Benzo pyrene-4,5-epoxide

Figure U. Anti and syn diastereoisomers of the benzo diol-epoxide (BDE). For the 7,8-diol-9,10-epoxide of benzo[a]pyrene (BPDE), these would be the (+)-anti or l(+) and (+)-syn or Il(+) isomers as indicated. Atom numbers for BDE are those for the diol epoxide of benzo[a]pyrene.

Fig. 10.13. Metabolism of benzo[ ]pyrene (10.34). Shown are stereoselective formation of three isomeric epoxides, EH-catalyzed, stereoselective hydration to the dihydrodiols 10.35, 10.36, and 10.37, and, finally, 9,10-epoxidation of 10.36 to the bay-region diol epoxide 10.38. The latter exists as...

Hydrolysis Benzo(a)pyrene epoxide, styrene oxide... 

Syn dihydrodiol epoxide adducts formed in mouse skin treated with benzo[ ]pyrene constitute only about 12% of the total binding (36) and dihydrodiol epoxide deoxyadenosine adducts account for even less (2 to 3%) of the total (37,38). DMBA is approximately 20 times more potent a carcinogen than BP and this difference cannot be explained by the 2- to 4-fold difference in overall binding to DNA by these two carcinogens in mouse skin (35). Thus, these more subtle differences in DNA reaction products, i.e. the difference in reaction of syn-stereoisomer with DNA or in the modification of deoxyadenosine residues, might account for the greater tumor-initiating potential of DMBA. 

Dehydrogenation A-Demethylation Hydroxylation Epoxidation Sulfoxidation Oxidations Acetaminophen, benzidine, DES, epinephrine Dimethylaniline, benzphetamine, aminocarb Benzo[a]pyrene, 2-aminofluorene, phenylbutazone 7,8-Dihydrobenzo[a]pyrene Methylphenylsulfide FANFT, ANFT, bilirubin Esterases and Amidases Paraoxon, dimethoate, phenyl acetate Epoxide Hydrolase Benzo(a)pyrene epoxide, styrene oxide DDT-Dehydrochlorinase p,p- DDT Glutathione Reductase Disulfiram... 

L. L. Shipman, in Polynuclear Aromatic Hydrocarbons, R. Freudenthal and P. W. Jones, Eds., Raven Press, New York, 1976. Ab Initio Quantum Mechanical Characterization of the Ground Electronic State of Benzo[ ]pyrene. Implications for the Mechanism of Polynuclear Aromatic Hydrocarbon Oxidation to Epoxides by Cytochrome P-450. 

It is postulated that this ultimate carcinogen reacts covalently with nucleic acids, producing nucleic acid adducts. It has been demonstrated that benzo[a]pyrene reacts covalently with nucleic acids in vitro, provided that the microsomal enzyme systems necessary for activation are present, and also in whole cell systems. The 7,8-dihydrodiol metabolite of benzo[ ]pyrene binds more extensively to DNA after microsomal enzyme activation than does benzo[a]pyrene or other benzo[a]pyrene metabolites, and the nucleoside adducts formed from the 7,8-dihydrodiol of benzo[tf]pyrene are similar to those obtained from cells in culture exposed to benzo[ ]pyrene itself. Furthermore, the synthetic 7,8-diol-9,10-epoxides of benzo[a]pyrene are highly mutagenic in mammalian as well as in bacterial cells. 

Benzo[fl]pyrene 9,10-diol, 184 Benzo[ ]pyrene 7,8-diol-9,10-epoxide, 177,... 

Many naturally occurring substances are epoxides You have seen two examples of such compounds already m disparlure the sex attractant of the gypsy moth (Section 6 18) and m the carcinogenic epoxydiol formed from benzo[a]pyrene (Section 118) In most cases epoxides are biosynthesized by the enzyme catalyzed transfer of one of the oxy gen atoms of an O2 molecule to an alkene Because only one of the atoms of O2 is trans ferred to the substrate the enzymes that catalyze such transfers are classified as monooxy genases A biological reducing agent usually the coenzyme NADH (Section 15 11) is required as well... 

FIGURE 2.6 The procarcinogen benzo[a]pyrene oriented in the CYPlAl active site (stereo view) via n- n stacking between aromatic rings on the substrate and those of the complementary amino acid side chains, such that 7,8-epoxidation can occur. The substrate is shown with pale lines in the upper structures. The position of metabolism is indicated by an arrow in the lower structure (after Lewis 1996). 

The pollutant (xenobiotic) forms a stable covalent bond with its target. Examples include the phosphorylation of cholinesterases by the oxon forms of OPs, the formation of DNA adducts by the reactive epoxides of benzo[a] pyrene and other PAHs, and the binding of organomercury compounds to... 

A-Hydroxy-4- acetylaminobiphenyl Benzo [a] pyrene diol epoxide Human TK6 lymphoblastoid Custom A-Hydroxy-4- acetylaminobiphenyl 10 xMfor27h Benzo[ajpyrene diol epoxide 10 xM for Ih Gene name, gene symbol, gene bank accession fold change in a table All data available online 116... 

Luo W, Fan W, Xie H, ling L, Ricicki E, Vouros P, et al. Phenotypic anchoring of global gene expression profiles induced by A -hydroxy-4-acetylaminobiphenyl and benzo[a]pyrene diol epoxide reveals correlations between expression profiles and mechanism of toxicity. Chem Res Toxicol 2005 18 619-29. 

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