Benzo pyrene conjugates

Ebert, B., Seidel, A., and Lampen, A. (2005) Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis 26, 1754-1763. 

Beside these bipolar, surface active compounds a broad spectrum of polar compounds, sulfonated azo dyes [159, 160], sulfonates [161], additives in commercial dyes [145], benzo[a]pyrene conjugates [162, 163], DNA adducts [164], ozonization products of surfactants [165, 166], explosives [167] and so forth applying FAB or CF-FAB were qualitatively determined or even quantified with success. Grange et al. [159] used accurate mass measurements for identification and confirmation of e.g. sulfonated azo dyes [159]. 

After initial metabolism, most of the detoxified portion of PAH compounds are excreted into the bile as metabolites, then subsequently eliminated in the faeces. A smaller proportion is excreted in urine. The two major metabolites of benzo( )pyrene found in urine are 3-hydroxy- and 9-hydroxybenzo(o)pyrene, part of them being conjugated to sulphate or glucuronic acid (Bouchard and Viau, 1997 Ramesh et al., 2001). The process of excretion of PAH compounds into the intestine via the bile, reabsorption, and return to the liver by the portal circulation (enterohepatic recirculation) has been demonstrated to occur for 7,12-dimethylbenzo( )anthracene, benzo(o)pyrene, anthracene and pyrene (Ramesh et al., 2004). Enterohepatic circulation extends the residence time of PAHs in the body and may lead to long half-lives of reactive PAH metabolites. Though enterohepatic recycling of PAHs has... 

Varanasi, U., M. Nishimoto, and J. Stover. 1984. Analyses of biliary conjugates and hepatic DNA binding in benzo[a]pyrene-exposed English sole. Pages 1315-1328 in M. Cooke and A.J. Dennis (eds.). Polynuclear Aromatic Hydrocarbons Mechanisms, Methods and Metabolism. Battelle Press, Columbus, OH. 

Phase i reactions (interconversion reactions). Type 1 reactions introduce functional groups into inert, apolar molecules or alter functional groups that are already present. In many cases, this is what first makes it possible for foreign substances to conjugate with polar molecules via phase 11 reactions (see below). Phase 1 reactions usually reduce the biological activity or toxicity of a substance ( detoxification ). However, some substances only become biologically active as a result of the interconversion reaction (see, for example, benzo[a]pyrene, p. 256) or become more toxic after interconversion than the initial substance ( toxification ). 

Figure 7.2 The metabolic activation of benzo[a]pyrene by cytochrome P-450 1A1 to a diol epoxide metabolite, a mutagen. This is believed to be the ultimate carcinogenic metabolite. Other routes of metabolism also catalyzed by cytochrome P-450 give rise to the 9,10, and 4,5 oxides and subsequent metabolites namely phenols, diols, and glutathione conjugates. The reactive site (carbon atom) on the metabolite is indicated.

Warshawsky, D., Keenan, T. H., Reilman, R., Cody, T.E. Radike, M.J. (1990). Conjugation of benzo[a]pyrene metabolites by freshwater green alga Selenastrum capricornulum. Chemko-Biological Interactions, 74, 93-105. 

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-... 

The oxidation of naphthalene was one of the earliest examples of an epoxide as an intermediate in aromatic hydroxylation. As shown in Figure 7.3, the epoxide can rearrange nonenzymatically to yield predominantly 1-naphthol, or interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or interact with glutathione S-transferase to yield the glutathione conjugate, which is ultimately metabolized to a mercapturic acid. These reactions are also of importance in the metabolism of other xenobiotics that contain an aromatic nucleus, such as the insecticide carbaryl and the carcinogen benzo(a)pyrene. 

Some of these oxidative metabolites are biologically active and may even be more toxic than their parent compounds. Conversion by conjugation reactions is considered to lead to termination of the toxicity of these compounds and excretion of the non-toxic conjugates.58 Oxidative metabolism of a parent compound can lead to different products which may be excreted at different rates, as has been demonstrated for hydroxylated benzo[a]pyrenes.58... 

Figure 13.7. Glutathione conjugation to reactive metabolites by GSTs. Ultimate carcinogens such as benzo[a]pyrene 7,8-diol 9,10-epoxide and aflatoxin B1 8,9-epoxide are glutathione-conjugated for detoxification by GSTM1, GSTp, and GST A, respectively. Lipid peroxidation product 4-hydroxy-2-nonenal is preferentially detoxified by GSTA.

The synthesis of LA-pyrenemethylamine conjugate 393 and its self-assembled organic monolayer formed on a gold surface, based as in previous examples on the anchoring ability of the cyclic disulfide moiety of LA, has been carried out <2000ELA21> for the purpose of the potential design of electrochemical immunosensors of monoclonal antibody-benzo [a pyrene interaction. 

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