Benzo pyrene adduct formation

Each plant tissue tends to have an obviously distinctive profile of flavonoids. The flavonoid content can reach about 0.5% in pollen, 10% in propolis, and about 6 mg/kg in honey. Havonoid aglycones appear to be present only in propolis and honey, while pollen contains flavanols in herosidic forms. The flavonoids in honey and propolis have been identified as flavanones and flavanones/flavanols (Campos et ah, 1990). The antimi-crobially active flavanone pinocembrine was foimd to be a major flavonoid in honey (Bogdanov, 1989). Amiot et ah (1989) studied two blossom and two honeydew Swiss honey samples and foimd that pinocembrine was the main flavonoid. Pinocembrine concentration varied between 2 and 3 mg/kg (Bogdanov, 1989). Berahia et ah (1993) analyzed sunflower honey samples and detected six flavone/flavols, four flavanone/ flavols, and pinocembrin, of which pinocembrin is the main flavonoid. The flavonoids in sunflower honey and propolis were characterized and assessed for their effects on hepatic drug-metabolizing enzymes and benzo [fl]pyrene-DNA adduct formation (Sabatier et ah, 1992 Siess et ah, 1996). 

A theoretical analysis is presented for the binding of the four dia-stereoisomers of benzo[a]pyrene diol epoxides (BPDEs) to N2(g), N6(a), 06(G) and NU(c). Molecular models for binding and stereoselectivity involving intercalation, intercalative covalently and externally bound forms are presented. Molecular mechanics calculations provide the energetics which suggest possible structures for the formation of each of the principal DNA-BPDE complexes. Stereographic projections are used to illustrate the molecular structures and steric fits. The results of previous calculations on intercalation and adduct formation of BPDE l(+) in kinked DNA (37) are summarized and extended to include the four diastereoisomers l( ) and II( ). The theoretical model is consistent with the observed experimental data. 

The results of a crystal structure formed by a trans opening of the BPDE l(+) to yield 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydro-benzo[a]pyrene (BPTOH) shows a Cde (90) conformation of the ring. The 07-HOT and O8-H8 groups are de, and the 09-H9 and 010-H10 are also de. The torsion angles of the benzo ring are in best agreement with our second most stable structure, Cde, of the anti BDE-N2(G) trans adduct as is seen from Table III. In adduct formation to N2(G) the trans adduct is the major product (13-22) ... 

McElroy, A.E., J.M. Cahill, J.D. Sisson, and K.M. Kleinow. 1991. Relative bioavailability and DNA adduct formation of benzo[a]pyrene and metabolites in the diet of the winter flounder. Comp. Biochem. Physiol. 100C 29-32. 

Wen X, and Walle T (2005) Preferential induction of CYP1B1 by benzo[a]pyrene in human oral epithelial cells Impact on DNA adduct formation and prevention by polyphenols. Carcingenesis 26 1774—1781. 

M. Funk, I. Ponten, A. Seidel, B. Jemstrom, Critical Parameters for Adduct Formation of the Carcinogen (+)-a t/-Benzo[a]pyrene-7,8-dihydrodiol 9,10-Epoxide with Oligonucleotides , Bioconjugate Chem. 1997, 8, 310 - 317. 

Denissenko MF, Pao A, Tang M, Pfeifer GP. (1996). Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 274(5286) 430-32. 

Daniel FB, Schut HAJ, Sandwisch DW, et al Interspecies comparisons of benzo[ ]pyrene metabolism and DNA-adduct formation in cultmed human and animal bladder and tracheobronchial tissues. Cancer Res MAI 2M 4729, 1983... 

Figure 7.4 The formation of a benzo[a]pyrene adduct alters the normal base pairing of guanosine with cytidine. The adduct pairs instead with the imine form of adenosine, leading to a base pair transversion after replication.

