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PubMed1989

Lipoxygenase-catalyzed epoxidation of benzo(a)pyrene-7,8-dihydrodiol.

Metabolism of resolved radioactive stereoisomer, [14C](+)-benzo-(a)pyrene-trans-7,8-dihydrodiol by highly purified soybean lipoxygenase plus linoleic acid was investigated. Trans-anti-7,8,9,10-tetrahydrotetrol, the product of hydrolytic breakdown of ultimate mutagenic benzo(a)pyrene-anti-7,8-dihydrodiol,9,10-epoxide, was detected as a major metabolite. The epoxidation, depended on the enzyme concentration and was inhibited by nordihydroguaiaretic acid. This study provides evidence on the ability of lipoxygenase to catalyze the epoxidation of benzo(a)pyrene-7,8-dihydrodiol.

Chromatography, High Pressure Liquid↗

PubMed1977

Benzo(a)pyrene metabolism in mouse epidermis. Analysis by high pressure liquid chromatography and DNA binding.

Mouse epidermal homogenates contain an inducible aryl hydrocarbon hydroxylase (AHH) complex that catalyzes the formation of benzo(a)pyrene-7,8-dihydrodiol from benzo(a)pyrene (BP) as assessed by high pressure liquid chromatography (HPLC). 5,6-Benzoflavone (5,6-BF), 7,8-benzoflavone (7,8-BF) and 17-beta-estradiol decreased and butylated hydroxytoluene (BHT) enhanced oxidative metabolism of BP when added in vitro. Epoxide hydrase activity (hydration of benzo(a)pyrene-4,5-epoxide) (BP-4,5-epoxide) was enhanced by 17-beta-estradiol, 5,6-BF, and 7,8-BF. BHT exhibited no significant effect and 1,2-epoxy-3,3,3-trichloropropane (TCPO) inhibited hydrase activity. The capacity of epidermal homogenates to catalyze the covalent binding of BP to DNA indicated that addition of both 5,6-BF and 7,8-BF decreased binding. BHT and TCPO did not significantly affect DNA-binding.

Animals↗

PubMed1977

Effect of various chemicals on the metabolism of benzo(a)pyrene by cultured rat colon.

The effect of various co- and anti-carcinogens of colon carcinogenesis on the metabolism of benzo(a)pyrene (BP) in cultured rat colon is reported. Rat colon enzymatically converted BP into metabolites which bind to cellular macromolecules i.e., DNA and protein. Activity of aryl hydrocarbon hydroxylase (AHH) activity and binding levels of BP to macromolecules were higher in the descending colon when compared to other segments. The major metabolites of BP, extractable with ethylacetate, were quinones, tetrols, 7,8-diol and a peak containing 9,10-dihydroxy-9,10-dihydrobenzo(a)pyrene and 7,8,9-trihydroxy-7,8-dihydrobenzo(a)pyrene. The binding levels of BP to DNA and protein in the explant was lowered by co-incubation with 7,8-benzoflavone (7,8-BF) (3.6 and 18.0 micron), a known inhibitor of AHH, and with disulfiram (100 micron), an anti-oxidant. The absence of vitamin A in the media also resulted in a lower level of BP binding to DNA and protein and in lower activity of AHH. Pretreatment with known inducers of AHH such as phenobarbital (PB) or benz(a)anthracene (BA), did not have any significant effect on the binding levels of BP to DNA or on the AHH activity. Of the bile acids investigated only taurodeoxycholic acid significantly increased the binding level of BP to DNA.

Animals↗

PubMed1979

Metabolism and covalent binding of benzo[alpha]pyrene in human peripheral lung.

Short-term organ cultures of peripheral lung from lung cancer patients metabolise benzo[alpha]pyrene to ethylacetate-soluble metabolites, which covalently bind to tissue macromolecules. The nature and quantities of metabolites formed and the extent of covalent binding are dependent upon the time of incubation, the substrate concentration and interindividual variability in the metabolic activity of the lung. Individuals whose lungs rapidly metabolise the carcinogen exhibit more extensive further metabolism of primary metabolites and higher levels of covalent binding. Certain striking differences in the relative retention in the tissue or release into the extra-cellular medium of different metabolites have been found as illustrated by the observation that the ratio of 7,8-dihydro-7,8-dihydroxybenzo[alpha]-pyrene to 9,10-dihydro-9,10-dihydroxybenzo[alpha]pyrene was always significantly higher in the tissue than in the extracellular medium.

