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PubMed1975

Regulation of aryl hydrocarbon (benzo-(A)-pyrene) hydroxylase activity in mammalian cells. Induction of hydroxylase activity by N6,O2'-dibutyryl8 adenosine 3':5'-monophosphate and aminophylline.

Treatment of hamster BHK cells with N6,O2'-dibutyryl adenosine 3':5'-monophosphate (Bt2cAMP), aminophylline, theophylline, or papaverine increased the level of aryl hydrocarbon (benzo(a)pyrene) hydrolxylase activity. The highese increase, 100-fold, was obtained with Bt2cAMP plus aminophylline or theophylline. N2,O2-Dibutyryl guanosine 3':5'-monophosphate gave a lower induction than Bt2cAMP. The level of hydroxylase activity started to decrease 6 hours after treatment with the inducer and was reduced to almost the uninduced level after 24 hours. Repeated addition of Bt2cAMP and aminophylline did not prevent this decrease. The hydroxylase can also be induced by treating cells with benz(a)anthracene, and the level of this induced activity was maintained for 24 hours. Aminophylline gave a 2- to 8-fold stimulation of the induction by benz(a)anthracene. The enzyme activity induced by Bt2cAMP, aminophylline, and benz(a)anthracene converted benzo(a)pyrene to similar alkali-extractable metabolities with a fluorescence spectra similar to that of 3-hydroxybenzo(a)pyrene. These induced enzyme activities also showed a similar heat stability. Induction by Bt2cAMP and aminophylline, like induction by benz(a)anthracene, required continued protein synthesis and only an initial period of RNA synthesis. Compared to the benz(a)anthracene-induced hydroxylase with a Km of 4.3 muM, the hydroxylase induced by Bt2cAMP and aminophylline showed a Km of 0.14 muM, and was 100-fold more sensitive to inhibition by 7,8-benzoflavone. Increasing the serum concentration in the culture medium stimulated the induction by aminophylline but did not stimulate induction by benz(a)anthracene. The results indicate that aryl hydrocaarbon (benzo(a)pyrene) hydroxylase can be induced by compounds that increase the level of adenosine 3':5'-monophosphate and that this induction and induced enzyme activity differs from that caused by benz(a)anthracene.

Aminophylline↗
PubMed1985

Protection against toxic redox cycles between benzo(a)pyrene-3,6-quinone and its quinol by 3-methylcholanthrene-inducible formation of the quinol mono- and diglucuronide.

Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma cells (H4IIE). Inhibition of quinol glucuronidation by salicylamide enhanced quinone-dependent oxygen uptake and cytotoxicity. Conjugation of benzo(a)pyrene-3,6-quinol was shown to proceed via the 6-monoglucuronide to the diglucuronide. Diglucuronide formation was low in hepatocytes from untreated controls and phenobarbital-treated rats. However, it was highly stimulated (26-fold) in hepatocytes from 3-methylcholanthrene-treated rats and was also high in Reuber hepatoma cells. Kinetic analysis with liver microsomes indicated that 3-methylcholanthrene-stimulated glucuronidation was due to an increased Vmax of UDP-glucuronosyltransferase which was enhanced 10- and 40-fold or mono- and diglucuronide formation, respectively. These findings suggest that the investigation of quinol glucuronidation (in particular the formation of benzo(a)pyrene-3,6-quinol diglucuronide) is a most useful probe for the 3-methylcholanthrene-inducible isoenzyme(s) of UDP-glucuronosyltransferase. Moreover, this isoenzyme may be particularly suited to protect against toxic redox cycles between benzo(a)pyrene quinones and quinols.

Animals↗
PubMed1977

Characterization of benzo(a)pyrene hydroxylase of trout liver.

