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PubMed1991

Determination of benzo[a]pyrene sulfate conjugates from benzo[a]pyrene-treated cells by continuous-flow fast atom bombardment mass spectrometry.

The level of certain water-soluble hydrocarbon conjugates, such as benzo[a]pyrene sulfates (BP-SO4), is a direct measure of carcinogenic polycyclic aromatic hydrocarbon metabolism and an indication of exposure. A new method, based on continuous-flow high-resolution fast atom bombardment mass spectrometry, has been developed for the analysis of BP-SO4 in the medium of cell cultures treated with benzo[a]pyrene. An organic solvent extract of medium from cultures of the human hepatoma cell line (HepG2) was fractionated by reversed-phase SEP-PAK chromatography and microbore high-performance liquid chromatography (HPLC). The HPLC fraction containing BP-SO4 was collected, dried, and injected into a stream of acetonitrile/water/glycerol that was continuously flowing to the tip of the sample probe which was being bombarded continuously by a beam of high-energy xenon atoms. Molecular anions of BP-SO4 (m/z 347) desorbed from the liquid were analyzed by a high-resolution (m/delta m 5000) mass spectrometer and recorded as a function of time. As little as 1.5 pg of BP-SO4 could be detected with a S/N ratio of 8. The mass spectrometer response was linear with respect to the quantity of BP-SO4 injected over the range from 15 to 625 pg. The results obtained with this method show that the HepG2 cultures metabolized 3% of the benzo[a]pyrene into the BP-SO4 conjugate in 24 h. This procedure, which was used to detect and quantify directly BP-SO4 in culture medium without the use of a radiolabeled precursor, should be generally applicable for analyses of sulfated conjugates resulting from the metabolism of different hydrocarbons.

Benzo(a)pyrene↗
PubMed1991

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

The metabolism of benzo[a]pyrene (B[a]P) and (-)-trans-benzo[a]pyrene-7,8-dihydrodiol [(-)-B[a]P-7,8-diol], a major putative proximate carcinogenic metabolite of B[a]P, was compared in freshly isolated hepatocytes from mirror carp, a strain of common carp (Cyprinus carpio, L.). Hepatocytes incubated with 40 microM [3H]B[a]P produced 1.22 nmol equivalents of B[a]P metabolites/mg dry wt of cells/h. Conjugated derivatives represented approximately 65% of all B[a]P metabolites and included glucuronides (38%), glutathione conjugates (21%) and sulfates (6%). About 14% of the total accumulated metabolites of B[a]P determined after 1 h incubations were identified as unconjugated derivatives, predominantly B[a]P-9,10-dihydrodiol and B[a]P-7,8-diol (7.4 and 3.1% of total metabolites respectively), with only traces of B[a]P tetrols (less than 1%). Hepatocytes incubated with 40 microM (-)-[14C]B[a]P-7,8-diol produced 4.78 nmol equivalents of metabolites/mg dry wt during a 1 h incubation, yielding an average rate of metabolism during this time period approximately 53% of that determined after a 5 min incubation. The profile of (-)-B[a]P-7,8-diol metabolites remained constant with incubation time (glucuronides, 30-33%; conjugates with glutathione, 43-46%; polyhydroxylated B[a]P derivatives plus sulfate conjugates, 22-24%). HPLC analysis revealed that polyhydroxylated metabolites amounted to 18% of the total metabolites; thus sulfate conjugates amounted to only 4% of the total metabolites. The trans-2 B[a]P-tetrol, which is the major hydrolysis product of (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (anti-BPDE), represented approximately 11% of the accumulated metabolites of (-)-B[a]P-7,8-diol. Despite the much larger amounts of BPDE formed from (-)-B[a]P-7,8-diol than from B[a]P, the amounts of B[a]P equivalents covalently bound to cellular DNA were the same following 1 h incubations with either substrate (247 +/- 42 or 212 +/- 42 pmol/mg DNA respectively). Thus biochemical and physiological factors other than the production of BPDE are critically involved in determining the level of DNA adducts in hepatocytes as well as the role of these adducts in hepatocarcinogenesis.

