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At least 19 recordsLinked to original sources

PubMed1976

Enzymatic conversion of benzo(a)pyrene leading predominantly to the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene through a single enantiomer of r-7, t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene.

Benzo(a)pyrene is metabolically and stereospecifically converted by mixed-function oxidases of rat liver microsomes and epoxide hydratase (glycol hydro-lyase (epoxide-forming), EC 4.2.1.63)to the single enantiomer (-)r-7,t-8-dihydroxy-7,8-dihydrobenzol (A) pyrene. This enantiomer is further metabolized stereoselectively by the mixed-function oxidases to predominantly the diol-epoxide, r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzol(a)pyrene in which the 7-hydroxyl and the 9,10-epoxide are trans. Other unidentified metabolites are also formed from the r-7,t-8-dihydroxy-7,8-dihydrobenzo(a)pyrene. Racemic r-7,t-8-dihydroxy-7,8-dihydrobenzo(a)-pyrene is converted metabolically to both r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. The diol-epoxides are unstable in aqueous medium, and their identification and characterization as r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene were accomplished by the identity of their tetrahydroxytetrahydrobenzo(a)pyrenes hydrolysis products with those of the authentic synthetic compounds with respect to mobility on high-pressure liquid chromatography and mass and ultraviolet absorption spectral analysis. The diol-epoxides were also reduced in the presence of NADPH to distinct trihydroxypentahydrobenzo(a)pyrenes. Since the synthetic racemic r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene is very highly mutagenic in mammalian cells, we suggest that it is the metabolically formed diol-epoxide that may be an ultimate carcinogenic form of benzo(a)pyrene.

Animals↗

PubMed1975

[Studies on the metabolism of benzo(a)pyren in alveolar-macrophages. I. Uptake of benzo(a)pyrene and induction of benzo(a)pyrene hydroxylase (author's transl)].

Alveolar macrophages play a significant role in the elimination of inhaled foreign compounds and particles from the lung. The question arises, if alveolar macrophages participate in the detoxification or activation of environmental carcinogenic compounds. In the first communication on this subject we describe experiments concerning the uptake of benzo(a)pyrene and the activity of the metobolizing enzymes. The alveolar macrophages are obtained by lung lavage from guinea pigs (Fig. 1,2,3). The cells are grown in monolayers in petri dishes or on the surface of cover slips or glass-vials. The uptake of benzo(a)pyrene in alveolar macrophages is measured by a microfluorimetric method in single cells and by using labelled substrate. The results obtained by both methods indicate that the uptake is terminated between 1-2 h (Fig. 4, 5). The kinetics of uptake and elimination (Fig. 8, 9). are influenced by the concentration of serum (Fig. 6) and benzo(a) pyrene (Fig. 7) in the medium. Two mechanism for the uptake in the alveolar macrophages are discussed: diffusion and pinocytose. The activity of the metabolizing enzymes (benzo(a)pyrene hydroxylase, aryl hydrocarbon hydroxylase)increases during incubation with benzo(a)pyrene (Fig. 10, 11) and is dependant on the concentration of benzo(a)pyrene in the growth medium (Fig. 12). The enzyme activity is inducible also by other polycyclic hydrocarbons (Tab. 1). The induction is inhibited by actinomycin D and cycloheximid (Tab. 2). The activity of the enzymes in guinea pig alveolar macrophages is comparable to the activity in leucocytes and alveolar-macrophages from humans (Tab. 3, 4).

Animals↗

PubMed1991

Metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol in human mammary epithelial cells: feedback inhibition by 7-hydroxybenzo[a]pyrene.