Trout liver microsomes contained as 0.40 nmole of cytochrome P-450 per mg of protein and a NADPH-cytochrome c reductase activity of 23 nmoles of cytochrome c reduced per mg of protein per min at 22 degrees. Associated with these was a high benzo(a)pyrene hydroxylase activity, which required NADPH and O2 and was inhibited by CO. With thin-layer chromatography, at least five metabolites could be identified (including dihydrodiols, phenols, and quinones of benzo(a)pyrene). Inhibitors such as 2-diethylaminoethyl-2,2-diphenylvalerate, aminopyrine, metyrapone, pyridine, n-octylamine, and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane were relatively ineffective in inhibiting trout benzo(a)pyrene hydroxylase. Typical inhibitors of 3-methylcholanthrene-induced cytochrome (P-448), such as alpha-naphthoflavone, zoxazolamine, and testosterone, were effective, however. With benzo(a)pyrene it was possible to induce type I spectral change in trout cytochrome P-450. In spite of the many enzymatic characteristics of cytochrome P-448, trout cytochrome P-450 had maximum absorbance at 450.6 nm. when in reduced form and complexed with CO. the ethyl isocyanide gave an interaction spectrum with reduced trout liver cytochrome P-450 resembling that of control rat.

Animals↗
PubMed1979

Benzo(a)pyrene oxidation, conjugation and disposition in the isolated perfused rabbit lung: role of the glutathione S-transferases.

The isolated perfused rabbit lung metabolised 7--11 % of 20 mumol of [14C]-benzo(a)pyrene added in the perfusion medium in 1 h. The major metabolite formed was 3-hydroxybenzo(a)pyrene, both free (30--40 % of the total metabolites) and conjugated (4 % of total metabolites). Quinones comprised 15 % of the total and metabolism at the 9, 10 position accounted for a further 10 %. Forty per cent of the water-soluble metabolites was chromatographically identical to the glutathione conjugate of benzo(a)pyrene 4,5-oxide. Sulphate and glucuronide conjugates were formed in small but detectable amounts, principally from phenols, but also from dihydrodiols. After 1 h the more water-soluble conjugates had diffused from the lung into the perfusion medium, but the majority (60--90 %) of the metabolic products were still concentrated within the lung. The lung's limited ability to conjugate its major metabolites of benzo(a)pyrene with sulphuric or glucuronic acid, coupled with slow elimination of the products formed, particularly dihydrodiols may contribute to the susceptibility of this organ to polycyclic aromatic hydrocarbon-induced carcinogenesis.

Animals↗
PubMedDate not supplied

Comparison of the clastogenic and carcinogenic effects of intravenous beta-propiolactone and benzo(a)pyrene in rats.

Scored at 24 hours, the LD-50 of a solution of beta-propiolactone administered intravenously to young rats was 225 +/- 55 mg/kg. Twenty-four hours after a single intravenous injection (100 mg/kg = 1.4 m mole/kg) of beta-propiolactone into male and female rats of both the Long-Evans and Sprague-Dawley strains, the incidence of breaks found in the chromosomes of metaphase marrow cells was low (8.8 percent vs. 5.0 percent in controls). The s5 chromosomes were preferentially damaged. A 200 mg/kg dose increased the incidence modestly to 11.3 percent. In comparison, a single intravenous dose of benzo(a)pyrene (40 mg/kg = 0.16 m mole/kg) produced a break incidence of 19 percent. In long-term experiments multiple (five) intravenous injections (100 mg/kg each) of beta-propiolactone given in a 6 week period elicited only two neoplasms (a chloro-leukemia and a mammary fibroadenoma) among 37 animals during the following 12-13 months. In contrast, four injections of benzo(a)pyrene (40 mg/kg) produced a 14-times greater mammary tumor incidence in the Sprague-Dawley female rat than did beta-propiolactone. Marrow cell chromosome examination indicated no significant chromosomal changes due to the earlier beta-propiolactone treatment except for one animal with a consistent 43-chromosome karyotype resulting from S1 trisomy; no neoplasm was evident in that animal. Earlier treatment with benzo(a)pyrene produced a persistent and significant elevation in break incidence. Both the carcinogenic and clastogenic effects of intravenous beta-propiolactone are low in rats and are not comparable in magnitude to those produced by benzo(a)pyrene.

Animals↗
PubMed1983

Prostaglandin synthetase and cytochrome P-450-dependent metabolism of (+/-)benzo(a)pyrene 7,8-dihydrodiol by enriched populations of rat Clara cells and alveolar type II cells.