Meehan T, Wolfe AR, Negrete GR, Song Q (1997) Benzo[a]pyrene Diol Epoxide-DNA cis Adduct Formation Through a trans Chlorohydrin Intermediate. Proc Natl Acad Sci USA 94 1749... 

Adducts to hemoglobin are perhaps the most useful means of biological monitoring by adduct formation. Hemoglobin is, of course, present in blood, which is the most accurate type of sample for biological monitoring. Adducts to blood plasma albumin are also useful monitors and have been applied to the determination of exposure to toluene diisocyanate, benzo(a)pyrene, styrene, styrene oxide, and aflatoxin Bj. The DNA adduct of styrene oxide has been measured to indicate exposure to carcinogenic styrene oxide.12... 

Treatment3 Tissue (Mice Strain) % Decrease in BPDE-DNA Adducts Formation in Mice % Decrease in Benzo(a)Pyrene induced neoplasia... 

BHA inhibition of in vivo BPDE-DNA adduct formation as a function of benzo(a)pyrene dose... 

Possible Mechanisms by Which BHA Treatment Inhibits Benzo(a)pyrene Metabolite-DNA Adduct Formation... 

Table II. Comparison of the inhibitory effects of aryl hydrocarbon hydroxylase inducers and a-angelicalactone on benzo(a)pyrene-induced neoplasia and on BPDE-DNA adduct formation.

Ioannou, Y.M., Wilson, A.G.E., and Anderson, M.W. Effect of Butylated Hydroxyanisole, a-angelicalactone and fl-naphtho-flavone on Benzo(a)pyrene-DNA Adduct Formation in Vivo in the Forestomach, Lung and Liver of Mice. Cancer Res., 42 1199-1205, 1982. 

Benzo[n]pyrene is an extensively studied PAH compound. The mutagenic metabolites of benzo[a]pyrene are the (+)-7R,85,95,101 -flm/-benzo[fl]pyrene-7,8-dihydrodiol-9,10-epoxide, (+)-a //-BPDE, and the (-)-7R,8S,9S,10R enantiomer, ( )-anti-BPDE (Figure 22.16A,B). DNA damage occurs mainly by adduct formation between the CIO position of anti-BPDE to the N2 position of guanine. Four stereoisomeric bulky adducts are produced 105 (+)-trans-anti-BPDE-N2-dG, 1 OR (+)-cis-anti-BPE>E-N2-dG, 1 OR (-)-trans-anti-BPDE-N2-dG, and 105 (-)-cis-anti-BPDE-A2-dG. In vitro, the reaction of (+)-anti-BPDE with DNA forms predominantly the (+)-trans-anti-BPE)E-N2-dG adduct, while the reaction of ( )-anti-BPDE produces mainly the ( )-trans-anti-BPDE-N2-dG adduct. In cells, the major benzo[a]pyrene DNA adduct is (+)-trans-anti-BPDE-N2-dG. 

Harrigan, J. A., Vezina, C. M., McGarrigle, B. P. et al. (2004). DNA adduct formation in precisionxut rat liver and lung slices exposed to benzo[n]pyrene. Toxicological Sciences, 77, 307—14. 

Bordelon NR, Donnelly KC, George SE. Pentachlorophenol potentiates benzo [a] pyrene DNA adduct formation in adult but not infant B6C3F1 male mice. Environ Mol Mutagen 2001 37 (2) 164 72. 

Akcha, F., Izuel, C., Venier, P., Budzinski, H., Burgeot, T. and Narbonne, J. (2000) Enzymatic biomarker measurement and study of DNA adduct formation un benzo(a)pyrene treated... 

Willett, K., M. Steinberg, J. Thomsen, T.R. Narasimhan, S. Safe, S. McDonald, K. Beatty and M.C. Kennicutt. Exposure of killifish to benzo[a ]pyrene comparative metabolism, DNA adduct formation and aryl hydrocarbon (Ah) receptor agonist activities. Comp. Biochem. Physiol. 112B 93—103, 1995. 

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