The metabolism of benzo[a]pyrene (B[a]P) and (-)-transbenzo[a]pyrene-7,8-dihydrodiol (B[a]P-diol) was compared in human mammary epithelial cells (HMEC) grown in serum-free medium, MCDB-170. Conversion of B[a]P-diol to the carcinogen (+)-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide (BPDE), as measured by analysis of their tetraol hydrolysis products, occurred much more efficiently in cultures incubated with [3H]B[a]P-diol than in cultures incubated with [3H]B[a]P. In cultures pretreated with unlabeled B[a]P (24 h, 400 nM), the conversion of [3H]-B[a]P-diol to [3H]tetraols is inhibited 49%, while the conversion of [3H]B[a]P to [3H]B[a]P-diol- is not affected. These observations led to the identification of a major B[a]P-derived metabolite as 7-hydroxybenzo[a]pyrene (B[a]P-7-ol), which was found to be an extremely potent and selective inhibitor of the conversion of B[a]P-diol to BPDE, with a KI estimated at 3-12 nM. Thus B[a]P activation in HMEC appears to be significantly limited by a feedback inhibition pathway induced by B[a]P-7-ol. The potency and selectivity of the B[a]P-7-ol-induced inhibition suggests that the diol to diolepoxide conversion is affected by a selective oxygenase in HMEC, rather than a non-enzymatic, peroxy radical-induced mechanism. B[a]P-7-ol should prove to be a valuable tool in the study of B[a]P carcinogenesis.

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

PubMed1979

Carcinogenicity and polarographic behaviour of dibenzo[a,h]pyrene, 4,11-diazadibenzo[a,h]pyrene and 7,14-diazadibenzo[a,h]pyrene.

In a simultaneous test of carcinogenicity the writers have studied the activities of dibenzo[a,h]pyrene (I), 4,11-diazadibenzo[a,h]pyrene (II) and 7,14-diazadibenzo[a,h]pyrene (III). These compounds were dispersed in paraffin disks and subcutaneously implanted in rats. Each experimental group consisted of 30 animals. The number of sarcomas induced by (I) and (II) was 23 and 16 respectively. The compound (III) has proved wholly inactive. Tumorigenicity of (I) and (II) was found to be proportional to their electron donation and inversely proportional to their electron acceptance in the performed polarographic test. Inactivity of (III) is being discussed from the aspect of molecular geometry.

Animals↗

PubMed1992

The time-dependent increase in the binding of benzo[a]pyrene to DNA through (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide in primary rat hepatocyte cultures results from induction of cytochrome P450IA1 by benzo[a]pyrene treatment.

The proportion and amount of benzo[a]pyrene (B[a]P) that binds to DNA through the carcinogenic (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide [(+)-anti-BPDE] increases with time of exposure to B[a]P in cell cultures derived from a number of species. Pretreatment of primary rat hepatocyte cultures for 12 h with 1 microgram B[a]P/ml medium increased the subsequent metabolism of [3H]B[a]P by 47% and [3H]B[a]P-DNA binding by 53% compared with acetone-pretreated hepatocytes. The amount of (+)-anti-BPDE bound to DNA in the B[a]P-pretreated hepatocytes increased 175%. B[a]P pretreatment also increased DNA-binding 2-fold in hepatocytes treated with [3H]7,8-dihydroxy-7,8-dihydro-B[a]P but had no effect on DNA binding in cells treated with anti-B[a]P-7,8-diol-9,10-epoxide. Western blotting showed that cytochrome P450IA1, which was not detectable prior to B[a]P treatment, was selectively increased by B[a]P treatment. A monoclonal antibody that specifically inhibits cytochrome P450IA1 reduced the binding of B[a]P to DNA by greater than 90% in microsomal preparations from B[a]P-pretreated hepatocytes. These results indicate that the time-dependent increase in the formation of (+)-anti-BPDE-DNA adducts results from an increase in the amount and proportion of B[a]P metabolized to this ultimate carcinogen by P450IA1 that is induced by the B[a]P treatment. The importance of P450IA1 induction by the B[a]P for its activation to this ultimate carcinogenic metabolite suggests that long-term exposure of cells to B[a]P could result in activation of a higher proportion of the B[a]P to the carcinogenic (+)-anti-BPDE.

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

PubMed1991

Comparative dose-response tumorigenicity studies of dibenzo[alpha,l]pyrene versus 7,12-dimethylbenz[alpha]anthracene, benzo[alpha]pyrene and two dibenzo[alpha,l]pyrene dihydrodiols in mouse skin and rat mammary gland.

Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a,l]pyrene (DB[a,l]P) versus 7,12-dimethyl-benz[a]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzo[a]pyrene (B[a]P), the most potent recognized carcinogenic environmental PAH; DB[a,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DB[a,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DB[a,l]P and B[a]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DB[a,l]P at all doses induced significantly more tumors than B[a]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DB[a,l]P was compared in the skin of female SENCAR mice to that of DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol and DB[a,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DB[a,l]P, DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol or DB[a,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DB[a,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DB[a,l]P was by far a much stronger tumor initiator than B[a]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DB[a,l]P, DMBA or B[a]P by intramammillary injection at eight teats. DB[a,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. B[a]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DB[a,l]P is the strongest PAH carcinogen ever tested.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1978

Comparative tumor initiating activity of 10-methylbenzo-[a]pyrene, 7,10-dimethylbenzo[a]pyrene and benzo[a]pyrene.

The tumor initiating activity on mouse skin of benzo[a]pyrene (BaP), 7,10-dimethylBaP, and 10-methylBaP was determined. Each compound was tested at initiating doses of 50 microgram and 100 microgram with promotion by application 3 times weekly of 2.5 microgram tetradecanoylphorbol acetate. BaP induced tumors in 40% (100 microgram) and 25% (50 microgram) of the animals. No tumors were observed in either group treated with 7,10-dimethylBaP. In the groups treated with 10-methyl-Bap, the incidence of tumor bearing animals was 20% at both doses. These results and the results of previous studies on other methylated BaP derivatives suggest that the mechanism of activation of these compounds is similar to that observed for the parent hydrocarbon and probably involves formation of an angular ring diol-epoxide or epoxide.

Animals↗

PubMed1976

Metabolism of benzo(a)pyrene and benzo (a)pyrene derivatives to mutagenic products by highly purified hepatic microsomal enzymes.

A highly purified and reconstituted hepatic microsomal monooxygenase system, completely free of epoxide hydrase and consisting of cytochrome P-448 from 3-methylcholanthrene-treated rats, NADPH-cytochrome c reductase, phosphatidylcholine, and NADPH, metabolizes benzo (a)pyrene to products highly mutagenic in strains TA 98 and TA 1538 of Salmonella typhimurium. The formation of mutagenic metabolites is completely dependent on the presence of benzo (a)pyrene, NADPH, NADPH-cytochrome c reductase, and cytochrome P-448 and is partially dependent on phosphatidylcholine. Mutation frequency in both strains is linearly related to amount of cytochrome P-448 and to time of incubation. Highly purified cytochrome P-450 from phenobarbital-treated rats is relatively poor in catalyzing the formation of mutagenic metabolites from benzo (a)pyrene. Addition of 7.5 to 75 units of highly purified epoxide hydrase to the cytochrome P-448-dependent monooxygenase system decreases the number of mutations by approximately 50% and30% in strains TA 1538 and TA 98, respectively. Additional amounts of epoxide hydrase (300 units) fail to further suppress mutations, indicating that at least some, but probably not all, of the mutagenic metabolites of benzo (a)pyrene are arene oxides. In the absence of a monooxygenase system, mutations induced by benzo (a)pyrene 4,5-oxide are readily quenched by epoxide hydrase, whereas mutations induced by a diol epoxide metabolite of benzo (a)pyrene [(+/-)-7 beta, 8alpha-dihydroxy-9beta, 10beta-epoxy-7,8,9,10-tetrahydrobenzo (a)pyrene] are not. Several known and potential phenolic and dihydrodiol metabolites of benzo (a)pyrene are metabolized to products mutagenic in the Salmonella. The number of mutations induced per nmol of hemoprotein is approximately 3- to 4-fold higher when trans-7,8-dihydroxy-7,8-dihydrobenzo (a)pyrene replaces benzo (a)pyrene as a substrate for the cytochrome P-448-dependent monooxygenase system. Little or no mutagenic activity is observed with trans-dihydrodiols at positions 4,5, 9,10, or 11,12 of the hydrocarbon, either in the absence or presence of the active monooxygenase system. Of the 12 possible isomeric monophenols of benzo (a)-pyrene, only 6- and 12-hydroxybenzo (a)pyrene are moderately active bacterial mutagens; 1-, 2-, 3-, 6-, 9-, and 12-hydroxybenzo (a)pyrene are premutagens (i.e. metabolized to mutagenic products); and 4-, 5-, 7-, 8-, 10-, and 11-hydroxybenzo (a)pyrene have little or no mutagenic activity with or without further oxidative metabolism. Benzo (a)pyrene 7,8-oxide, a carcinogen on mouse skin, is weakly mutagenic but can be further metabolized to a highly active bacterial mutagen(s), presumably diol epoxide(s), by a combination of epoxide hydrase and the cytochrome P-448 monooxygenase system. This is the first example of a direct role of epoxide hydrase in the metabolic activation of a chemical to a toxic product.

