Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides

Gill, Harpal S.; Kole, Panna L.; Wiley, James C.; Li, K. M.; Higginbotham, Sheila; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.1093/carcin/15.11.2455

Cited by 56 publications

(54 citation statements)

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“…DB[a,/]P-l 1,12-dihydrodiol (DB[a,/]P-l 1,12-diol), (±)-anri-DB[a,/]P diol epoxide (an/i-DB[a,/]PDE), and (±)-syn-DB [a,l]P diol epoxide (ryn-DB[a,/]PDE) were obtained from the National Cancer Institute Chemical Carcinogen Repository (Chemsyn Science Laboratories, Lenexa, KS) (Gill et al, 1994). DB[a,/]P-8,9-dihydrodiol (DB[a,/]P-8,9-diol) was prepared by NADPHsupported metabolism of DB[a,/]P with 3-methylcholanthrene-induced rat liver microsomes, as previously described (Devanesan et at, 1990).…”

Section: Chemicalsmentioning

confidence: 99%

“…Recently, dibenzo [a,/]pyrene (DB[a,/]P) was shown to be the most potent carcinogenic polycyclic aromatic hydrocarbon (PAH) in mouse skin and rat mammary gland (Cavalieri et al, 1991;Gill et al, 1994;Higginbotham et al, 1993;LaVoie et al, 1993). Of particular interest is the observation that the carcinogenic potency of DB[a,/]P in mouse skin is associated with an inflammation unique among PAH and expressed as dermal erythema.…”

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confidence: 99%

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Inflammatory Response of Mouse Skin Exposed to the Very Potent Carcinogen Dibenzo[a,l]pyrene: A Model for Tumor Promotion

CASALE¹,

HIGGINBOTHAM²,

Johansson³

et al. 1997

Toxicol Sci

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The potent carcinogenicity of dibenzo [a,/]pyrene in mouse skin is associated with an inflammation unique among polycyclic aromatic hydrocarbons and expressed as erythema. The time course of erythema and the associated histological events in the skin of female SENCAR mice were determined after a single application of 6.25-200 nmol dibenzo[a,/]pyrene or selected metabolites. Dibenzo [a,/]pyrene and dibenzo[a,/]pyrene-ll,12-dihydrodiol, precursor to the bay-region diol epoxide, induced an erythema first present 5-6 days after treatment Dibenzo[a,/]pyrene-8,9-dihydrodiol and other dibenzo[a,/]pyrene metabolites, however, did not induce erythema. These findings suggest a central role for the bayregion diol epoxide in the induction of the observed inflammation. The intensity and duration of erythema were dose-dependent, whereas the delayed appearance of erythema was constant and dose-independent. These results suggest induction of an immune hypersensitivity by dibenzo[a,/]pyrene and its 11,12-dihydrodiol. Histological changes in the skin were consistent with a contact hypersensitivity reaction and included, in association with erythema, epidermal hyperplasia and the presence of mononuclear leukocytes in the dermis. Animals were tested for dibenzo[a,/]-pyrene-induced contact hypersensitivity. Female SENCAR mice were treated with a single dermal application of dibenzo[a,/]pyrene or 7,12-dimethylbenz[a]anthracene. Five days later, the animals were challenged with a single application of dibenzo[a,/]pyrene or 7,12-dimethylbenz [a]anthracene to the ear pinna. Ear swelling exhibited features of a contact hypersensitivity reaction, including (1) delayed appearance after challenge, (2) noninducibility in animals not previously exposed to chemical sensitizer, and (3) chemical specificity. The results suggest that dibenzo[a,/]pyrene induces, via its bay-region diol epoxide, a contact hypersensitivity reaction that may promote tumor development and thereby enhance carcinogenic potency. V 1997 Sod«y of Toiteology.

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Section: Chemicalsmentioning

confidence: 99%

mentioning

confidence: 99%

Inflammatory Response of Mouse Skin Exposed to the Very Potent Carcinogen Dibenzo[a,l]pyrene: A Model for Tumor Promotion

CASALE¹,

HIGGINBOTHAM²,

Johansson³

et al. 1997

Toxicol Sci

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“…The PAH and their derivatives (BP, BPDHD, anti-BPDE, DMBA, DB[a,l]P and anti-DB[a,l] PDE) were either purchased from the Chemical Carcinogen Repository of the National Cancer Institute or synthesized in our laboratory as described previously [91,92]. These PAH are hazardous and handled according to NIH guidelines [93].…”

Section: Chemicalsmentioning

confidence: 99%

“…Tumors induced by the initiation-promotion protocol in previously described experiments and stored frozen at −80 °C [16,91,94] were analyzed for mutations. To obtain these tumors the PAH-treated mice were promoted by twice weekly doses of 3 nmol 12-O-tetradecanoyl phorbol 13-acetate (TPA) in 100 μL acetone, until papilloma induction was complete (7-9 wks).…”

Section: Papillomasmentioning

confidence: 99%

The role of polycyclic aromatic hydrocarbon–DNA adducts in inducing mutations in mouse skin

