis by 32P-postlabelling of DNA isolated from mouse skin that had been treated in vivo with the polycyclic hydrocarbon chrysene revealed the presence of 7 adducts. All 7 adducts were also present in DNA from mice treated with trans-1,2-dihydro-1,2-dihydroxychrysene (chrysene-1,2-diol), and one of them, adduct 2, was formed from the triol derivative 9-hydroxy-trans-1,2- dihydro-1,2-dihydroxychrysene (9-hydroxychrysene-1,2-diol) and from 3-hydroxychrysene. Adducts were not detected in DNA from mice treated with trans-3,4-dihydro-3,4-dihydroxychrysene (chrysine-3,4-diol) or with 1-, 2-, 4-, 5- or 6-hydroxychrysene. In vitro modification of DNA by the anti-isomer of the bay-region diol-epoxide yielded adducts 3-7, while the corresponding triol-epoxide yielded adducts 2. It is concluded that chrysene activation in mouse skin proceeds principally via the bay-region diol-epoxide and to a lesser extent via the related bay-region triol-epoxide.

Animals↗
PubMed1987

Monooxygenase induction by various xenobiotics and its influence on rat liver microsomal metabolism of chrysene in comparison to benz[a]anthracene.

The potencies of various xenobiotics for induction of monooxygenases and their influence on the rat liver microsomal metabolite profile of the environmentally relevant weak carcinogen, chrysene, was determined. Among the widely distributed chemicals, polychlorinated biphenyls (PCB) and preferentially 3,3',4,4'-tetrachlorobiphenyl as well as PAHs and their heterocyclic analogues such as benzo[a]pyrene, benzo[b]- and -[j]fluoranthene, indeno[1,2,3-cd]pyrene, dibenz[a,h]acridine, benzo[b]naphtho-[2,1-d]thiophene, and 5,6-benzoflavone were found to be potent inducers stimulating the formation of the proximate, and some of them also the ultimate carcinogen of chrysene. Lindane, carbaryl, DDT, and pentachlorophenol were found to be inefficient or weak inducers. With the exception of phenobarbital no inducers were found among the pharmaceuticals investigated. Sex-dependent metabolism was found for Wistar-rats. No 1,2-oxidation was observed in females, and turnover rates were lower than in males. These findings confirm the results previously obtained with benz[a]anthracene as substrate. The inducing potencies of various compounds tested were similar for both of these substrates. It is interesting to note that in most cases the same effective xenobiotic induces the bay-region diolepoxide in both, chrysene and benz[a]anthracene.

Animals↗
PubMed1987

Comparison of chrysene metabolism in epithelial human bronchial and Syrian hamster lung cells.

Chrysene is metabolized to 1-, 2-, 3-, and 4-hydroxychrysene and trans-1,2- as well as trans-3,4-dihydroxydihydrochrysene in human and Syrian hamster epithelial lung cells as indicated by GC/MS analysis, whereas K-region oxidation is at most a very minor pathway. Cells of a permanent clonal line of fetal hamster lung metabolized 97% of the chrysene whereas fetal human bronchial epithelial cells converted 24% of the substrate within 8 days incubation. In human cells oxidation at the 3,4-position predominates, whereas oxidation at the 1,2-position is the major pathway in hamster cells. Indication for a bay-region oxidation of chrysene in hamster cells has been obtained.