Animals↗
PubMed1993

Effects of benzo[a]pyrene and (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene on mitosis in Chinese hamster V79 cells with stable expression of rat cytochrome P4501A1 or 1A2.

The effect of bioactivation of benzo[a]pyrene (B[a]P) and (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol) on spindle disturbances and toxicity has been investigated in V79 Chinese hamster cells genetically engineered to express cytochrome P4501A1 (CYP1A1) and cytochrome P4501A2 (CYP1A2). B[a]P induces spindle disturbances in native V79 Chinese hamster cells. This effect was enhanced by the expression of CYP1A1 but not CYP1A2. The increased effect seen in the CYP1A1-expressing cell line could be brought back to the level seen in the native cell line by alpha-naphthoflavone in a dose-dependent manner. This strongly suggests that a CYP1A1-dependent metabolite, conceivably (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BPDE) accounts for the increased spindle disturbing effect. B[a]P-7,8-diol induced spindle disturbances at remarkably low concentrations, 10(-8) M, irrespective of expression of the two CYPs. Our data suggest that B[a]P-7,8-diol is the most potent spindle-disturbing metabolite, whereas BPDE is the most important metabolite concerning mutagenesis. The concentrations inducing spindle disturbances correspond to those that are positive in mutation assays. We hypothesize that B[a]P is a complete carcinogen because of its ability to induce both aneuploidy and mutations after metabolic conversion of low non-cytotoxic concentrations.

Animals↗
PubMed1982

Structures of covalent adducts derived from the reactions of the 9,10-epoxides of 7,8,9,10-tetrahydrobenzo [a] pyrene and 9,10,11,12-tetrahydrobenzo [e] pyrene with DNA.

The reaction of the racemic mixture of 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo [a] pyrene (B[a]PDE) and its enantiomer with DNA is highly stereoselective. About 90% of the adducts are derived from the former enantiomer reacting with the amino group of guanine residues. To investigate this stereoselectively we compared the reactions of 9,10-epoxy-7,8,9,10-tetrahydrobenzo [a] pyrene and 9.10-epoxy-9,10,11-12-tetrahydrobenzo [e] pyrene with DNA. Most of the stereoselectivity seen with B [a] PDE is lost. Both epoxide give mainly adducts on the N2 group of guanine by both cis and trans additions to the epoxide. Other adducts, tentatively identified as deoxyadenosine derivatives, were also detected.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1982

Inactivation of DNA-binding metabolites of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by glutathione and glutathione S-transferases.

The binding to DNA of reactive metabolites of trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (BP-7,8-diol) was studied following the incubation of tritiated benzo[a]pyrene (BP) and BP-7,8-diol with nuclei from livers of 3-methylcholanthrene-treated rats. Binding was inhibited to a small extent by glutathione (GSH) alone and to a much greater extent by GSH and cytosol or purified GSH-transferases B and E. In this respect GSH-transferases A and C were also active, but less so. Inhibition of binding of BP-7,8-diol metabolites to DNA mediated by GSH-transferases was associated with the formation of GSH conjugates. The extent of inhibition of binding was similar in incubations of nuclei alone, nuclei and rat liver microsomes, and calf thymus DNA and rat liver microsomes. This indicates that reactive metabolites of BP-7,8-diol, formed either by nuclei or microsomes, are readily accessible to soluble GSH-transferases. GSH and cytosol were also active in inhibiting DNA-binding of reactive metabolites from 9-hydroxybenzo[a]pyrene (9-OH-BP). Thus, in the rat hepatocyte GSH and GSH-transferases may be important in protecting DNA from electrophilic attack by reactive BP-7,8-diol and 9-OH-BP species.

Animals↗
PubMed1984

Metabolic activation of benzo[a]pyrene-7,8-dihydrodiol and benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and the inhibitory effect of glutathione and cysteine.

Trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) and the anti-isomer of trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) were found to be activated by microsomes isolated from 3-methylcholanthrene (MC)-treated rats to reactive intermediates that bound covalently to microsomal proteins. The extent of binding was markedly reduced by the presence of reduced glutathione (GSH) or cysteine. Fluorescence spectroscopic studies on the products derived from BP-7,8-diol and BPDE after microsomal activation in presence of GSH or cysteine revealed the formation of a common reactive intermediate with unique fluorescence properties. The involvement of cytochrome P-448 in the activation of BP-7,8-diol and BPDE to protein-binding products was inferred by the requirement for NADPH and almost complete inhibition by alpha-naphthoflavone. Furthermore, microsomes from MC-treated rats could be replaced by a reconstituted system containing purified cytochrome P-448, NADPH-cytochrome reductase and co-factors. The conjugation of the reactive intermediates from BP-7,8-diol and BPDE with GSH or cysteine did not require the presence of either microsomes or cytosol, thus indicating a non-catalytic reaction. These results emphasize the importance of cellular nucleophiles such as GSH and cysteine in the deactivation of reactive benzo[a]pyrene (BP) intermediates and also provides evidence for the further activation of the ultimate carcinogen BPDE to more reactive electrophiles and may thus have relevance concerning the regulation of BP-induced carcinogenesis.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Glutathione depletion suppresses conjugation of benzo[a]pyrene metabolites and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene metabolites with glutathione but does not affect their binding to DNA in C3H/10T1/2 mouse fibroblasts.

The study was aimed at determining the role of glutathione (GSH) conjugation in the binding of reactive benzo[a]pyrene (BaP) species to DNA of C3H/10T1/2 cells. In order to suppress GSH conjugation cells were depleted of GSH by treatment with buthionine sulfoximine for 18 h and 1-chloro-2,4-dinitrobenzene for 1 h prior to incubation with radiolabelled substrates. Under these conditions GSH levels decreased to less than 1% of the control value. C3H/10T1/2 cells produced GSH conjugates with 7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaPDE) comprising 6% of the total metabolites formed from BaP or (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BaP-7,8-diol). In GSH-depleted cells formation of GSH conjugates with metabolic products of BaP or BaP-7,8-diol was suppressed to 1% of total metabolites during an 8-h incubation period. Metabolic activation of BaP and BaP-7,8-diol by C3H/10T1/2 cells resulted in the formation of DNA adducts which largely consisted of BaPDE:deoxyguanosine. Depletion of GSH altered neither the degree of DNA binding nor the pattern of DNA adducts to any significant extent. When C3H/10T1/2 cells were co-incubated with microsomes from liver of 3-methylcholanthrene-treated rats for 1 h in order to activate BaP or BaP-7,8-diol extracellularly, the same pattern of GSH conjugates and DNA adducts was generated as by intracellular metabolism of the polycyclic hydrocarbons. No GSH conjugates were detected following co-incubation of microsomes with GSH-depleted C3H/10T1/2 cells. The formation of DNA adducts again remained unaffected by the suppression of conjugation. C3H/10T1/2 cells are apparently capable of conjugating BaPDE with GSH but are not capable of trapping by GSH conjugation those BaPDE moieties which bind to DNA. The results are compatible with the notion that BaPDE is partially contained in a cellular compartment--presumably the lipid environment of membranes--where it is inaccessible to GSH transferases of C3H/10T1/2 cells.

Animals↗
PubMed1987

Human hair follicle benzo[a]pyrene and benzo[a]pyrene 7,8-diol metabolism: effect of exposure to a coal tar-containing shampoo.

