Benzo[
            <i>a</i>
            ]pyrene Diol Epoxides as Intermediates in Nucleic Acid Binding in Vitro and in Vivo

Weinstein, I. Bernard; Jeffrey, A.M.; Kw, Jennette; Blobstein, Steven H.; Rg, Harvey; Harris, Curtis C.; Autrup, Herman; Kasai, Hiroshi; Nakanishi, Koji

doi:10.1126/science.959820

Cited by 565 publications

(225 citation statements)

References 11 publications

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“…Recently, in the process of BP-induced carcinogenesis, BP-diolepoxide has been implicated as the ultimate carcinogen since it appears as a conjugate of nucleic acids when BP is incubated with cells in culture (19)(20)(21)(24)(25)(26)(27). Osborne et al (26) found that both anti-and syn-BP-diolepoxide isomers react readily with DNA, yielding similar products.…”

Section: Resultsmentioning

confidence: 99%

A bacteriophage system for screening and study of biologically active polycyclic aromatic hydrocarbons and related compounds.

Hsu¹,

Harvey²,

Lin³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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ABSIRACT The usefulness of bacterial viruses for detecting substances that are potentially carcinogenic is reexamined as a model system for screening biologically active polycyclic aromatic hydrocarbons. A modification of the original assay procedure allows one to distinguish between aromatics that can modify the biological activity of infectious nucleic acids directly and those polycyclic aromatic hydrocarbons that require metabolic activation by Escherichia coli enzymes. The effect of chemical modification of several different polycyclic aromatic hydrocarbons, with respect to their biological activity in the phage assay system, is described. Among the 31 different compounds examined, (anti-benzo apyrene-7,8-diol-9,1O-epoxide was the most potent inhibitor of infectious phage nucleic acid. The (+) and (-) isomers of the above racemic mixture did not differ significantly in their capacity to inhibit phage replication.Studies done in this laboratory more than a decade ago indicated the usefulness of bacterial viruses in the detection of substances that were potentially carcinogenic (1, 2). In these studies we used the incubation of Escherichia coli spheroplasts with infectious nucleic acid, prepared either from MS2 or 4X174 bacteriophages, and determined the extent of inhibition of viral replication after addition of polycyclic aromatic hydrocarbons (PAH). A high correlation between carcinogenic activity in rats and inhibition of viral replication was observed with different hydrocarbons. These findings were confirmed by another laboratory using this same system (3, 4).The present report is an extension of our earlier work in which biologically reactive hydrocarbons are identified in an infectious nucleic acid-spheroplast assay system. By applying a simple modification of the original assay procedure, it is possible to distinguish between aromatics that can inactivate infectious nucleic acids directly and those that require metabolic activation by E. coli spheroplasts. METHODS Preparation of Spheroplasts and Infectious Nucleic Acid.Spheroplasts were prepared by treatment of E. coil strain K12W1485 with lysozyme according to a method described (1). For QB phage production and phenol extraction of the viral RNA, the method of Eoyang and August (5) H4BP,7,8,9,10-tetrahydro-BP; anti-BP-diolepoxide, (+)trans-7,8-dihydroxy-anti-9,10-epoxy-H4BP; syn-BP-diolepoxide, (+)-trans-7,8-dihydroxy-syn-9,10-epoxy-H4BP; BP-4,5-diol, trans-4,5-dihydroxy-4,5-dihydro-BP; Method A. In this procedure, infectious nucleic acid and the test compound were mixed for a few minutes at room temperature and then added to a suspension of E. coli spheroplasts. After 5-10 min of incubation at 250, 3 ml of soft agar and two drops of a suspension of indicator E. coli were added, and the entire mixture was plated and incubated as described above.Modified Method A. Immediately before use, E. coli spheroplasts were first infected with the test infectious nucleic acid by mixing of equal volumes of both and kept at 40. Aliquots of infected spheroplasts...

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Section: Resultsmentioning

confidence: 99%

A bacteriophage system for screening and study of biologically active polycyclic aromatic hydrocarbons and related compounds.

Hsu¹,

Harvey²,

Lin³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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“…The results indicated that BP is metabolized in cells to the 7,8-dihydrodiol which is a precursor to the 7,8-dihydrodiol-9,10-epoxide (BPDE) that reacts with cellular DNA. The BPDE bound mainly to guanine residues of DNA (Weinstein et al, 1976). The diol epoxides of DMBA and DB(a,l)P bind extensively to adenine residues of DNA (Cheng et al, 1988;Ralston (Burdette, 1955).…”