Animals↗
PubMed2006

Investigation of the genotoxicity of dibenzo[c,p]chrysene in human carcinoma MCF-7 cells in culture.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants that have been linked to certain human cancers. The fjord region PAH dibenzo[a,l]pyrene exhibits the highest levels of carcinogenic activity of all PAH as yet tested in rodent tumor models. Another hexacyclic aromatic hydrocarbon, dibenzo[c,p]chrysene (DBC), is a unique PAH that possesses one bay region and two fjord regions within the same molecule. Due to its structure, which is a merger of the fjord region PAHs benzo[c]phenanthrene, benzo[c]chrysene, and benzo[g]chrysene, DBC is of considerable research interest. In order to investigate the pathway of regioselective metabolism we have studied the cytotoxicity, metabolic activation and DNA adduct formation of DBC in human mammary carcinoma MCF-7 cells in culture. The cytotoxicity assay indicated undisturbed cell proliferation even at concentrations as high as 4.5 microM (1.5 micro g/ml) DBC. Concurrently, DNA adducts were detected in MCF-7 cells treated with DBC only in low amounts (0.6 pmol adducts/mg DNA). On the contrary, exposure to anti-DBC-1,2-diol-3,4-epoxide and anti-DBC-11,12-diol-13,14-epoxide, two putatively genotoxic metabolites of DBC, resulted in high levels of DNA adducts (33 and 51 pmol adducts/mg DNA, respectively). Although DBC was not efficiently transformed into DNA-reactive metabolites in MCF-7 cells in culture, the results from our study indicate that the two fjord region diol-epoxide derivatives of DBC may serve as ultimate genotoxic metabolites once they are enzymatically generated under certain circumstances in vitro or in vivo.

Cell Line, Tumor↗
PubMed2004

An evaluation of two fluorescence screening methods for the determination of chrysene metabolites in fish bile.

Two screening methods, synchronous fluorescence spectrometry (SFS) and high performance liquid chromatography with fluorescence detection (HPLC-F), have been evaluated for their suitability in determining chrysene metabolites in fish bile. The optimal wavelength pair, excitation/emission 272/374 nm, for SFS measurements of chrysene metabolites was identified by analysis of bile taken from fish exposed to the pure compound. This analysis revealed in addition some information about the metabolite pattern. However, when bile from fish exposed to complex and environmentally relevant mixtures of polycyclic aromatic hydrocarbons (PAHs) was analysed using these methods, identification of the chrysene metabolites was poor. Analysis of bile taken from fish exposed to single PAHs identified other three- and four-ring aromatics as the main interfering compounds. Both methods were equally able to discriminate between impacted and reference sites by determination of relative concentrations of fluorescent three- and four-ring aromatics.

Animals↗
PubMed2005

Nitrogen-substitution effects on the mutagenicity and cytochrome P450 isoform-selectivity of chrysene analogs.

Nitrogen-containing analogs of chrysene, 1,10-diazachrysene (1,10-DAC) and 4,10-DAC, were tested for mutagenicity in Salmonella typhimurium TA100 in the presence of rat liver S9 and human liver microsomes to investigate the effect of nitrogen-substitution. Although these DACs could not be converted to the bay-region diol epoxide because of their nitrogen atoms in the bay-region epoxide or diol moiety, DACs were mutagenic in the Ames test with rat liver S9. Both DACs also showed mutagenicity in the Ames test using pooled human liver microsomes, although chrysene itself was not mutagenic in the presence of pooled human liver microsomes. The mutagenicity of DACs (50nmol/plate) in Ames tests using human liver microsome preparations from 10 individuals was compared with cytochrome P450 (CYP) activity in each microsome preparation to investigate the CYP isoform involved in the activation of DACs to the genotoxic forms. The numbers of induced revertants obtained by 1,10-DAC varied 6.2-folds (109-680) and those by 4,10-DAC 4.8-folds (155-751) among the 10 individuals. The number of induced revertants obtained by 1,10-DAC significantly correlated with the CYP1A2-selective catalytic activity (r=0.84, P<0.01) in each microsome preparation. On the other hand, the number of induced revertants obtained by 4,10-DAC significantly correlated with the combined activity of CYP2A6 and 1A2 (CYP2A6+0.51xCYP1A2; r=0.75, P<0.01). However, in Ames tests using microsomes from insect cells expressing various human CYP isoforms, the mutagenicity of 1,10-DAC was induced only by recombinant human CYP1A2, whereas both recombinant human CYP2A6 and 1A2 contributed to the mutagenicity of 4,10-DAC. These results suggest that 1,10-DAC shows the mutagenicity through involvement of CYP1A2 in human liver, and 4,10-DAC does so through both CYP2A6 and 1A2. In conclusion, our results suggested that the difference in the nitrogen-substituted position in the chrysene molecule might affect the mutagenic activity through influencing the ratio of participation of the metabolic activation enzyme isoforms of CYP.