Animals↗

PubMed1991

Indigenous and enhanced mineralization of pyrene, benzo[a]pyrene, and carbazole in soils.

We studied the mineralization of pyrene, carbazole, and benzo[a]pyrene in soils obtained from three abandoned coal gasification plants in southern Illinois. The soils had different histories of past exposure to hydrocarbon contamination and different amounts of total organic carbon, microbial biomass, and microbial activity. Mineralization was measured by using serum bottle radiorespirometry. The levels of indigenous mineralization of 14C-labeled compounds ranged from 10 to 48% for pyrene, from undetectable to 46% for carbazole, and from undetectable to 25% for benzo[a]pyrene following long-term (greater than 180-day) incubations. Pyrene and carbazole were degraded with short or no lag periods in all soils, but benzo[a]pyrene mineralization occurred after a 28-day lag period. Mineralization was not dependent on high levels of microbial biomass and activity in the soils. Bacterial cultures that were capable of degrading pyrene and carbazole were isolated by enrichment, grown in pure culture, and reintroduced into soils. Reintroduction of a pyrene-degrading bacterium enhanced mineralization to a level of 55% within 2 days, compared with a level of 1% for the indigenous population. The carbazole degrader enhanced mineralization to a level of 45% after 7 days in a soil that showed little indigenous carbazole mineralization. The pyrene and carbazole degraders which we isolated were identified as a Mycobacterium sp. and a Xanthamonas sp., respectively. Our results indicated that mineralization of aromatic hydrocarbons can be significantly enhanced by reintroducing isolated polycyclic aromatic hydrocarbon-degrading bacteria.

Bacteria↗

PubMed1992

Linoleate-dependent co-oxygenation of benzo(a)pyrene and benzo(a)pyrene-7,8-dihydrodiol by rat cytosolic lipoxygenase.

1. Co-oxygenation of 14C-labelled benzo(a)pyrene and benzo(a)pyrene-7,8-dihydrodiol was studied in rat lung cytosol, using linoleic acid as a co-substrate. Covalently bound and soluble metabolites were quantified by radiometry and h.p.l.c., respectively. 2. The co-oxygenation resulted in the production of reactive metabolites capable of protein binding as well as a series of soluble derivatives. 3. Co-oxygenation of benzo(a)pyrene yielded primarily a significant amount of benzo(a)pyrene-6,12-dione while benzo(a)pyrene-7,8-dihydrodiol led to a significant amount of benzo(a)pyrene-trans-anti-tetrol. 4. Their production was abolished by addition of 25 microM of the lipoxygenase inhibitor and antioxidant NDGA. 5. It is postulated that the linoleic acid peroxyl radicals, formed by rat lung lipoxygenase, initiate the one-electron oxidation of benzo(a)pyrene to its quinones, and epoxidation of benzo(a)pyrene-7,8-diol to the ultimate carcinogenic benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide.

Animals↗

PubMed1976

Metabolism of benzo[a]pyrene: conversion of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to highly mutagenic 7,8-diol-9,10-epoxides.