Assay systems for the evaluation of carcinogen interaction with human tissues are essential for assessing cancer risk. Hair follicles are a readily available source of human epithelial tissue and offer an excellent system with which to study carcinogen metabolism in human populations. In this study freshly plucked human hair follicles were employed to measure the metabolism of benzo[a]pyrene (BP), benzo[a]pyrene-7,8-diol (BP 7,8-diol), and the enzyme-mediated binding of [3H]-BP to DNA. The effect of human exposure to a crude coal tar (CCT)-containing shampoo, a preparation rich in polycyclic aromatic hydrocarbons (PAHs), on these parameters was also evaluated. Twelve healthy volunteers were studied before and after shampooing their hair daily for 4 days with the CCT-containing shampoo. Wide interindividual variation was observed in basal cytochrome P-450-dependent aryl hydrocarbon hydroxylase (AHH) activity which ranged from 0.6-17.6 fmol water-soluble BP metabolites/h/hair follicle (mean +/- SE of 32 individuals was 9.7 +/- 0.9). After use of the shampoo for 4 days AHH activity increased in 10 of the 12 volunteers (50-148%) and enhancement of enzyme-mediated binding of BP to DNA was detected in most subjects. Hair follicles were shown to convert BP to several metabolic species including BP 7,8-diol, a major precursor of the ultimate carcinogenic metabolite of BP. Benzo[a]pyrene-7,8-diol itself was also metabolized by the human hair follicles in this system. Clotrimazole, a known inhibitor of the metabolism of BP as well as the carcinogenicity of the hydrocarbon in rodent skin, was found to inhibit AHH and the in vitro metabolism of BP and BP 7,8-diol in human hair follicles. Oral administration of a similar antifungal imidazole, ketoconazole at a dose of 200 mg daily for 5 days, to healthy volunteers also resulted in greater than 90% inhibition of hair follicle AHH activity. These studies indicate that hair follicles represent an accessible tissue suitable for assessing the extent of PAH carcinogen metabolism in human subjects. Furthermore, enzyme activity critical to cancer induction by PAHs was shown to be inducible following the use of a CCT-containing shampoo. This carcinogen-activating enzyme system was substantially inhibited by imidazole compounds, suggesting that they may prove effective as anticarcinogens in human populations.

Aryl Hydrocarbon Hydroxylases↗
PubMed1985

Inhibition of benzo(a)pyrene and benzo(a)pyrene-trans-7,8-diol metabolism and DNA binding in mouse lung explants by ellagic acid.

The effect of ellagic acid, a naturally occurring plant phenol, on the binding to DNA and metabolism of benzo(a)pyrene (BP) and trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene (BP 7,8-DHD) in cultured explants of strain A mouse lung was investigated. The explants were cultured in a rocking organ culture chamber for 16 h in the presence or absence of 10, 25, 50, and 100 microM ellagic acid. These concentrations of ellagic acid were nontoxic as determined by biochemical and histological methods. The ellagic acid was then removed from the cultures, and the explants were incubated with either 1 microM [3H]BP or [3H]BP 7,8-DHD for 24 h. Explant DNA was isolated using hydroxylapatite chromatography, and the BP metabolites in the medium were analyzed by high-pressure liquid chromatography. Ellagic acid (50 microM) inhibited the binding of BP and BP 7,8-DHD to lung DNA by 46 to 50% and 60 to 70%, respectively. High-pressure liquid chromatography analysis showed that ellagic acid (100 microM) inhibited the metabolism of BP by 20 to 40% and of BP 7,8-DHD by 20%, as indicated by the increased amounts of unmetabolized substrates and decreased amounts of metabolites in the medium. The major BP:DNA adduct in the explants was 7R-N2-[10 beta-[7 beta, 8 beta, 9 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene]yl: deoxyguanosine, and its formation was reduced by 60 to 65% in the presence of 100 microM ellagic acid. These data suggest that the reduction of BP and BP 7,8-DHD metabolite binding to DNA by ellagic acid may have been due to inhibition of the formation and/or removal of BP 7,8-diol-9,10-epoxide prior to its binding to DNA.

Animals↗
PubMed1977

[Transplacental effect of benz(a)pyrene and pyrene].

The transplacental and direct effect of benzo(a)pyrene (BP) and pyrene on A and C57BL mice and their offspring was studied. BP proved to present blastomogenic danger for the offspring. In A mice offspring the greatest blastomogenic effect was expressed with the dose of 6 mg: lung tumours developed in 76.8% against 12.3% in the control (P less than 0,001). Tumours of the liver were revealed in the offspring of C57BL mice, chiefly in males. Their incidence with the dose of 12 mg of BP was 31.6% in males: and 9.1% in female; in the controls--1.2% in males, in the control females no tumours of the liver were observed. Noncarcinogenic analogue of BP--pyrene produced no blastomogenic effect.