Animals↗
PubMedDate not supplied

Selective covalent binding of the active sulfate ester of the carcinogen 5-(hydroxymethyl)chrysene to the adenine residue of calf thymus DNA.

5-(Hydroxymethyl)chrysene (5-HCR) sulfate, an active metabolite of the carcinogen 5-HCR, bound significantly in a covalent manner to the purine bases of calf thymus DNA through its 5-methylene carbon with loss of a sulfate anion when incubated at pH 7.4 and 37 degrees C. From the DNA were isolated two purine base adducts by high-pressure liquid chromatography, and they were identified as N6-[(chrysen-5-yl)methyl]adenine and N2-[(chrysen-5-yl)methyl]guanine with the corresponding synthetic specimens. The purine base adducts, appearing in the ratio 1 to 27 for guanine to adenine in the chromatogram, accounted for about 60% of the total covalent binding of 5-HCR sulfate to the DNA. 5-HCR sulfate also reacted specifically with the exocyclic amino groups of the purine bases of 2'-deoxyadenosine 5'-phosphate and 2'-deoxyguanosine 5'-phosphate at much lower rates than did with those of calf thymus DNA. Denaturing the DNA by heating followed by rapid cooling, covalent binding of 5-HCR sulfate to it markedly decreased with the increasing ratio of N2-guanine to N6-adenine adducts (1:3.6). These results strongly suggest that secondary structure of DNA has an influence on the covalent binding of 5-HCR sulfate and that intercalation of the sulfate ester into DNA base pairs plays an important role in its preferential binding to N6 of the adenine residue of native DNA.

Adenine↗
PubMed1999

Metabolic activation of 4H-cyclopenta[def]chrysene in human mammary carcinoma MCF-7 cell cultures.

The tumor initiating activities of 4H-cyclopenta[def]chrysene (C[def]C) and its two putative reactive metabolites, trans-1, 2-dihydroxy-anti-3,3a-epoxy-1,2,3, 3a-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-3,3a-DE) and trans-6,7-dihydroxy-anti-8,9-epoxy-6,7,8, 9-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-8,9-DE), were evaluated previously in mice [Amin, S., et al. (1995) Carcinogenesis 16, 2813-2817]. C[def]C-3,3a-DE was the more active inducer of lung tumors and elicited twice as many tumors as C[def]C-8,9-DE. In this study, the route of metabolism of C[def]C to DNA-reactive metabolites in the human mammary carcinoma cell line (MCF-7) was investigated using the 32P-postlabeling assay. The results show that metabolic activation to DNA-binding species proceeds through the formation of both trans-1,2-dihydrodiol and trans-6,7-dihydrodiol metabolites of C[def]C. At a 1 microM dose, adducts from the methylene-bridged (C[def]C-3,3a-DE) and bay region (C[def]C-8,9-DE) dihydrodiol epoxides were detected in comparable amounts. In contrast, the majority of the postlabeled adducts recovered from cells exposed to a 10 microM dose were derived from the bay region dihydrodiol epoxide, C[def]C-8,9-DE. Using markers from reactions of the dihydrodiol epoxides with deoxyguanosine 3'-phosphate and deoxyadenosine 3'-phosphate, it was shown that the major radioactive spots formed with both anti-C[def]C-3,3a-DE and anti-C[def]C-8,9-DE chromatographed with deoxyguanosine adduct markers. Thus, the human cells used in these studies can activate C[def]C to carcinogenic metabolites.

Animals↗
PubMed1985

The formation of 9-hydroxychrysene-1,2-diol as an intermediate in the metabolic activation of chrysene.