Chakravarti

Venugopal

Mailander

et al. 2008

Mutation Research/Genetic Toxicology and Environmental Mutagene

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Polycyclic aromatic hydrocarbons (PAH) form stable and depurinating DNA adducts in mouse skin to induce preneoplastic mutations. Some mutations transform cells, which then clonally expand to establish tumors. Strong clues about the mutagenic mechanism can be obtained if the PAH-DNA adducts can be correlated with both preneoplastic and tumor mutations. To this end, we studied mutagenesis in PAH-treated early preneoplastic skin (1 day after exposure) and in the induced papillomas in SENCAR mice. Papillomas were studied by PCR amplification of the H-ras gene and sequencing. For benzo [a]pyrene (BP), 7, anthracene (DMBA) and dibenzo [a,l]pyrene (DB[a,l]P), the codon 13 (GGC to GTC) and codon 61 (CAA to CTA) mutations in papillomas corresponded to the relative levels of Gua and Adedepurinating adducts, despite BP and BPDHD forming significant amounts of stable DNA adducts. Such a relationship was expected for DMBA and DB[a,l]P, as they formed primarily depurinating adducts. These results suggest that depurinating adducts play a major role in forming the tumorigenic mutations. To validate this correlation, preneoplastic skin mutations were studied by cloning Hras PCR products and sequencing individual clones. DMBA-and DB[a,l]P-treated skin showed primarily A.T to G.C mutations, which correlated with the high ratio of the Ade/Gua-depurinating adducts. Incubation of skin DNA with T.G-DNA glycosylase eliminated most of these A.T to G.C mutations, indicating that they existed as G.T heteroduplexes, as would be expected if they were formed by errors in the repair of abasic sites generated by the depurinating adducts. BP and its metabolites induced mainly G.C to T.A mutations in preneoplastic skin. However, PCR over unrepaired anti-BPDE-N 2 dG adducts can generate similar mutations as artifacts of the study protocol, making it difficult to establish an adduct-mutation correlation for determining which BP-DNA adducts induce the early preneoplastic mutations. In conclusion, this study suggests that depurinating adducts play a major role in PAH mutagenesis.

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“…The remaining compounds can be synthesized by the routes cited ( [44]; (±) trans-10,11-dihydroxy-10,11-dihydrobenz[g]chrysene [45]; and (±) trans-11,12-dihydroxy-11,12-dihydro-dibenzo [a,l] pyrene [46].…”

Section: Pah Trans-dihydrodiol Oxidationmentioning

confidence: 99%

Aldo-Keto Reductases and Formation of Polycyclic Aromatic Hydrocarbon o-Quinones

Penning¹

2004

Quinones and Quinone Enzymes, Part A

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IntroductionAldo-Keto Reductases (AKRs) are a rapidly growing protein superfamily that is highly conserved across prokaryotes and eukaroytes [1,2]. These are generally monomeric NAD(P) H linked oxidoreductases, that are soluble, and consist of approximately 320 amino acids and have mol. wts = 34-37 kDa. These enzymes often convert carbonyl containing substrates to alcohols; aldehydes are converted to primary alcohols and ketones are converted to secondary alcohols. When the carbonyl functionality is found on a natural substrate (steroid hormone or prostaglandin) or a drug or xenobiotic, conversion to the corresponding alcohol functionalizes the product for conjugation and elimination. These enzymes thus play a central role in the metabolism of endogenous substrates, drugs, xenobiotics, and carcinogens and are likely to be as important as the CYP superfamily in dealing with toxic insults.Currently, there are 114 members in the AKR superfamily distributed across 14 families. For a complete listing and nomenclature visit www.med.upenn.edu/akr. Proteins that belong to separate families have less than 40% sequence identity, and proteins that have greater than 60% similarity belong to the same subfamily. Each of the AKRs have common properties. They catalyze an ordered bi-bi reaction in which pyridine nucleotide binds first and leaves last. They are A-face specific dehydrogenases and catalyze the transfer of the 4-pro-R-hydride ion from the nicotinamide cofactor to the acceptor carbonyl [3]. NADP(H) binding is accompanined by the formation of a loose complex that isomerizes to a tight complex [4,5]. The rate of release of NADP + is a slow event and is controlled by the slow isomerization of the tight-complex to the loose-complex prior to release of cofactor.There are 13 crystal structures of AKRs in the PDB. Each crystal structure has a common (α/ β) 8 -barrel motif, in which an α-helix and a β-strand alternate 8-times [6][7][8]. The β-strands coalesce at the core of the structure to comprise the staves of a barrel, Fig. 1. In the available ternary complexes, the cofactor lies across the lip of the barrel and the substrate is orientated perpendicular to the cofactor. Three large loops at the back of the barrel define substrate specificity. At the base of the barrel a catalytic tetrad exists that is almost entirely conserved across the superfamily and consists of Tyr, Lys, His and Asp; where the catalytic tyrosine functions as the general acid-base in the proton relay to the substrate [9].Several AKRs have been implicated in carcinogen metabolism, these include the dihydrodiol dehydrogenases that oxidize polycyclic aromatic hydrocarbon trans-dihydrodiols to reactive and redox-active o-quinones (AKR1C1-AKR1C4 and AKR1A1) [10][11][12][13][14]; the NNK (4-(Nmethyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone) carbonyl reductases that reduce tobaccospecific nitrosamino-ketones (NNK) to the corresponding alcohols (AKR1C1-AKR1C4) [ NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript and the aflatoxin dialde...

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Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides

Cited by 56 publications

References 0 publications

Inflammatory Response of Mouse Skin Exposed to the Very Potent Carcinogen Dibenzo[a,l]pyrene: A Model for Tumor Promotion

Inflammatory Response of Mouse Skin Exposed to the Very Potent Carcinogen Dibenzo[a,l]pyrene: A Model for Tumor Promotion

The role of polycyclic aromatic hydrocarbon–DNA adducts in inducing mutations in mouse skin

Aldo-Keto Reductases and Formation of Polycyclic Aromatic Hydrocarbon o-Quinones

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