Acetates↗

PubMed1982

Chemical and enzymatic oxidation of alkylated benzo[a]pyrenes.

The chemical and enzymatic oxidations of 6-, 7- and 10-methylbenzo[a]-pyrenes, 6,10- and 7,10-dimethylbenzo[a]pyrenes and benzo[a]pyrene (BP) itself have been investigated to study the effects of alkyl substitution on the pathways of oxidation. The chemical oxidizing systems employed were Fenton's reagent (FeSO4/H2O2); trifluoroacetic acid-hydrogen peroxide (TFA/H2O2); thallium tristrifluoracetate in trifluoroacetic acid (TTFA/TFA) and H2SO4. The enzymatic systems were horseradish peroxidase (HRP/H2O2) and rat liver microsomes. The oxidations were investigated by electron paramagnetic resonance (EPR) spectroscopy to detect radical intermediates and by high performance liquid chromatography (HPLC) to separate the products. All the compounds studied produced radicals, identified as cationic species, in both H2SO4 and TTFA/TFA. In addition the 7-methyl-, 10-methyl- and 7,10-dimethyl-BP's produced 6-oxy radicals in some or all of the remaining oxidizing systems. Both chemically and enzymatically these same three compounds were observed to produce quinones as stable products. Microsomal oxidations gave the broadest range of products exhibiting HPLC peaks in the diol, quinone and phenol regions of the chromatograms, however, there were considerable differences between products from the individual derivatives and those from the parent molecule. 6-Methyl and 6,10-dimethyl-BP's showed no evidence of oxy radical intermediates or quinones under any set of conditions, the 6-substituent effectively blocking this oxidation pathway. The observations are consistent with the expected effects of alkyl substituents at particular positions and indicate that studies such as this one are potentially useful in better understanding oxidation and possible activation pathways of polycyclic aromatic hydrocarbons.

Alkylation↗

PubMed1985

Absolute configuration of trans-7,8-dihydroxy-7,8-dihydro-7-methylbenzo[a]pyrene enantiomer and the unusual quasidiequatorial conformation of the diacetate and dimenthoxyacetate derivatives.

The enantiomers of trans-7,8-dihydroxy-7,8-dihydro-7-methylbenzo[a]pyrene (7-MBaP 7,8-dihydrodiol) and of trans-7,8-dihydroxy-7,8,9,10-tetrahydro-7-methylbenzo[a]pyrene (7-MBaP 7,8-tetrahydrodiol) were directly resolved by high-performance liquid chromatography (HPLC) using a commercially available column packed with an (R)-N-(3,5-dinitrobenzoyl)-phenylglycine derivative of gamma-aminopropylsilanized silica. The absolute configurations of the resolved enantiomers were determined by the exciton chirality method. Circular dichroism (CD) spectral analysis of the quasidiequatorial benzo[a]pyrene 7R,8R-dihydrodiol enantiomer and its diacetate and dimenthoxyacetate derivatives indicated conformational changes were induced upon derivatization. However, the characteristic CD Cotton effects of the quasidiequatorial 7-MBaP 7,8-dihydrodiol and its diacetate and dimenthoxyacetate derivatives were similar indicating that the conformation of 7-MBaP trans-7,8-dihydrodiol was not altered upon derivatization. Proton nuclear magnetic resonance (NMR) spectral analyses confirmed that 7-MBaP 7,8-dihydrodiol, its diacetate and dimenthoxyacetate derivatives all have quasidiequatorial conformations. The results indicate that the methyl substituent of 7-MBaP 7,8-dihydrodiol maintains a quasiaxial position regardless of the size of the acyl derivatives linked to the hydroxyl groups.

Adsorption↗

PubMed1977

Mutagenicity of isomeric diol-epoxides of benzo[a]pyrene and benz[a]anthracene in S. typhimurium TA98 and TA100 and in V79 Chinese hamster cells.