9-Hydroxy-trans-1,2-dihydro-1,2-dihydroxychrysene (9-hydroxychrysene-1,2-diol), which may be the triol involved in the formation of a chrysene triol-epoxide-DNA adduct in mouse skin, was not detected when chrysene was incubated with rat-liver microsomal preparations. In separate experiments an excess of synthetic 9-hydroxychrysene-1,2-diol was added during the incubation of 3H-labelled chrysene with rat-liver microsomes and was then re-isolated. The triol was found to contain a radioactive product that had chromatographic properties identical to those of 9-hydroxychrysene-1,2-diol when examined by reverse-phase h.p.l.c., both before and after acetylation, by normal-phase h.p.l.c. and by t.l.c. both before and after oxidation. When treated with m-chloroperoxybenzoic acid, the synthetic 9-hydroxychrysene-1,2-diol formed products that possessed alkylating activity and that reacted with DNA in vitro. Examination of the triol-epoxides produced by oxidation of a mixture of synthetic and metabolic 9-hydroxychrysene-1,2-diol by t.l.c. suggested that the anti-isomer was formed.

Animals↗
PubMed1986

Mutagenic potential of DNA adducts formed by diol-epoxides, triol-epoxides and the K-region epoxide of chrysene in mammalian cells.

The syn- and anti-isomers of chrysene-1,2-diol-3,4-oxide (syn-diol-epoxide and anti-diol-epoxide) and of 9-hydroxychrysene-1,2-diol-3,4-oxide (syn-triol-epoxide and anti-triol-epoxide), and chrysene-5,6-oxide, the K-region epoxide, were tested for their ability to induce 6-thioguanine-resistant mutants in V79 Chinese hamster cells. The levels of DNA adducts formed by each compound in the V79 cells were determined by 32P-post-labelling analysis. The most potent mutagen, in terms of the mutation frequency/nmol compound administered, was the anti-triol-epoxide, which was 1.7 times as active as the anti-diol-epoxide. The anti-diol-epoxide was approximately 10 times more active than both the syn-triol-epoxide and the syn-diol-epoxide, which in turn were several times more active than the K-region epoxide. However, when the results were expressed as mutations/pmol total adducts formed, the anti-triol-epoxide and anti-diol-epoxide were shown to be of similar potency and approximately twice as active as the other three compounds. Thus differences in the conformation of adducts formed with DNA by syn- and anti-isomers may be responsible for their different mutagenic potentials; the presence of a phenolic OH-group at the 9-position of a chrysene-1,2-diol-3,4-oxide appears to increase its chemical reactivity.

Cell Line↗
PubMed1988

Comparative tumor-initiating activity of methylene-bridged and bay-region methylated derivatives of benz[a]anthracene and chrysene.

Polycyclic aromatic hydrocarbons (PAHs) with a methylene-bridge spanning the bay region are often detected in higher concentrations in the environment than PAHs which have a bay-region methyl substituent. The tumor-initiating activity of methylene-bridged bay-region derivatives of chrysene and benz[a]anthracene was evaluated on the skin of female CD-1 mice. 4,5-Methylenechrysene elicited twice as many tumors as chrysene at each of the doses tested. At total initiation doses of 1.5, 0.5 and 0.15 mumol/mouse 4,5-methylenechrysene gave rise to 8.5, 6.8 and 1.1 tumors/animal respectively. There was a 100% incidence of tumor-bearing mice at the two higher doses and a 65% incidence at the lowest dose. This methylene-bridged hydrocarbon was less tumorigenic than 5-methylchrysene at each dose tested. Animals treated with 1,12-methylenebenz[a]anthracene developed 7.6, 4.9 and 1.6 tumors/animal at total initiating doses of 4.0, 2.0 and 0.5 mumol/mouse. The incidence of tumor-bearing mice was 90% at the higher doses and 75% at the lowest dose tested. 12-Methylbenz[a]anthracene was more tumorigenic than the methylene-bridged derivative at each dose. The keto-derivative of 1,12-methylenebenz[a]anthracene did not display significant (P greater than 0.05) tumor-initiating activity at these dose levels. Results from these bioassays indicate that methylene-bridged bay-region derivatives of chrysene and benz[a]anthracene contribute to the overall genotoxicity of environmentally occurring PAHs.

Animals↗