Metabolites of (+/-)-trans 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene formed by a rat liver microsomes and by a highly purified monoxygenase system were analyzed by high-pressure liquid chromatography. Four stereoisomeric tetraols of 7,8,9,10-tetrahydrobenzo[a]pyrene, known solvolysis products of the two highly mutagenic stereoisomers of the 9,10-epoxide of the 7,8-dihydrodiol, were identified as products. The ratio of the two highly unstable diol epoxides formed (7 beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, diol epoxide 1; 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, diol epoxide 2) ranged from about 1.7 to 0.4. The diol epoxides are sufficiently reactive to alkylate phosphate buffer (pH 7.4) at 37 degrees. Microsomes, particularly those from control animals, formed a substantial amount of an additional metabolite that appears to be phenolic. In analogy to benzo[a]pyrene, the metabolism of the 7,8-dihydrodiol shows similar induction after pretreatment of rats with phenobarbital or 3-methylcholanthrene. Neither diol epoxide appears to be a substrate for epoxide hydrase based on the ratis of tetraols formed in the presence or absence of epoxide hydrase. In view of the known carcinogenicity of benzo[a]pyrene 7,8-oxide and 7,8-dihydrodiol and of the marked mutagenicity of the stereoisomeric diol epoxides, both of these diol epoxides qualify for consideration as "ultimate carcinogen(s)" of benzo[a]pyrene.

Animals↗

PubMed1976

(+/-)-7alpha,8beta-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)-pyrene is an intermediate in the metabolism and binding to DNA of benzo(a)pyrene.

The addition of borate buffer to the aqueous methanol used to elute hydrocarbon-deoxyribonucleoside derivatives from an LH 20 Sephadex column resulted in the separation of the products of reaction with DNA of the stereoisomers, (+/-)7alpha,8beta-dihydroxy-9alpha,10alpha-epoxy- and (+/-)-7alpha,8beta-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrenes, i.e., the syn- and anti-benzo(a)pyrene-diolepoxide, respecitvely. By this technique it was shown that the microsome-mediated binding to DNA of benzo(a)pyrene-7,8-dihydrodiol involved exclusively the anti-benzo(a)pyrene-diolepoxide. The benzo(a)pyrene binding to DNA that resulted on exposure of BHK21/C13 cells to this carcinogen was also shown to result predominantly by reaction of the anti-benzo(a)pyrene-diolepoxide. However, in this case other derivatives, including the syn-benzo(a)pyrene diolepoxide, might also be involved.

Animals↗

PubMed1976

Nonenzymatic reduction of benzo(a)pyrene diol-epoxides to trihydroxypentahydrobenzo(a)pyrenes by reduced nicotinamide adenine dinucleotide phosphate.

The diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene is a potent mutagen and possibly the ultimate carcinogenic form of benzo(a)pyrene. A (7/8,9)-trihydroxy-7,8,9,10,10-pentahydrobenzo(a)pyrene is formed from the diol-epoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydroxybenzo(a)pyrene by reduction with reduced nicotinamide adenine dinucleotide phosphate. Its formation is linear with reduced nicotinamide adenine dinucleotide phosphate concentration and does not require the presence of enzyme. A (7,9/8)-trihydroxy-7,8,9,10,10-pentahydrobenzo(a)pyrene is similarly formed from the diol-epoxide r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene by reduction with reduced nicotinamide adenine dinucleotide phosphate. The structures of the trihydroxypentahydrobenzo(a)pyrenes were established by their ultraviolet absorption and mass spectra and their reaction with potassium triacetylosmate.

Benzopyrenes↗

PubMed1991

Synthesis of a novel fluorinated benzo[a]pyrene: 4,5-difluorobenzo[a]pyrene.

The synthesis of 4,5-difluorobenzo[a]pyrene, as a fluorinated probe to investigate the involvement of the K-region in the further metabolic activation of benzo[a]pyrene metabolites, is described. Benzo[a]pyrene-4,5-dione obtained from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation of cis-4,5-dihydro-4,5-dihydroxybenzo[a]pyrene was fluorinated with dimethylaminosulfur trifluoride to give 4H,5H,4,4,5,5,-tetra-fluorobenzo[a]pyrene. Defluorination using lithium aluminum hydride in tetrahydrofuran gave 4,5,-difluorobenzo[a]pyrene.

Benzo(a)pyrene↗

PubMed1977