Adenoma↗
PubMed1986

Effect of aliphatic amides on oncogenic transformation, sister chromatid exchanges, and mutations induced by cyclopenta[cd]-pyrene and benzo[a]pyrene.

We examined the effects of the aliphatic amides isopropyl-valeramide (IVA) and allylisopropylacetamide (AIA) on oncogenic transformation and sister chromatid exchanges (SCE) induced by cyclopenta[cd]pyrene (CPP) and benzo[a]pyrene (B[a]P) in C3H/10T1/2 cells and on B[a]Pdiol-epoxide (BPDE)-induced mutation at the HGPRT locus in Chinese hamster ovary (CHO) cells. IVA and AIA significantly suppressed B[a]P and CPP transformation in vitro. Both amides were effective when given just prior to, simultaneously with, or 24 h after carcinogen exposure. On the other hand, IVA and AIA did not affect cytotoxicity, the frequencies of SCE induced by CPP or B[a]P, nor BPDE-induced mutations in CHO cells. These and previous results suggest that the mechanism of inhibition of transformation by IVA or AIA may be very specific and probably not related to the early initiation event in oncogenic transformation in vitro.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1976

The role of 9-hydroxybenzo(a)pyrene in the microsome mediated binding of benzo(a)pyrene to DNA.

A study of the liver microsome-mediated binding to added DNA of the phenol metabolites of benzo(a)pyrene (BP-OH) and of 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene (BP-7,8-diol) suggested that as in the case of BP itself the reaction was catalysed by the enzyme aryl hydrocarbon hydroxylase. The addition of glutathione to the microsomal incubation inhibited the binding of BP and BP-OH more than that of BP-7,8-diol. Analysis by LH20 chromatography of the deoxyribonucleoside products from BP-DNA showed greater inhibition by glutathione of formation of the major product believed to result from further metabolism of BP-OH, than of the product arising by metabolism of BP-7,8-diol. The chromatographic behaviour and fluorescence spectrum of this major product were consistent with its derivation from 9-hydroxybenzo(a)pyrene (BP-9-OH) and furthermore suggested that BP-9-OH-4,5-oxide was the derivative whose reaction with DNA yielded this microsome-mediated BP-DNA product.

Alkylation↗
PubMedDate not supplied

Metabolism and mutagenicity of dibenzo[a,e]pyrene and the very potent environmental carcinogen dibenzo[a,l]pyrene.

Dibenzo[a,l]pyrene (DB[a,l]P) is one of the most potent carcinogens ever tested in mouse skin and rat mammary gland. DB[a,l]P is present in cigarette smoke and, presumably, in other environmental pollutants. Metabolism and mutagenicity studies of this compound compared to the weak carcinogen dibenzo[a,e]pyrene (DB[a,e]P) can provide preliminary evidence on its mechanism of carcinogenesis. The mutagenicity of DB[a,l]P, DB[a,e]P, and benzo[a]pyrene (BP) was compared in the Ames assay with Aroclor-induced rat liver S-9. BP was the strongest mutagen. In strain TA100, DB[a,l]P and DB[a,e]P were marginally mutagenic. In strain TA98 both compounds were mutagenic, and DB[a,l]P induced more than twice as many revertants as DB[a,e]P. The mutagenicity of DB[a,l]P does not correlate with its carcinogenicity, since DB[a,l]P is a much stronger carcinogen, but a much weaker mutagen, than BP. The NADPH-supported metabolism of DB[a,e]P and DB[a,l]P was conducted with uninduced and 3-methylcholanthrene-induced rat liver microsomes. Metabolites were analyzed by reverse-phase HPLC and identified by NMR, UV, and mass spectrometry. Uninduced microsomes produced only traces of metabolites with either compound. The major metabolites of DB[a,l]P with induced microsomes were DB[a,l]P 8,9-dihydrodiol, DB[a,l]P 11,12-dihydrodiol, 7-hydroxyDB[a,l]P, and a DB[a,l]P dione. The metabolites of DB[a,e]P with induced microsomes were DB[a,e]P 3,4-dihydrodiol, 3-hydroxyDB[a,e]P, 7-hydroxyDB[a,e]P, and 9-hydroxyDB[a,e]P. Some of these metabolites are very useful in assessing possible pathways of activation in the initiation of cancer.