Section: Metabolism Of Pahs and Binding To Dnamentioning

confidence: 99%

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Rubin

2002

Oncogene

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Historically our knowledge about the direct carcinogenic activity of cigarette smoke and its constituents grew from painting experiments on the skin of mice to produce papillomas and carcinomas. The neutral fraction of cigarette smoke condensate had most of the carcinogenic activity in this test and was rich in carcinogenic polycyclic aromatic hydrocarbons (PAHs), the most abundant by far being BP. However, the concentration of BP in the condensate was only about 2% the amount of pure BP required to cause skin tumors. In other fractions there were non-carcinogenic constituents that promoted tumor formation when applied repeatedly to mouse skin that had been initiated by a single subcarcinogenic application of BP. There were also constituents of cigarette smoke that acted as cocarcinogens when applied simultaneously with repeated applications of BP. BP was effective as an initiator at lower concentrations than as a complete carcinogen, and some non-carcinogenic PAHs in the condensate were also active initiators. It was concluded from these studies that cigarette smoke condensate is primarily a tumorpromoting and co-carcinogenic agent with weak activity as a complete carcinogen. A major effect of promoters, and possibly of co-carcinogens, is a diffuse hyperplasia which includes selective expansion of clones carrying endogenous mutations and/or mutations induced by PAHs and other carcinogens such as NNK. The induced mutations as well as damaged cells would occur throughout the exposed region and, along with the hyperplasia, increase the permissiveness of the cellular microenvironment for neoplastic expression of any potential tumor cell in its midst. Since neither the promoters nor co-carcinogens in tobacco smoke are known to interact directly with DNA, their effects can be considered epigenetic processes that act upon genetically altered cells. Examples are cited from studies of experimental skin carcinogenesis, smoking-induced histopathological changes in human lung and spontaneous transformation in cell culture to illustrate the genetic and epigenetic interactions of neoplastic development in general and their significance for smoking-induced lung cancer in particular. Certain dietary modifications that appear to be effective in moderating the promotional phase of animal and human carcinogenesis are suggested for trial in managing lung cancer.

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“…There is circumstantial evidence that initial steps in chemical carcinogenesis with polycyclic aromatic hydrocarbons (PAH) involve metabolism to chemically reactive species by microsomal mixed-function oxidases (1) and the modification of nucleic acid bases by adduct formation (2)(3)(4)(5). Much of the recent work on PAH metabolism and carcinogenicity has focused on benzo [a]pyrene (BzP) and has led to the identification of many polar products of microsomal enzyme metabolism including the particularly reactive diol epoxide, BzP-7,8-diol-9,10-oxide (3), which accounts for most of the material covalently bound to DNA (2)(3)(4).…”

mentioning

confidence: 99%

Cyclopenta[c,d]pyrene: a highly mutagenic polycyclic aromatic hydrocarbon.

Eisenstadt¹,

Gold²

1978

Proc. Natl. Acad. Sci. U.S.A.

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A polycyclic aromatic hydrocarbon recently isolated from carbon black and identified as cyclopenta[cdpyrene (CPP) is highly mutagenic. By the criteria of the Salmonelia/mammalian-microsome mutagenicity test, the mutagenic potency of CPP is equalled by only two other naturally occurring polycyclic aromatic hydrocarbons-benzo[alpyrene and dibenz a,clanthracene. The potent mutagenicity of CPP is noteworthy for two reasons: (i) CPP is a mutagenic polycyclic aromatic hydrocarbon without a "bay-region" and (ii) there is evidence that it is distributed widely in the environment. On the basis of experimental observations and perturbational molecular orbital calculations we propose that a mutagenic metabolite of CPP will be the 3,4-oxide. The carbonium ion derived from opening of CPP 3,4-oxide is identical to that derived from opening of benzo [alpyrene 7,8-diol-9,10-oxide, the metabolite now thought to be an ultimate mutagenic and carcinogenic species.There is circumstantial evidence that initial steps in chemical carcinogenesis with polycyclic aromatic hydrocarbons (PAH) involve metabolism to chemically reactive species by microsomal mixed-function oxidases (1) and the modification of nucleic acid bases by adduct formation (2-5). Much of the recent work on PAH metabolism and carcinogenicity has focused on benzo[a]pyrene (BzP) and has led to the identification of many polar products of microsomal enzyme metabolism including the particularly reactive diol epoxide, BzP-7,8-diol-9,10-oxide (3), which accounts for most of the material covalently bound to DNA (2-4). This metabolite is suspected of being an ultimate carcinogen via an SN1 reaction with DNA of the benzylic carbonium ion derived from epoxide opening (6-8). This carbonium ion intermediate is the basis of a model proposed by Jerina and coworkers (9) to explain in chemical terms the biological activity of PAH consisting of fused aromatic six-membered rings. They suggest that epoxide formation on a saturated, angular benzo-ring adjacent to a "bay region" is a principal determinant of PAH activity because of the energetically favorable opening of "bay region" epoxides to reactive benzylic carbonium ions. The geometric "bay region" feature is exemplified by the area enclosed between the C(10) and C(11) positions of BzP (Fig. 1B).We became interested in a PAH, cyclopenta[cd]pyrene (CPP) (Fig. 1A), recently identified as a component of carbon black (10, 11), automobile exhaust (12), and atmospheric soot (ref. 13; Gold, unpublished observation) and reported to be carcinogenic to mice (14). We have begun an investigation of the biological activity and metabolism of CPP and report here that it is a potent mutagen by the criteria of the Salmonella/ mammalian-microsome mutagenicity test (15). "Bay region" theory does not explain the activity of CPP, which contains a fused five-membered ring and lacks the geometric "bay region" feature; however, we propose, on the basis of experimental observation and perturbational molecular Perkin-Elmer Model 1250 high-pressure l...

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Benzo[ a ]pyrene Diol Epoxides as Intermediates in Nucleic Acid Binding in Vitro and in Vivo

Cited by 565 publications

References 11 publications

A bacteriophage system for screening and study of biologically active polycyclic aromatic hydrocarbons and related compounds.

A bacteriophage system for screening and study of biologically active polycyclic aromatic hydrocarbons and related compounds.

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis

Cyclopenta[c,d]pyrene: a highly mutagenic polycyclic aromatic hydrocarbon.

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