Pairs of isomeric vicinal diol-epoxides derived from benzo[a]pyrene 7,8- and 9,10-dihydrodiols and from benz[a]anthracene 8,9-dihydrodiol were tested for their abilities to revert salmonella typhimurium strains TA98 and TA100 to histidine prototrophy and to induce the formation of 8-azaguanine- or of ouabain-resistant V79 Chinese hamster cells. All six diol-epoxides were active in both bacterial strains, but 7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (the syn isomer) was considerably more mutagenic than the other diol-epoxides. Within the three pairs of stereo-isomeric diol-epoxides, the ratio of the mutagenic potencies of the syn over the related anti isomers varied bothwith the chemical structure and the bacterial strain. The half lives of hydration of these diol-epoxides at pH 7.4 were inversely related to their mutagenic potencies in bacteria. In V79 cells, the two benzo[a]pyrene 7,8-diol 9,10-oxides were mutagenic and the anti isomer was more active than the syn isomer; a reversed order of mutagenic potency with these stereo isomers was observed in S. typhimurium. The other four diol-epoxides were non-mutagenic in V79 cells at the concentrations tested.

Benz(a)Anthracenes↗

PubMed1978

Excision repair by human fibroblasts of DNA damaged by r-7, t-8-dihyroxy-t-9,10-oxy-7,8,9,10- tetrahydrobenzo(a)pyrene.

Benzo(a)pyrene diol-epoxide I (r-7,t-8,dihydroxy-t-9,10 oxy-7,8,9,10 tetrahydrobenzo(a)pyrene) was used to treat either human adenovirus 5 or cultures of human fibroblasts. The survival of diol-epoxide I treated adenovirus was greater when infecting fibroblasts from normal persons than when infecting fibroblasts from patients with xeroderma pigmentosum (XP). One diol-epoxide I molecule bound per viral genome correlated with one lethal hit as measured using XP fibroblasts. Normal fibroblasts blocked in semi-conservative DNA synthesis incorporated into their DNA more [3H]thymidine in response to diol-epoxide I treatment than did XP fibroblasts, and also excised more diol-epoxide I from their DNA. All of the effects described above were similar to those obtained when the inactivating agent was ultraviolet light rather than benzo(a)pyrene diol-epoxide I.

Adenoviruses, Human↗

PubMed1979

The effect of caffeine on cytotoxicity, mutagenesis, and sister-chromatid exchanges in Chinese hamster cells treated with dihydrodiol epoxide derivatives of benzo[a]pyrene.

The effect of caffeine on Chinese hamster V79 cells after treatment with the highly mutagenic (+/-)-7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-7,8,9,10-tetrahydrobenzo[a]pyrene, and the weaker mutagen (+/-)-7 beta,8 alpha-dihydroxy-9 beta,10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, B[a]P-deiol-epoxide II, was studied at both the biological and molecular levels. Caffeine, at nontoxic dose levels, caused a synergistic reduction in cell survival induced by both isomers and also inhibited DNA elongation as measured by alkaline sucrose-gradient analysis of nascent DNA. However, caffeine did not affect the induction of either ouabain-resistant mutants or sister-chromatid exchanges by either isomer. These results suggest that enhanced cell killing by caffeine in benzo[a]pyrene-diol-epoxide treated V79 cells may be related to caffeine's inhibitory effect on DNA elongation. However, inhibition of DNA elongation by caffeine did not influence the resulting induced levels of mutagenesis or sister-chromatid exchanges.

Animals↗

PubMed1979

Mutagenic effects of benzo[a]pyrene after metabolic activation by hepatic 9000 g supernatants or intact hepatocytes.

The activating capacities of isolated rat hepatocytes and 9000 g supernatant from these cells with respect to the mutagenic effect of benzo[a]pyrene on Salmonella typhimurium TA100 were investigated. No mutagenicity of benzo[a]pyrene was found with the cell-mediated assay, unless the hepatocytes were disrupted after pre-incubation with benzo[a]pyrene or the intracellular glutathione content was reduced. It is suggested that a retention of active metabolites and an effective detoxication may account for the absence of mutagenic response.

Benzopyrenes↗

PubMed1979

Effects of the hepatic S9 fraction from aroclor-1254-treated rats on the mutagenicity of benzo[alpha]pyrene and 2-aminoanthracene in the Salmonella/microsome assay.

The mutagenicity of benzo[alpha]pyrene and 2-aminoanthracene for Salmonella typhimurium TA98 in the plate-incorporation test was studied using liver S9 from untreated and aroclor-1254-treated rats. The induction of liver S9 protein, arylhydrocarbon hydroxylase (AHH), and cytochrome P448/450 was followed with time. There was no change in protein concentrations with induction; AHH and cytochrome levels were increased at 1, 3, 5 and 7 days post Aroclor treatment. Benzo[alpha]pyrene mutagenicity was enhanced with Aroclor treatment while 2-aminoanthracene mutagenicity was depressed. The benzo[alpha]pyrene mutagenicity showed a positive correlation with the levels of AHH and cytochrome on the plate; 2-aminoanthracene showed a negative correlation with activity in induced samples.