Animals↗
PubMedDate not supplied

32P-postlabeling analysis of the DNA adducts of 6-fluorobenzo[a]pyrene and 6-methylbenzo[a]pyrene formed in vitro.

Studies of benzo[a]pyrene (BP) and selected derivatives are part of the strategy to elucidate mechanisms of tumor initiation by polycyclic aromatic hydrocarbons. Substitution of BP at C-6 with fluorine to form 6-fluorobenzo[a]pyrene (6-FBP) or a methyl group to form 6-methylbenzo[a]pyrene (6-CH3BP) decreases tumorigenicity compared to BP. BP, 6-FBP, and 6-CH3BP formed adducts with DNA when (1) they were activated by 3-methylcholanthrene-induced rat liver microsomes, (2) they were activated by horseradish peroxidase (HRP), (3) their 7,8-dihydrodiols were activated by microsomes, or (4) the radical cation of BP, 6-FBP, or 6-CH3-BP was directly reacted with DNA. With microsomes, 6.5 mumol of [3H]6-FBP/mol of DNA-P and 10 mumol of [14C]6-CH3BP/mol of DNA-P were bound vs 15 mumol of [3H]BP. With microsomes, two major 6-FBP adducts and some minor adducts were obtained. One major adduct coincided with that from 6-FBP-7,8-dihydrodiol. With microsomes, the minor 6-FBP adducts coincided with the adducts obtained from 6-FBP radical cation plus DNA and the major adduct of HRP-activated 6-FBP. With microsomes, 6-CH3BP showed adducts similar to some formed with HRP and one from 6-CH3BP radical cation. 6-CH3BP-7,8-dihydrodiol produced a small amount of one adduct that did not coincide with any from 6-CH3BP. The adducts of 6-FBP appear to be formed mostly through the diolepoxide pathway, whereas those of 6-CH3BP appear to arise mostly via one-electron oxidation.

Animals↗
PubMedDate not supplied

Adducts of 6-methylbenzo[a]pyrene and 6-fluorobenzo[a]pyrene formed by electrochemical oxidation in the presence of deoxyribonucleosides.

Studies of the DNA adducts of benzo[a]pyrene and selected derivatives are part of the strategy to elucidate mechanisms of tumor initiation by aromatic hydrocarbons. Reference adducts formed by reaction of deoxyribonucleosides with electrophilic intermediates of 6-fluorobenzo[a]pyrene (6-FBP) and 6-methylbenzo[a]pyrene (6-CH3BP) are investigated here because they are essential for identifying the structures of adducts formed in biological systems. Electrochemical oxidation of 6-FBP in the presence of deoxyribonucleosides led to adducts from the 6-FBP radical cation. With dG, a mixture of 6-FBP bound at C-1 or C-3 to the N-7 of Gua was formed in 10% yield, whereas 6-FBP plus dC gave a mixture of 3-(6-FBP-1-yl)Cyt and 3-(6-FBP-3-yl)Cyt (15%). No adducts of 6-FBP were formed with dA or dT. Electrochemical oxidation of 6-CH3BP in the presence of dG produced 8-(BP-6-CH2-yl)dG (5%) and a mixture of 7-(6-CH3BP-1-yl)Gua and 7-(6-CH3BP-3-yl)Gua (23%). The only adduct formed with dA was 3-(BP-6-CH2-yl)Ade (9%). 6-CH3BP did not afford any adducts with dC or dT. The noncarcinogenic 6-ClBP and 6-BrBP did not produce adducts with dG, dA, dC, or dT. These results are consistent with the chemical properties of the 6-FBP and 6-CH3BP radical cations: that is, 6-FBP reacts at C-1 and C-3, whereas 6-CH3BP reacts competitively at C-1 and C-3, as well as at the 6-CH3 position.