The metabolism of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol) by prostaglandin synthetase and cytochrome P-450-dependent monooxygenases was studied using enriched fractions of Clara cells and alveolar type II cells from rat lung. Arachidonic acid-fortified fractions enriched in Clara cells and alveolar type II cells metabolized BP-7,8-diol to the 7,10/8,9-tetrol of benzo(a)pyrene and the 7/8,9,10-tetrol of benzo(a)pyrene. These tetrols are formed upon solvolysis of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha- epoxy-7,8,9,10-tetrahydrobenzo(a)-pyrene (BP diol-epoxide I). Arachidonic acid-dependent metabolism of BP-7,8-diol to BP diol-epoxide I in enriched Clara cells and alveolar type II cells was completely inhibited by indomethacin, a classical inhibitor of prostaglandin synthetase. Enriched Clara cells and alveolar type II cells also metabolized BP-7,8-diol to BP diol-epoxide I in the presence of NADPH. Amounts of BP diol-epoxide I-derived tetrols formed from BP-7,8-diol by the prostaglandin synthetase-dependent and the cytochrome P-450-dependent pathways varied significantly between the two pulmonary cell fractions examined. In fractions enriched in Clara cells, cytochrome P-450-dependent BP-7,8-diol oxidation was higher than was prostaglandin synthetase-dependent BP-7,8-diol oxidation; while in fractions of alveolar type II cells, prostaglandin synthetase-dependent BP-7,8-diol oxidation to BP diol-epoxide I predominated. Pretreatment of rats with beta-naphthoflavone resulted in a 2- to 3-fold increase in BP diol-epoxide I formation by prostaglandin synthetase and cytochrome P-450-dependent monooxygenases in both enriched Clara cells and alveolar type II cells. These increases in BP-7,8-diol oxidation to BP diol-epoxide I appear to be due to induction of the two enzymatic pathways in both pulmonary cell types. No qualitative changes in the pattern of BP-7,8-diol metabolism by either enzymatic pathway in enriched Clara cells or alveolar type II cells were observed following beta-naphthoflavone treatment. The results suggest that pulmonary prostaglandin synthetase may serve as either an additional or an alternative bioactivating enzyme to the cytochrome P-450-dependent monooxygenases for the formation of reactive chemical carcinogens in the lung.

Animals↗
PubMedDate not supplied

[Benz(a)pyrene content in the salt samples obtained from the borehole waters of the Krasnodar deposit].

Benz(a)pyrene content in the samples of salt obtained from water ground of the Krasnodar field was assayed by means of the spectral fluorescent method. The table salt "Extra" manufactured by the Slavyansk salt-works supplying the trade network (GOST 13830-68) served as control. 15 samples (60 reference standards) were examined. It was established that 3 of 5 tested samples obtained from purified concentrated brine of water ground of the Krasnodar field contained benz(a)pyrene in an amount of 0.0351 microgram/kg up to 0.16 microgram/kg. Benz(a)pyrene (0.104 microgram/kg) was detected in 1 of 4 tested samples of the salt "Extra". It is concluded that tested salt samples obtained from concentrated brine of water ground of the Krasnodar field contain an insignificant amount of benz(a)pyrene.

Benzopyrenes↗
PubMed1982

Conformation change of DNA induced by 6-oxybenzo[a]pyrene radical.

The interaction of 6-oxybenzo[a]pyrene radical with DNA in 50% methanol solution was studied in order to determine whether the radical molecule influences DNA conformation. The mode of the interaction of 6-oxybenzo[a]pyrene radical with DNA differed from that of other benzo[a]pyrene derivatives such as 6-hydroxybenzo[a]pyrene, diol-epoxides, etc. The physical binding of the radical molecule to DNA seemed to be transient. This physical binding is most likely due to adsorption at the external surface of DNA, i.e., simply contact in character. It is likely that the local base-pairs are tilted by the contact due to hydrophobic interactions. Furthermore, it is concluded that the covalently bound radical molecule, which is mainly introduced on guanine base, induces a twist of the base plane with respect to other base planes.