Animals↗

PubMed1980

The induction of sister-chromatid exchanges in Chinese hamster ovary cells by some epoxides and phenolic derivatives of benzo[a]pyrene.

The induction of sister-chromatid exchanges in Chinese hamster ovary cells by in vivo treatment with a number of epoxy and phenolic derivatives of the carcinogenic polycyclic hydrocarbon, benzo[a]pyrene, has been investigated. Of the 3 vicinal diol-epoxides tested the anti-isomer of the bay-region 7,8-dihydrodiol-9,10-epoxide was the most active since, when tested at a 10-fold lower concentration, it induced the same number of sister-chromatid exchanges as the corresponding syn-isomer. The anti-isomer of the non-bay-region 9,10-dihydrodiol-7,8-epoxide was much less active than either of the bay-region diolepoxides and its activity was comparable with those of the 2 simple oxides tested, the K-region 4,5- and the non-K-region 7,8-oxides, of benzo[a]pyrene. The 2 phenols tested, 3- and 4-hydroxybenzo[a]pyrene, were only slightly active in inducing sister-chromatid exchanges.

Animals↗

PubMed1986

Genotoxic activity of two furan analogues of benzo[a]pyrene and their 2-nitro derivatives.

We measured the genotoxic activities in two bacterial tests, the Salmonella/histidine assay (a reverse mutation assay) and the SOS Chromotest (an assay for SOS induction in E. coli), of two pairs of isomeric furan analogues of benzo[a]pyrene: pyreno[1,2-b]furan (R7490) and pyreno[2,1-b]furan (R7692) and their 2-nitro derivatives, 8-nitro-pyreno[1,2-b]furan (R7489) and 8-nitro-pyreno[2,1-b]furan (R7691). We found that: For all 4 compounds, the responses were correlated in the two tests. For the 2-nitro derivatives, R7489 and R7691, the responses were extremely high, reaching SOS-inducing potencies of 5.2 X 10(3) and 10(5)/nmole in the SOS Chromotest and mutagenic potencies of 6.3 X 10(4) and 3.7 X 10(7) revertants/nmole in the Salmonella/histidine assay (strain TA98), respectively; the responses were only slightly decreased in nitroreductase-deficient strains. The responses to the two pyrenofurans were increased in the presence of an "activating mixture" but were still lower than that to benzo[a]pyrene. In contrast to benzo[a]pyrene and pyreno[2,1-b]furan (R7692), pyreno[1,2-b]furan (R7490) also gave a response in the absence of an "activating mixture". (5) Compounds with the oxygen heteroatom within the "bay region" gave lower responses than their isomers with the oxygen heteroatom outside the "bay region".

Animals↗

PubMedDate not supplied

Relationships between structure of nitrated arenes and their mutagenicity in Salmonella typhimurium; 2- and 2,7-nitro substituted fluorene, phenanthrene and pyrene.

In order to elucidate the mechanisms of mutagenic activation of nitroarenes, we studied the relationships between the mutagenic potency and chemical structure of 2-nitro- and 2,7-dinitro-arenes including nitrated fluorene (Fl), dihydrophenanthrene (DHPh), phenanthrene (Ph), tetrahydropyrene (THPy), dihydropyrene (DHPy) and pyrene (Py) together with 9-NO2-Ph, 1-NO2-Py and 1.3-diNO2-Py. The mutagenicity tests were carried out on Salmonella typhimurium TA98, TA98NR and TA98/1,8-DNP6 in the absence of S9 mix. The order of mutability of mononitro- and dinitro-arenes in TA98 is as given below: 2-NO2-THPy less than 2-NO2-Fl less than 2-NO2-DHPh less than 9-NO2-Ph less than 2-NO2-Ph less than 2-NO2-DHPy less than 1-NO2-Py less than 2-NO2-Py, and 2,7-diNO2-DHPh less than 2,7-diNO2-Fl less than 2,7-diNO2-THPy less than 2,7-diNO2-Ph less than 2,7-diNO2-DHPy less than 2,7-diNO2-Py less than 1,3-diNO2-Py. 9-NO2-Ph and 1-NO2-Py, which have been detected in environmental samples, are not as potent mutagens as 2-nitrated phenanthrene and pyrene, respectively. 2-NO2THPy (37.7 rev/nmole) was a weak mutagen, but 2,7-diNO2-THPy (3197 rev/nmole) was as potent a mutagen as 2,7-diNO2 (3925 rev/nmole). Tetrahydropyrene has a twisted form in its structure. 1,3-diNO2-Py (99660 rev/nmole) was more mutagenic than 2,7-diNO2-Py (37960.0 rev/nmole), and their mutagenicities were correlated with the behavior of the K-band in their UV spectra by the introduction of nitro groups on pyrene.