Benzopyrenes↗
PubMed1978

Effects of administration to mice of butylated hydroxyanisole by oral intubation on benzo[a]pyrene-induced pulmonary adenoma formation and metabolism of benzo[a]pyrene.

Administration of butylated hydroxyanisole (BHA) by oral intubation 4 hours before challenge with benzo[a]pyrene (BP) inhibited the formation of pulmonary adenomas in A/HeJ mice. Incubation of BP with liver microsomes from mice that received BHA 2,4, or 8 hours before being killed resulted in less binding of BP metabolites to added DNA than occurred with control microsomes. High-pressure liquid chromatography studies of the BP metabolite pattern produced by the incubation of BP with liver microsomes from mice given BHA by oral intubation showed a decrease in formation of BP-4,5-oxide and 9-hydroxybenzo[a]pyrene. In contrast, the formation of 3-hydroxybenzo[a]-pyrene was increased. The was increased. The short interval between the administration of BHA by oral intubation and the observed biochemical changes indicated that BHA could exert a direct effect on the microsomal metabolism of BP. These changes in metabolism of BP occurred under conditions of BHA administration that produced a decreased neoplastic response to this carcinogen.

Adenoma↗
PubMed1975

Comparison of the cellular DNA-bound products of benzo(alpha)pyrene with the products formed by the reaction of benzo(alpha)pyrene-4,5-oxide with DNA.

DNA isolated from mouse embryo cell cultures that had been treated with [3H]benzo(alpha)pyrene was degraded with enzymes to deoxyribonucleosides, and the hydrocarbon-deoxyribonucleoside products were isolated by chromatography on a Sephadex LH20 column eluted with a water: methanol gradient. The hydrocarbon-deoxyribonucleoside products were not identical to those found in similar chromatograms of enzyme digests of DNA that had been reacted with benzo(alpha)pyrene-4,5-oxide in aqueous ethanol solution. This finding suggests that the metabolic activation of benzo(alpha)pyrene that results in this hydrocarbon becoming covalently bound to DNA in mouse embryo cells in culture may be more complex than simply formation of a K-region epoxide and reaction of that compound with the cellular DNA.

Animals↗
PubMed1979

Carcinogenicity of 2-hydroxybenzo(a)pyrene and 6-hydroxybenzo(a)pyrene in newborn mice.

Benzo(a)pyrene (BP), 2-hydroxybenzo(a)pyrene (2-HOBP), and 6-hydroxybenzo(a)pyrene (6-HOBP) were tested for tumorigenicity by i.p. injection into newborn mice. The mice were treated sequentially with 200, 400, and 800 nmol of compound on the first, eighth and fifteenth day of life, and the animals were killed at 24 weeks of age. Treatment with 2-HOBP caused about 4-fold more pulmonary tumors than BP, while 6-HOBP had little or no tumorigenic activity. Newborn mice treated with 2-HOBP, BP, and 6-HOBP had a 98, 81, and 11% incidence of pulmonary adenomas with an average of 24, 6.4, and 0.11 adenomas per mouse, respectively. In the control group, 7.5% of the animals had pulmonary adenomas with an average of 0.08 adenoma per mouse. When 25, 50, or 100 nmol of BP or 2-HOBP was applied to mouse skin once every 2 weeks for 60 weeks, both compounds had about the same carcinogenic activity. These results demonstrate the importance of evaluating the carcinogenic potential of chemicals in more than one tumor system. BP and 2-HOBP were tested for mutagenicity towards two strains of Salmonella typhimurium and towards Chinese hamster V79 cells in the presence of hepatic microsomes from rats pretreated with Aroclor 1254. The products formed during the metabolism of 2-HOBP or BP by liver microsomes had significant mutagenic activity.

Adenoma↗