Benzopyrenes↗
PubMed1980

Prediction of pulmonary benzo(a)pyrene 4,5-oxide clearance: a pharmacokinetic analysis of epoxide-metabolizing enzymes in rabbit lung.

Extrapolation of in vitro data to predict occurrences in vivo is an uncertain process at best. In this study, clearance concepts initially developed to describe elimination of drugs and other substances by kidney and liver have been extended to calculate pulmonary extraction of circulating benzo(a)pyrene 4,5-oxide. Apparent kinetic parameters (Km and Vmax) for pulmonary microsomal epoxide hydrolase and cytosolic glutathione S-transferase were estimated by using in vitro enzyme assays, and whole tissue Vmax values of the two epoxide-metabolizing pathways were determined. From these data, a whole organ extraction ratio for benzo(a)pyrene 4,5-oxide was derived. The calculated extraction ratio (nearly one) was greater than, but in reasonable agreement with, the measured extraction ratio determined by using isolated perfused rabbit lungs exposed to circulating benzo(a)pyrene 4,5-oxide. The actual extraction ratio was 0.64 +/- 0.04 (x +/- S.D.,N = 3), which indicated that the rabbit lung was capable of removing a large percentage of circulating benzo(a)pyrene 4,5-oxide in a single pass through the organ. Therefore, the lung may play an important role in removing and biotransforming circulating arene oxides, as the entire cardiac output passes through the pulmonary capillary bed.

Animals↗
PubMed1981

Activation and inhibition of benzo(a)pyrene and aflatoxin B1 metabolism in human liver microsomes by naturally occurring flavonoids.

The effects of several naturally occurring and synthetic flavonoids on the metabolism of benzo(a)pyrene and aflatoxin B1 were evaluated. Addition of apigenin, chrysin, fisetin, flavonone, galangin, hesperitin, kaempferol, morin, myricetin, haringenin, or quercetin to human liver microsomes inhibited the hydroxylation of benzo(a)pyrene. In contrast to these results, the addition of flavone, nobiletin, tangeretin, or 7,8-benzoflavone to human liver microsomes caused a many-fold stimulation in the hydroxylation of benzo(a)pyrene, the metabolism of aflatoxin B1 to 2,3-dihydro-2,3-dihydroxyaflatoxin B1, and the metabolic activation of aflatoxin B1 to mutagenic products. Quercetin, morin, and kaempferol inhibited cytochrome c (P-450) reductase in human liver microsomes whereas flavone and 7,8-benzoflavone had no effect. These results suggest that the inhibitory effects of quercetin, morin, and kaempferol on monooxygenase activity may be caused at least in part by an inhibition in the reduction of cytochrome P-450. An examination of the structural features required for the inhibition and stimulation of benzo(a)pyrene hydroxylation indicated that all of the 12 flavonoid inhibitors that were studied possessed hydroxyl groups whereas the flavonoid activators were less polar molecules that lacked hydroxyl groups.

Aflatoxins↗
PubMed1977

Marked differences in the tumor-initiating activity of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene on mouse skin.

The ability of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to initiate skin tumors in mice was determined with a two-stage tumorigenesis system. A single application of 50 to 200 nmoles of (+)- or (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to the backs of CD-1 mice followed by twice-weekly applications of 12-O-tetradecanoyl-phorbol-13-acetate revealed that the (-)-enantiomer was 5- to 10-fold more potent than was the (+)-enantiomer as a tumor initiator at the three dosage levels tested. When the tumor-initiating activities of the (+)0 and (-)-enantiomers of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene were compared to the activity of benzo(a)pyrene at an equimolar dose, the (-)-enantiomer was more active while the (+)-enantiomer was considerably less active. This is the first report of differences in the carcinogenic activity between optical enantiomers.

Animals↗
PubMedDate not supplied

Suppressive effects of benzo[a]pyrene upon fish immune function: evolutionarily conserved cellular mechanisms of immunotoxicity.

