Benzo pyrene activation

The mutagenicity of benzofa]pyrene for bacteria was demonstrated by Ames et al. (60) They found that in the presence of rat liver homogenates benzo[a]pyrene induced both frameshift and base-pair substitution mutations. When the chemistry of benzo[a]pyrene activation had been worked out and the ultimate carcinogenic form identified as a diolepoxide, BPDE (reviewed in 61-62), several investigators (63-66) showed that BPDE was an extremely potent mutagen, also capable of inducing both frameshift and base-pair substitution mutations. 

In a two-year toxicological study (Culp et al., 2000), the incidences of tumours and DNA adducts in mice fed either coal tar or pure benzo[a] pyrene were examined. Benzo[a]pyrene formed adducts readily with DNA and appeared to be responsible for forestomach tumours, like those induced by ingestion of coal tar, but not for lung tumours. Other mice that were fed coal tar (Koganti et al., 2001) had DNA adducts with benzo[u]pyrene, benzo[c]fluorene and benzo[Z)]fluoranthene in the lungs, but those fed coal tar-contaminated soil had only the adducts with benzo[c]fluorene and benzo[ ]fluoranthene. Although benzo[u]pyrene activation has been studied extensively, little is known about the activation mechanisms of benzofluor-enes and benzofluoranthenes. 

Reaction Substrate Control Benzo[a]pyrene Activity ratio... 

Khanduja KL, Majid S. 1993. Ellagic acid inhibits DNA binding of benzo[a]pyrene activated by different modes. J Clin Biochem Nutr 15 1-9. 

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. 

It shows DNA damaged by the environmental chemical carcinogen benzo[ ]pyrene in the active site of the human DNA bypass polymerase k. 

Kelly, S.L., D.C. Lamb, B.C. Baldwin, and D.E. Kelly (1993). Benzo[a]pyrene activity in yeast is mediated by P450 other than sterol 14a-demethy-lase. Biochem. Biophys. Res. Commun. 197, 428- 32. 

Benzo[e]pyrene (1,2-benzpyrene) [192-97-2] M 252.3, m 178-179 , 178-180 . Purified by passage through an AI2O3 column (Woelm, basic, activity I) and eluted with CgHg and recrystd from 2 volumes of EtOH- CeHe (4 1). Forms colourless or light yellow prisms or needles. [J Chem Soc 3659 1954 Justus Liebigs Ann Chem 705 190 1967.] 1,3,5-Trinitrobenzene complex m 253-254° (orange needles from... 

Benzo[a]pyrene, a molecule with five, fused, hexagonal rings, is among the most carcinogenic of the polycyclic aromatic hydrocarbons (PAHs). Such biological activity may be related to the electronic structure of benzo[a]pyrene and its metabolites. Ionization energies of these molecules therefore have been investigated with photoelectron spectroscopy [28]. 

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). 

There is evidence for immunosuppressive effects of PAHs in rodents (Davila et al. 1997). For example, strong immunosuppressive effects were reported in mice that had been dosed with benzo[fl]pyrene and 3-methyl cholanthrene, effects that persisted for up to 18 months (Environmental Health Criteria 202). Multiple immu-notoxic effects have been reported in rodents, and there is evidence that these result from disturbance of calcium homeostasis (Davila et al. 1997). PAHs can activate protein tyrosine kinases in T cells that initiate the activation of a form of phospholipase C. Consequently, release of inositol triphosphate—a molecule that immobilizes Ca + from storage pools in the endoplasmic reticulum—is enhanced. 

Webb, R.E., Randolph, W.C., and Horsfall, E. Jr. (1972). Hepatic benzo(a)pyrene monooxygenase activity in endrin susceptible and resistant pine mice. Life Science 11 Part 2, 477 84. 

SPARNINS V L, BARANY G, WATTENBERG Lw. (1988) Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis. 9 131-4. 

Livingstone DR, SV Farrar (1984) Tissue and subcellular distribution of enzyme activities of mixed-function oxygenase and benzo[a]pyrene metabolism in the common mussel Mytilis edulis L. Sci Tot Environ 39 209-235. 

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