Biotransformation↗

PubMed1980

Acute tobacco smoke exposure alters the profile of metabolites produced from benzo[alpha]pyrene by the isolated perfused rabbit lung.

The influence of whole tobacco smoke or the gas phase from smoke on the metabolism of [14C]benzo[alpha]pyrene was examined using the isolated perfused rabbit lung model. Fresh whole tobacco smoke mixed with the air ventilating the perfused lung produces an immediate and dose related decrease in the metabolism of [14C]benzo[alpha]pyrene. The metabolites of [14C]benzo[alpha]pyrene, diols, quinones, phenols and polar compounds are generally decreased in quantity. At the lowest level of smoke administered the percentage of BP-7,8-diol produced is increased dramatically. The results indicate that one of the factors contributing to the carcinogenicity of tobacco smoke may be its ability to produce an immediate alteration in the pulmonary metabolism of polycyclic aromatic hydrocarbons.

Animals↗

PubMed1980

Sensitivity of Syrian golden hamster fetal lung cells to benzo[a]pyrene and other polycyclic hydrocarbons in vitro.

Dose responses were compared of cultured fetal Syrian golden hamster lung cells (FSHL) to the toxic and transforming effects of benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[B]F), benz[a]anthracene (B[a]A, indeno[1,2,3-c,d]pyrene (I[c,d]P), benzo[k]fluoranthene (B[k]F) and benzo[e]pyrene (B[e]P). Effort was first given to standardising the techniques for evaluating B[a]P dose-responses. These polycyclic aromatic hydrocarbons (PAH) were then tested at concentrations of up to 1 microgram/ml, and only B[a]P showed clear cytotoxicity. The transforming effects of B[b]F, B[a]A and I[c,d]P at 1 microgram/ml appeared comparable to those of B[a]P at 0.05 microgram/ml.

Animals↗

PubMed1982

Induction of benzo[a]pyrene hydroxylase in skin and liver by cutaneous application of jute batching oil.

Skin painting with 30 microliter of jute batching oil (JBO) for 8 days resulted in increased gross liver weight, microsomal protein content and benzo[alpha]pyrene hydroxylase activity of liver. Skin benzo[alpha]pyrene hydroxylase activity at the treated site increased by 10-fold. An investigation of cytochrome pigment status in liver and skin of treated animals showed a specific increase in P-448 level in both tissues. Single skin applications of JBO elevated the level of skin and liver benzo[alpha]pyrene hydroxylase activity to its maximum after 1 day and 2 days, respectively, which, in absence of further treatment with mineral oil, declined gradually to normal levels in due course. The results suggest that single or multiple cutaneous exposure(s) with JBO can increase carcinogen metabolising status of skin and liver which may be one of the causative factors for the tumorigenic effects of JBO in skin.

Administration, Topical↗

PubMed1979

Patterns of benzo[alpha]pyrene metabolism in normal human pulmonary alveolar macrophages.

Pulmonary alveolar macrophages (PAMs) obtained by bronchopulmonary lavage from 6 normal non-smoking volunteers were incubated with [3H]-benzo[alpha]pyrene to ascertain the normal metabolism and conjugation of polycyclic aromatic hydrocarbons. Through the use of a crude glucuronidase preparation, both glucuronic acid and sulfate conjugates were examined. Phenols and quinones were identified by high-pressure liquid chromatography as the principal free metabolites formed during 1 h incubation with benzanthracene induced PAMs. In addition, phenols and quinones were major substrates utilized by these cells for conjugation during the incubation period. The ranges of benzo[alpha]pyrene metabolites produced by PAMs from non-smokers were compiled and the variation in production as well as detoxification of proximate carcinogenic benzo[alpha]pyrene metabolites are presented.

Adult↗