Knowledge gained through the use of alternative animal models has significantly enhanced our understanding of life at all levels of biological organization. The discipline of toxicology is under considerable pressure to develop such models due to increasing public concern regarding the experimental use of mammals. Studies in this laboratory have focused on the utility of a small laboratory fish model, the Japanese medaka (Oryzias latipes), to investigate immunotoxicological effects of benzo[a]pyrene (BaP). BaP is a ubiquitous environmental contaminant and known mammalian immunotoxicant. This laboratory has demonstrated that in vivo exposure of medaka to BaP (2-200 microg/g BW) significantly depresses both innate and humoral immunity. Further studies have indicated that BaP activates its own biotransformation pathway within medaka immune cells following both in vivo and in vitro exposure. In addition, reduction of BaP metabolism with alpha-naphthoflavone results in the reversal of BaP-induced suppression of antibody production in vitro. Inhibition of CYPlA-mediated metabolism within medaka immune cells also alleviates the immunotoxicity induced by benzo[a]pyrene-7,8-dihydrodiol, but not benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). This suggests that BPDE may be an ultimate immunotoxicant. Results from this study in medaka are in agreement with previously conducted rodent studies that indicated a role for immunotoxic BaP metabolites in BaP-induced suppression of humoral immunity.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2000

Determination of r-7,t-8,9,c-10-tetrahydroxy-7,8,9, 10-tetrahydrobenzo[a]pyrene in human urine by gas chromatography/negative ion chemical ionization/mass spectrometry.

r-7,t-8,9,c-10-Tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (trans-anti-BaP-tetraol) is the major hydrolysis product of r-7, t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE), the principal ultimate carcinogen of the environmental pollutant benzo[a]pyrene (BaP). As part of a program to establish activation/detoxification profiles of urinary metabolites of BaP in humans, we developed a method for quantifying trans-anti-BaP-tetraol. Urine was collected from three groups of individuals exposed to BaP: psoriasis patients treated with a coal tar-containing ointment, steel workers, and smokers. [(2)H(12)]-trans-anti-BaP-tetraol was added to the urine as an internal standard. The urine was treated with beta-glucuronidase and sulfatase, and then the BaP-tetraols were enriched by reverse-phase and phenylboronic acid solid-phase extraction. The resulting fraction was treated with sodium hydride and methylmethane sulfonate to convert BaP-tetraols to the corresponding tetramethyl ethers (BaP-TME). The mixture was purified by normal-phase HPLC and analyzed by gas chromatography/negative ion chemical ionization/mass spectrometry with selected ion monitoring. [(13)CH(3)](4)-trans-anti-BaP-TME was used as an external standard. Ions at m/z 376, 380, and 388 were monitored for quantitation of trans-anti-BaP-TME, [(13)CH(3)](4)-trans-anti-BaP-TME, and [(2)H(12)]-trans-anti-BaP-TME, respectively. The instrumental detection limit was approximately 1 fmol of trans-anti-BaP-TME. trans-anti-BaP-tetraol (as trans-anti-BaP-TME) was detected in 20 of 20 individuals receiving coal tar therapy (mean, 16 fmol/mL of urine), 13 of 13 exposed steel workers (mean, 4.1 fmol/mL of urine), and nine of 21 cigarette smokers (mean, 0.5 fmol/mL of urine). The means in these groups were significantly different (P < 0.0001). The urine of steel workers was also analyzed for cis-anti-BaP-tetraol and cys-syn-BaP-tetraol, but neither was found. The results of this study provide a quantitative method for determination of parts per trillion levels of trans-anti-BaP-tetraol in human urine. Ultimately, this method can be employed as part of a phenotyping approach for assessing BaP metabolites in human urine.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1991

Immunocytochemical visualization of DNA adducts in mouse tissues and human white blood cells following treatment with benzo[a]pyrene or its diol epoxide. A quantitative approach.

