Benzo pyrene oxides from

Figure 8 Schematic representation of binding interactions of aiene oxides at the H site of GST A, (4R,5S -benzo[a]pyrene oxide B, (5S,6R)-benzo[a]anthracene oxide C, (4R,5S)-pyiene oxide D, (7S)-styrene oxide, and E, (7R)-styrene oxide. (Taken from Dostal et al., 1986.)...

Well established is the activation of polycyclic hydrocarbons to arene oxides 3,4-benzo(a)pyrene forms several arene oxides from which a secondary metabolite, the 9,lO-dihydrodiol-7,8-epoxide has been proved highly carcinogenicIt preferentially binds to deoxyguanosine and deoxyadenosine in DNA and by a series of further still unknown events leads to the formation of cancerous cells. The microsomal epoxide hydrase converts arene oxides and epoxides to inactive dihydrodiols and therefore coijipetes with the covalent binding process ... 

Benzo[a]pyrene-3,6-quinol and other quinols are involved in toxic quinone/quinol redox cycles (Lo-RENTZEN and Ts o 1977, Loeentzen etal. 1979). Quinols are formed from the corresponding qui-nones by several reductases. They are rapidly auto-xidizes while superoxide anions are formed. Benzo[fl]pyrene-3,6-quinone has been shown to be mutagenic in the Ames test, using tester strain TA 104 (Chesis et al. 1984) or TA 102, strains which are particularly sensitive to reactive oxygen species. In male Sprague-Dawley rats, a rapid increase of unmetabolised benzo[fl]pyrene was observed in sera 3h after benzo [a] pyrene treatment followed by a sharp decrease (Kim et al. 2000). The time-dependent pattern of serum lipid peroxidation and the level of erythrocyte antioxidant enzymes were shown to be related to the concentrations of the formation of benzo[ ]pyrene-quinones, oxidatively altered lipids and antioxidant enzymes in the blood. 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

The metabolite responsible for the carcinogenicity of benzo[a]pyrene (i.e., the ultimate carcinogenic metabolite) is the 7,8-dihydrodio 1-9,10-oxide. Some of the evidence is as follows the 7,8-dihydrodiol metabolite of benzo[a]pyrene binds more extensively to DNA after microsomal enzyme activation than other metabolites or benzo[alpyrene itself the nucleoside adducts formed are similar to those formed from benzo [a] pyrene itself the synthetic 7,8-dihydrodiol 9,10-oxides are highly mutagenic the 7,8-dihydrodiol is carcinogenic whereas the 4,5- and 9,10-epoxides are not. 

Both procaryotic and eukaryotic microorganisms have the enzymatic potential to oxidize aromatic hydrocarbons that range in size from a single ring (e.g., benzene, toluene and xylene) to polycyclic aromatics (PC As), such as naphthalane, anthracene, phenanthrene, benzo [a] pyrene and benz [a] anthracene (Table 4.4). However, the molecular mechanisms by which bacteria and higher microorganisms degrade aromatic compounds are fundamentally different. 

The cis- 1,2-glycols, obtainable from the parent aromatic hydrocarbon by osmium tetroxide hydroxylation, can be converted to the corresponding trans-1,2-glycols by oxidation-reduction, using a mixture of dimethyl sulfoxide, sulfur trioxide, and pyridine, followed by lithium aluminum hydride reduction. The trans- 1,2-glycols can be dehydrated to arene oxides using DMF-DMA as mentioned above. Benzo[a]pyrene 4,5-oxide (28) and 7,12-dimethylbenz[a]anthracene 5,6-oxide (30) have been prepared by this method in 68 and 80% yields, respectively.18... 

Comparison of the reactivities of benzene oxides, naphthalene oxides, phenanthrene oxides, and arene oxides derived from benzo [a] pyrene and 7,12-dimethylbenz[a] anthracene with hepatic glutathione S-epoxide transferase showed that benzene oxides without electron-withdrawing groups are poor substrates as also are polycyclic arene oxides. Only naphthalene oxide was a good substrate. 

Based on this sequence, Blum et a/.158 have reported a general synthesis of unsubstituted K-region arene imines from the corresponding arene oxides. K-Imines of benz[a] anthracene, 7-methylbenz[a]anthracene, dibenz [a,/i] anthracene, and benzo[a] pyrene have been prepared. Azido alcohol formation from these oxides is generally nonregiospecific and both possible regioisomers of the azido alcohols are formed in different proportions. 

Armstrong et al.223 have shown that nonenzymatic trans addition of glutathione to synthetic ( + )-(4S,51 )- and (—)-(4R,5S)-benzo [a]pyrene 4,5-oxides (364 and 365) occurs at carbons 4 and 5 to give two diastereomeric pairs of positional isomers to almost equal extents. Correlations of the glutathione conjugates obtained from the 4,5-oxide derived from cytochrome P-450c-catalyzed oxidation of benzo [a] pyrene with those obtained from the syn-... 

Many chemicals are metabolized to carcinogens by processes that do not seem to involve free radicals a well-understood example is the oxidation of benzo(a)pyrene [B(a)P] to the diol epoxide by the cytochrome P450 system. However, the oxidation of B(a)P and other polynuclear aromatic hydrocarbons (PAH) to carcinogenic compounds can involve radicals. This statement, while once controversial, now has ample evidence (12.,22,25.). Although it is clear that some products arise from radical-mediated metabolism of PAH, the involvement of these products in tumorigenesis is less clear nevertheless, I believe that such evidence does now exist (12,12). 

Nutritional and nutritional status markedly influence xenobiotic metabolism in laboratory animals. Microsomes were prepared from the livers of rats which had been fed chow or modified AIN-76 diets with or without oxidized or unoxidized sulfur amino acids for 7 days. The pattern of benzo(a)pyrene (BaP) metabolites formed by each microsomal preparation in the presence of a NADPH-generating system was determined using high performance liquid chromatography (HPLC). The results indicate that oxidized sulfur amino acids induce different forms of cytochromes P-450 in rat liver Which are reflected by different BaP metabolic profiles. 

---