The formation and stability of benzo[a]pyrene DNA adducts were studied in tissues of BALB/c mice exposed to benzo[a]pyrene (B[a]P). The DNA adducts were visualized with an immunocytochemical peroxidase staining technique using an antiserum specific for the major B[a]P-derived adduct in DNA [(+/-)trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (BPDE-N2-dG)]. The nuclear staining density was measured by microdensitometry. When mice were treated with an increasing dose of B[a]P the nuclear staining increased in the tissues studied (lung, heart and kidney). A linear relationship was found between the immunocytochemical nuclear staining signal and the actual DNA adduct level in the lung as measured by 32P-postlabeling. Maximum adduct formation was found 5 days after a single i.p. injection of B[a]P. Adduct levels decreased gradually after 7 days, but even after 61 days a slight specific staining was still present, suggesting that not all adducts had disappeared at that time. As judged from the disappearance of [3H]thymidine from prelabeled DNA the loss of adducts from the lung was not a result of DNA repair but one of cell turnover. In human white blood cells B[a]P-derived adducts could be detected after in vitro incubation with the reactive metabolite of B[a]P (BPDE). Dose-response studies demonstrated a positive relationship between BPDE-DNA adduct formation, the immunocytochemical staining signal and the BPDE concentration in the culture medium.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1993

Reactivity of benzo[a]pyrene-7,8-dione with DNA. Evidence for the formation of deoxyguanosine adducts.

Polycyclic aromatic hydrocarbon (PAH) o-quinones are products of the dihydrodiol dehydrogenase-catalyzed oxidation of trans-dihydrodiols which are proximate carcinogens. The PAH o-quinones are highly reactive molecules and have the potential to alkylate DNA. In this study, the reactivity of [3H](+-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene ([3H] (+/-)-anti-BPDE), [3H]benzo[a]pyrene-7,8-dione ([3H]BPQ) and [3H](+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene ([3H](+/-)-B[a]P-diol) with DNA were compared. (+/-)-anti-BPDE reacted equally well with native, deproteinated and deproteinated/sheared calf thymus DNA. In each case DNA adducts were formed which upon digestion to deoxyribonucleosides comigrated on reverse-phase (RP)-HPLC with adducts synthesized by reacting (+/-)-anti-BPDE with oligo-p(dG)10. (+/-)-anti-BPDE also reacted with plasmid (pGEM-3) DNA to yield multiple adducts one of which comigrated with the (+)-anti-BPDE-deoxyguanosine adduct. Under identical conditions [3H]BPQ reacted preferentially with native calf thymus DNA but displayed low reactivity with deproteinated and deproteinated/sheared calf thymus DNA. RP-HPLC analysis of deoxyribonucleoside-BPQ adducts indicated that the predominant adduct formed comigrated with a standard synthesized by reacting BPQ with oligo-p(dG)10. BPQ also reacted with pGEM-3 DNA to yield multiple adducts one of which comigrated with the BPQ-deoxyguanosine adduct. Reactions between [3H]BPQ and poly(dA), poly(dT), poly(dC) and oligo-p(dG)10 indicated that BPQ preferentially formed deoxyguanosine adducts. In this study, [3H]BPQ and [3H](+/-)-anti-BPDE covalently labeled native calf thymus DNA to an equal extent, however, less [3H]BPQ was recovered as deoxyguanosine adducts. By contrast, no covalent modification of calf thymus DNA, pGEM-3 DNA or oligonucleotides was observed with [3H](+/-)-B[a]P-diol. These studies indicate that BPQ has the potential to be genotoxic in vitro; that reactivity is heightened in the presence of protein or circular DNA and that the major adduct formed is a deoxyguanosine adduct.

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

Solid matrix, room temperature phosphorescence identification and quantitation of the tetrahydrotetrols derived from the acid hydrolysis of benzo[a]pyrene-DNA adducts from human lung.

A new method, suitable for human biomonitoring, that uses room temperature phosphorescence for the detection of DNA damage by carcinogenic metabolites of polycyclic aromatic hydrocarbons is described. Samples of human lung DNA (1 mg) that had been subjected to immunoaffinity chromatography (anti-benzo[a]pyrene-diol-epoxide deoxyguanosine monoclonal antibodies) were acid hydrolyzed (0.1 N HCl, 90 degrees C, 3 h) and the resulting DNA lung hydrolyzates separated by high performance liquid chromatography. Relevant fractions were combined with a solid matrix support which consisted of a mixture of alpha-cyclodextrin (alpha-CD):NaCl (1:9) or alpha-CD:TINO3: aNO3 (1:1:8). The dried and powdered sample-matrix material was analyzed by phosphorescence spectroscopy at room temperature. Certain fractions of human lung samples were found to contain materials that yielded phosphorescence spectra that were indistinguishable from those produced when an authentic r-7, t-8, t-9, c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene reference standard was analyzed. The data confirm previous studies that have reported the presence of r-7, t-8 dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-DNA adducts in human tissues at levels of 1 adduct/10(7)-10(8) nucleotides. The alpha-cyclodextrin solid matrix, room temperature phosphorescence technique was performed with a commercially available instrument, but is 50 times more sensitive than the synchronous fluorescence spectroscopic technique previously used.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2000

Effects of benzyl isothiocyanate and phenethyl isothiocyanate on benzo[a]pyrene metabolism and DNA adduct formation in the A/J mouse.

Benzyl isothiocyanate (BITC) inhibits lung tumorigenesis induced in A/J mice by benzo[a]pyrene (B[a]P). In contrast, phenethyl isothiocyanate (PEITC) does not. We tested the hypothesis that BITC inhibits B[a]P tumorigenicity in mouse lung by inhibiting DNA adduct formation, and compared the effects of BITC and PEITC. In mouse liver or lung microsomal incubations, BITC and PEITC inhibited formation of 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (B[a]P-7, 8-diol) and some other B[a]P metabolites. The metabolism of B[a]P was compared in mouse lung and liver microsomes, 6 or 24h after treatment with BITC or PEITC. In lung, 6 h after treatment, B[a]P-7, 8-diol and some other metabolites were inhibited by BITC and PEITC. However, 24 h after treatment, no inhibition of B[a]P-7,8-diol was observed in microsomes from BITC-treated mice, whereas it was substantially increased in mice treated with PEITC. Effects on B[a]P metabolism in liver microsomes were generally modest. Conversion of B[a]P-7,8-diol to mutagens by mouse liver microsomes was more strongly inhibited by BITC than PEITC. Effects on 7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA adduct formation were evaluated in DNA from mice treated with isothiocyanates and B[a]P, and killed 2-120h later. The area under the curve (AUC) for BPDE-DNA adducts in lung was 29.5% less (P = 0. 001) in the BITC-B[a]P treated mice and 19.0% less (P = 0.02) in the PEITC-B[a]P mice than in the mice treated with B[a]P alone. Similar results were obtained in liver DNA. There were no significant differences between the reduction of BPDE-DNA AUC values by BITC versus PEITC. The results of this study support the hypothesis that BITC inhibits B[a]P-induced lung tumorigenesis in A/J mice by inhibiting the metabolic activation of B[a]P to BPDE-DNA adducts. However, differences in BPDE-DNA adduct formation do not appear to explain fully the contrasting effects of BITC and PEITC on B[a]P-induced lung tumorigenesis.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1985

Influence of isopropylvaleramide and allylisopropylacetamide on transformation of C3H/10T1/2 cells induced by benzo[a]pyrene derivatives.

We examined the effect of aliphatic amides isopropylvaleramide (IVA) and allylisopropylacetamide (AIA) on the oncogenic transformation of C3H/10T1/2 cells induced by benzo[a]pyrene (B[a]P) or its proximate and ultimate metabolites (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol) and (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene (B[a]P-diol-epoxide), respectively. IVA and AIA given prior to, simultaneously with, or for 24 h intervals beginning up to 48 h after removal of carcinogens significantly suppressed transformation induced by B[a]P or the 7,8-diol metabolite. Both modifiers were most effective when added for 24 h immediately following carcinogen exposure. IVA and AIA were also very potent inhibitors of B[a]P-diol-epoxide transformation; however they were most effective when added for 24 h simultaneously with the B[a]P-diol-epoxide. No significant difference in B[a]P-diol-epoxide binding to DNA in C3H/10T1/2 cells was observed during 1 or 24 h exposure to this carcinogen in the presence or absence of IVA or AIA. Neither modifier affected X-ray transformation when added for 24 h immediately following X-irradiation of C3H/10T1/2 cells. These results suggest that AIA and especially IVA might be important tools in studies directed at non-metabolic aspects of B[a]P carcinogenesis.

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